B All Protokoll Definition und Merkmale

Akute Lymphatische Leukämie (ALL). covid Therapie älterer Patienten mit ALL. Therapie Therapie der reifzelligen B-ALL. Öffentlicher Titel, Therapieoptimierung bei B-ALL und hochmalignem NHL Protokoll, Vollständiges Protokoll nach Amendment IX (passwortgeschützt). und hochmaligner Non-Hodgkin-Lymphome bei. Erwachsenen (ab 18 Jahre). (​GMALL-B-ALL/NHL ). KURZPROTOKOLL. Studienleiter. nicht als Protokollpatienten an einer ALL- bzw. Ausnahme: Patienten mit reifzelliger B-ALL werden nicht nach dem Therapieplan der "Non-. B"-ALL, sondern. Merkmale wie die reifzellige B-ALL (ALL = Akute übernommenen, angepassten Protokoll. Wegen timierten GMALL-B-ALL/NHL-Studie für Burkitt-.

B All Protokoll

Multizentrische Therapieoptimierungsstudie für die Therapie der B-ALL und hochmaligner Non-Hodgkin-Lymphome bei Erwachsenen (ab Im Rahmen der Therapie gemäß AIEOP-BFM ALL sind dies die Zytostatika Prednison Die eigentliche Induktionstherapie (Protokoll Ia) besteht aus einer intensiven Informationen zur Behandlung von B-ALL finden Sie hier. Akute Lymphatische Leukämie (ALL). covid Therapie älterer Patienten mit ALL. Therapie Therapie der reifzelligen B-ALL.

B All Protokoll - Navigationsmenü

Für die Diagnosestellung ist eine Untersuchung des Knochenmarks essentiell, da es vorkommen kann, dass bei Diagnosestellung noch keine feststellbare Ausschwemmung von Leukämiezellen aus dem Knochenmark in das Blut vorliegt. Jedoch finden sich auch hier seltene rekurrente genetische Veränderungen. Nat Med , B All Protokoll Multizentrische Therapieoptimierungsstudie für die Therapie der B-ALL und hochmaligner Non-Hodgkin-Lymphome bei Erwachsenen (ab In dieser Phase können Patienten mit B-ALL an der Randomisierung R-HR teilnehmen. Darauf folgt die Therapiephase „Protokoll III“ (4 Wochen) mit. Die akute lymphatische Leukämie (syn. akute lymphoblastische Leukämie, kurz ALL) ist eine Die reifzellige B-ALL ist eine Sonderform der ALL und kann als die UKALL (United Kingdom ALL Study Group) – Behandlungsprotokoll der UK​. Im Rahmen der Therapie gemäß AIEOP-BFM ALL sind dies die Zytostatika Prednison Die eigentliche Induktionstherapie (Protokoll Ia) besteht aus einer intensiven Informationen zur Behandlung von B-ALL finden Sie hier. Die Abgrenzung der reifzelligen Burkitt B-ALL hat eine hohe Relevanz, durch die Anwendung intensiverer Chemotherapie-Schemata nach ALL-BFM Protokoll​.

B All Protokoll Video

Acute myeloid \u0026 lymphoblastic leukemia - causes, symptoms \u0026 pathology

Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency homozygous mutant of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.

On the basis of these findings, SJCRH modified the agents used in the rotating pair schedule during the maintenance phase.

On the Total XV study, standard-risk and high-risk patients received three rotating pairs mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine throughout this treatment phase; low-risk patients received more standard maintenance without cyclophosphamide and cytarabine.

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of contemporary multiagent chemotherapy regimens remains controversial.

From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents.

The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.

Maintenance chemotherapy generally continues for 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls;[ 61 ] on others, there is no difference in the duration of treatment based on sex.

Nonadherence to treatment with mercaptopurine during maintenance therapy is associated with a significant risk of relapse. Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk of treatment failure.

The Risk-Based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.

All patients receive a three-drug induction no anthracycline. After completion of induction, patients are classified into one of three groups on the basis of biology and early response measures:.

NCI standard-risk Down syndrome patients who meet definition of standard-risk average will be treated in the same way as non-Down syndrome standard-risk average patients, as detailed above.

All other Down syndrome patients, including NCI high-risk Down syndrome patients, those with unfavorable biology, and those with high day 29 MRD will be considered Down syndrome-high, and will be nonrandomly assigned to receive two cycles of blinatumomab added to a deintensified chemotherapy regimen that omits intensive elements of the augmented BFM treatment backbone.

All patients, regardless of risk group, will receive the same duration of therapy 2 years from the start of interim maintenance 1 phase. This represents a reduction in treatment duration by 1 year for boys compared with standard treatment.

Patients enrolled on this trial will undergo leukapheresis to collect autologous T cells, which will then be sent for manufacturing of tisagenlecleucel.

While awaiting completion of manufacturing, patients will proceed with interim maintenance phase 1 high-dose methotrexate ; this phase may be interrupted as soon as product is available.

Once available, patients will then receive lymphodepleting chemotherapy and infusion of tisagenlecleucel. No further anti-leukemic treatment is to be administered after tisagenlecleucel.

Marrow samples will be obtained at regular intervals postinfusion, beginning at day 29 after tisagenlecleucel administration to assess disease status; tests of peripheral blood will also be sent to screen for evidence of B-cell aplasia.

Patients must have evidence of CDpositivity at diagnosis to enroll on trial. For patients with B-ALL, the protocol is testing whether the addition of two blocks of inotuzumab ozogamicin to a modified-BFM backbone will improve DFS and whether reducing duration of treatment in boys from 3 years from the start of interim maintenance 1 phase to 2 years from the start of that phase does not adversely impact DFS.

All patients receive a four-drug induction including daunorubicin. After completion of induction, subsequent therapy depends on age, biology, and response to therapy.

All patients will receive the same duration of therapy 2 years from the start of interim maintenance 1 phase. This represents a reduction in treatment duration by 1 year for boys, compared with standard treatment.

Patients are assigned an initial risk group by day 10 of therapy. Initial high-risk patients include all other patients lacking very high-risk features, including all patients with T-ALL.

Intensity of induction depends on initial risk group. Initial low-risk patients receive a three-drug induction no anthracycline.

All other patients receive a four-drug induction with an anthracycline. Final risk group, which determines the intensity of postinduction therapy, is assigned on the basis of MRD assessed by next-generation sequencing at the end of induction day 32; first time point and week 10 second time point.

Treatment for all risk groups includes 30 weeks of pegaspargase 15 doses given every 2 weeks during postinduction therapy. In all patients, nadir serum asparaginase activity NSAA is checked before each pegaspargase dose; any patient found to have a nondetectable NSAA is switched to Erwinia asparaginase.

The trial is also piloting a strategy to rechallenge patients with grade 2 hypersensitivity reactions to pegaspargase with pharmacokinetic-monitoring to determine whether such patients will switch to Erwinia or may continue to receive pegaspargase with premedication.

Therefore, all children with acute lymphoblastic leukemia ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis.

Because the CNS is a sanctuary site i. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.

Standard treatment options for CNS-directed therapy include the following:. All of these treatment modalities have a role in the treatment and prevention of CNS leukemia.

The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for select situations.

Data suggest that the following groups of patients are at increased risk of CNS relapse:. A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.

All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation and, in many protocols, continued throughout the maintenance phase.

Intrathecal chemotherapy typically consists of one of the following:[ 5 ]. Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.

In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis.

The following systemically administered drugs provide some degree of CNS prophylaxis:. The proportion of patients receiving cranial radiation therapy has decreased significantly over time.

At present, most newly diagnosed children with ALL are treated without cranial radiation therapy. Ongoing trials seek to determine whether radiation therapy can be eliminated from the treatment of all children with newly diagnosed ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.

Additional systemic therapy may be required depending on the agents and intensity used. The use of cranial radiation therapy is not a necessary component of CNS-directed therapy for these patients.

Controversy exists as to whether high-risk and very high-risk patients should be treated with cranial radiation therapy, although there is a growing consensus that cranial radiation therapy may not be necessary for most of these patients.

Both the proportion of patients receiving radiation therapy and the dose of radiation administered has decreased over the last two decades.

Larger prospective studies will be necessary to fully elucidate the safety of omitting cranial radiation therapy in CNS3 patients.

The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.

Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.

Subsequent neoplasms are observed primarily in survivors who received cranial radiation therapy. Meningiomas are common and typically of low malignant potential, but high-grade lesions also occur.

Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy.

In general, patients treated without cranial radiation therapy have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.

Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.

Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments.

A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.

In a review of a large number of patients treated on Children's Oncology Group COG trials over a year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis.

The use of prophylactic cranial radiation therapy in the treatment of patients with T-ALL is declining. Some groups, such as St.

Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.

Infants diagnosed within the first few months of life have a particularly poor outcome. Infants have significantly higher relapse rates than older children with ALL and are at higher risk of developing treatment-related toxicity, especially infection.

Infants with KMT2A gene rearrangements are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL.

However, despite these intensified approaches, EFS rates remain poor for these patients. Evidence intensified chemotherapy regimens for infants with KMT2A rearrangements :.

The optimal treatment for infants without KMT2A rearrangements also remains unclear, in part because of the paucity of data on the use of standard ALL regimens used in older children.

Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in almost all studies of treatment are inferior in this age group compared with children younger than 10 years.

In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of treatment-related mortality [ 30 - 33 ] and nonadherence to therapy.

Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens.

Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.

Evidence use of a pediatric treatment regimen for adolescents and young adults with ALL :. The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following:[ 36 ].

Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.

The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.

Most cases are diagnosed within the first 2 years of therapy and the symptoms are often recognized during maintenance.

In the past, this subtype of ALL has been recognized as extremely difficult to treat with a poor outcome. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.

Standard-risk patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy 2 years of treatment. The objective of the standard-risk randomization is to determine whether the less-intensive chemotherapy backbone is associated with a similar DFS but lower rates of treatment-related toxicity compared with the standard therapy EsPhALL chemotherapy backbone.

The prognosis for a child with acute lymphoblastic leukemia ALL whose disease recurs depends on multiple factors. The following two important risk factors after first relapse of childhood ALL are key to determining prognosis and treatment approach:.

Patients who have isolated extramedullary relapse fare better than those who have relapse involving the marrow. For patients with relapsed B-ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses.

Age 10 years and older at diagnosis and at relapse have been reported as independent predictors of poor outcome.

For patients with B-ALL who were diagnosed at age 18 years or younger and experienced a late relapse, age was not a significant predictor of subsequent outcome when analyzed by quartiles.

However, the outcome for patients aged 18 years and older at time of relapse was significantly inferior to the outcome for patients relapsing at age younger than 18 years Children with Down syndrome and ALL who relapse have generally had inferior outcomes resulting from increased induction deaths, treatment-related mortality, and relapse.

The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute NCI standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.

Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second complete remission CR.

Changes in mutation profiles from diagnosis to relapse have been identified by gene sequencing. The presence of RAS pathway mutations at relapse was associated with early relapse.

However, presence of RAS pathway mutations at relapse was not an independent predictor of outcome. Patients with ETV6-RUNX1 -positive ALL appear to have a relatively favorable prognosis at first relapse, consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.

Immunophenotype is an important prognostic factor at relapse. Patients with T-ALL who experience a marrow relapse isolated or combined at any time during treatment or posttreatment are less likely to achieve a second remission and long-term EFS than are patients with B-ALL.

Standard treatment options for first bone marrow relapse include the following:. Initial treatment of relapse consists of reinduction therapy to achieve a second CR.

The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation. Patients with relapsed T-ALL have much lower rates of achieving second CR with standard reinduction regimens than do patients with B-cell phenotype.

Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT, especially if MRD becomes low or nondetectable refer to the Late-relapsing B-ALL section of this summary for more information on MRD risk stratification.

Approaches have traditionally included the use of drug combinations distinct from the first attempt at treatment; these regimens often contain newer agents under investigation in clinical trials.

Although survival is progressively less likely after each attempt, two to four additional attempts are often pursued, with diminishing levels of success measured after each attempt.

For B-ALL patients with an early marrow relapse, allogeneic transplant from an HLA-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in higher leukemia-free survival than a chemotherapy approach.

A number of studies have shown that patients with a late marrow relapse who have high end-reinduction MRD have better outcomes if they receive an allogeneic HSCT in second CR after achieving low or nondetectable MRD status.

For patients with T-ALL who achieve remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor,[ 5 ] and these patients are usually treated with allogeneic HSCT in second CR, regardless of time to relapse.

Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant has generally been considered a reasonable approach for those achieving remission.

Given the poor outcomes for multiply relapsed B-ALL patients who are treated with chemotherapy followed by HSCT, CAR T-cell therapy has been tested in this population and has resulted in high rates of remission and improved short-term survival long-term follow-up pending; refer to the CAR T-cell therapy section of this summary for more information.

Immune therapies such as blinatumomab and inotuzumab have also greatly facilitated the achievement of remission, which has generally been followed by HSCT.

An expert panel review of indications for HSCT was published in Two registry studies and a small randomized trial showed that transplant conditioning regimens that include TBI resulted in higher cure rates than chemotherapy-only preparative regimens.

Fractionated TBI total dose, 12—14 Gy is often combined with cyclophosphamide, etoposide, thiotepa, or a combination of these agents.

Study findings with these combinations have generally resulted in similar rates of survival,[ 76 - 78 ] although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary.

On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 12 Gy resulted in worse survival resulting from excessive toxicity.

Remission status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates.

When patients have received two to three cycles of chemotherapy in an attempt to achieve an MRD-negative remission, the benefit of further intensive therapy for achieving MRD negativity must be weighed against the potential for significant toxicity.

In addition, there is not clear evidence showing that MRD positivity in a patient who has received multiple cycles of therapy is a biological disease marker for poor outcome that cannot be modified, or whether further intervention bringing such patients into an MRD negative remission will overcome this risk factor and improve survival.

One study showed higher sensitivity for predicting relapse using next-generation sequencing assays than with flow cytometry, especially early after HSCT.

Survival rates after matched unrelated donor and umbilical cord blood transplantation have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.

Another CIBMTR study suggested that outcome after one- or two-antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor.

Most studies of pediatric and young adult patients that address this issue suggest an effect of both acute and chronic GVHD in decreasing relapse.

To harness this GVL effect, a number of approaches to prevent relapse after transplantation have been studied, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.

The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial. However, many patients will be unable to undergo a second HSCT procedure because of failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.

Reduced-intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a CR confirmed by flow cytometry.

A small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.

The following two immunotherapeutic agents have been studied for the treatment of patients with refractory B-ALL:. Chimeric antigen receptor CAR T-cell therapy is a therapeutic strategy for pediatric B-ALL patients with refractory disease or those in second or subsequent relapse.

This treatment involves engineering T cells with a CAR that redirects T-cell specificity and function. Treatment with CAR T cells has been associated with cytokine release syndrome, which can be life-threatening.

Severe cytokine release syndrome has been effectively treated with tocilizumab, an anti—interleukin-6 receptor IL-6R antibody.

Neurotoxicity, including aphasia, altered mental status, and seizures, has also been observed with CAR T-cell therapy, and the symptoms usually resolve spontaneously.

Other CAR T-cell therapy side effects include coagulopathy, hemophagocytic lymphohistiocytosis HLH —like laboratory changes, and cardiac dysfunction.

Published trials have involved the use of two types of costimulatory molecules, BB and CD CDbased approaches have led to high rates of remission, but CAR T cells in these trials rarely persist longer than 1 to 2 months, necessitating HSCT for long-term survival.

Studies looking specifically at inotuzumab rescue of CDnegative relapse have not been published, but two groups have reported high rates of subsequent achievement of remission and survival, generally when CD22 CAR T-cell therapy is followed by HSCT therapy.

With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has decreased.

Patients with an isolated CNS relapse who show greater than 0. While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.

The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.

The results of treatment of isolated testicular relapse depend on the timing of the relapse. Standard treatment options in North America for childhood ALL that has recurred in the testes include the following:.

Standard approaches for treating isolated testicular relapse in North America include local radiation therapy along with intensive chemotherapy.

In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation.

Biopsy of the other testicle is performed at the time of relapse to determine if additional local control surgical removal or radiation is to be performed.

A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.

There are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy. Treatment protocols that have tested this approach have incorporated intensified dosing of chemotherapy agents e.

Multiple clinical trials investigating new agents and new combinations of agents are available for children with second or subsequent relapsed or refractory ALL and should be considered.

These trials are testing targeted treatments specific for ALL, including monoclonal antibody—based therapies and drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.

Multiple clinical trials investigating new agents, new combinations of agents, and immunotherapeutic approaches are available. Refer to the ClinicalTrials.

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Added text to state that in another study, doses of pegaspargase were reduced in an attempt to decrease toxicity. While lower doses were successful in maintaining appropriate asparaginase levels of more than 0.

This study did not report on the impact of lower doses of pegaspargase on event-free survival cited Kloos et al. Added text about the results of the Nordic Society for Pediatric Hematology and Oncology ALL protocol that evaluated minimal residual disease before transplantation in children with very high-risk ALL cited Ifversen et al.

Added Ifversen et al. Added Yeshurun et al. This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia.

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Prenatal exposure to x-rays. Postnatal exposure to high doses of radiation e. Previous treatment with chemotherapy. Genetic conditions that include the following: Down syndrome.

Refer to the Down syndrome section of this summary for more information. Neurofibromatosis NF1. Association with genetic syndromes.

Increased risk can be associated with the genetic syndromes listed above in which ALL is observed, although it is not the primary manifestation of the condition.

Common alleles. Another category for genetic predisposition includes common alleles with relatively small effect sizes that are identified by genome-wide association studies.

Genome-wide association studies have identified a number of germline inherited genetic polymorphisms that are associated with the development of childhood ALL.

ARID5B is a gene that encodes a transcriptional factor important in embryonic development, cell type—specific gene expression, and cell growth regulation.

Germline variants that cause pathogenic changes in genes associated with ALL and that are observed in kindreds with familial ALL i. A germline variant in PAX5 that substitutes serine for glycine at amino acid and that reduces PAX5 activity has been identified in several families that experienced multiple cases of ALL.

Provisional entity: Early T-cell precursor lymphoblastic leukemia. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.

Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage. Genomics of childhood ALL The genomics of childhood ALL has been extensively investigated, and multiple distinctive subtypes have been defined on the basis of cytogenetic and molecular characterizations, each with its own pattern of clinical and prognostic characteristics.

Subclassification of childhood ALL. Chromosome number. High hyperdiploidy 51—65 chromosomes. Treatment regimen.

Notch pathway signaling. T-ALL cases with SPI1 fusions had a particularly poor prognosis; six of seven affected individuals died within 3 years of diagnosis of early relapse.

Genes encoding epigenetic regulators e. Introduction to Risk-Based Treatment Children with acute lymphoblastic leukemia ALL are usually treated according to risk groups defined by both clinical and laboratory features.

Factors used by the COG to determine the intensity of induction include the following: Immunophenotype. The presence or absence of extramedullary disease.

Steroid pretreatment. The presence or absence of Down syndrome. Patient and clinical disease characteristics.

Leukemic characteristics. Response to initial treatment. Age at diagnosis. WBC count at diagnosis. Central nervous system CNS involvement at diagnosis.

Testicular involvement at diagnosis. Down syndrome trisomy Race and ethnicity. Weight at diagnosis and during treatment.

Infants younger than 1 year. ALL subtype. The reason for better outcomes in white and Asian children than in black and Hispanic children is at least partially explained by the different spectrum of ALL subtypes.

Treatment adherence. Differences in outcome may also be related to treatment adherence, as illustrated by a study of adherence to oral mercaptopurine 6-MP in maintenance therapy.

In the first report from the study, there was an increased risk of relapse in Hispanic children compared with non-Hispanic white children, depending on the level of adherence, even when adjusting for other known variables.

Ancestry-related genomic variations may also contribute to racial and ethnic disparities in both the incidence and outcome of ALL. Three studies did not demonstrate an independent effect of obesity on EFS.

However, obese patients at diagnosis who then normalized their weight during the premaintenance period of treatment had outcomes similar to patients with normal weight at diagnosis.

In a retrospective study of patients treated at a single institution, obesity at diagnosis was linked to an increased risk of having minimal residual disease MRD at the end of induction and an inferior EFS.

OS was lower in patients with a high BMI, primarily resulting from treatment-related mortality and inferior salvage after relapse. Male sex. Older age.

Mediastinal mass. MRD determination. Day 7 and day 14 bone marrow responses. Peripheral blood response to steroid prophase.

Peripheral blood response to multiagent induction therapy. Peripheral blood MRD before end of induction day 8, day Persistent leukemia at the end of induction induction failure.

For patients with B-ALL, evaluating MRD at two time points end-induction and end-consolidation can identify the following three prognostically distinct patient subsets:[ ] Low or undetectable end-induction MRD: best prognosis.

Detectable or high MRD at end-consolidation week 12 of therapy : worst prognosis. High risk high MRD after the second cycle of chemotherapy.

In a COG study involving nearly 2, children with ALL, the presence of MRD in the peripheral blood at day 8 was associated with adverse prognosis; increasing MRD levels were associated with a progressively poorer outcome.

A smaller study assessed the prognostic significance of peripheral blood MRD at day 15 after 1 week of a steroid prophase and 1 week of multiagent induction therapy.

T-cell phenotype. Unfavorable biology. KMT2A rearrangement. The authors suggested that using both morphologic and MRD criteria to define induction failure would more precisely identify patients with poor outcomes.

Morphology and MRD were concordant in However, only Presence of extramedullary disease. Down syndrome.

Infants with KMT2A rearrangements. Patients with initial induction failure. Standard risk: Patients who are MRD negative i.

Patients with a poor response to the prednisone prophase are also considered high risk, regardless of subsequent MRD. Favorable cytogenetic features include the following: Hyperdiploidy with double trisomies of chromosomes 4 and 10 double trisomy ; or ETV6-RUNX1 fusion.

KMT2A rearrangements. Standard risk. CNS1 status and no testicular disease at diagnosis. No steroid therapy pretreatment.

Intermediate risk. Any CNS status at diagnosis. Very high risk. Any CNS status. Overt testicular leukemia evidenced by ultrasonography.

Very high-risk features must be absent. Final low risk: Initial low risk and MRD less than 0. Final high risk: Initial low risk with MRD greater than 0.

Final very high risk: Initial very high-risk patients or any patient with MRD greater than 0. Special Considerations for the Treatment of Children With Cancer Because treatment of children with acute lymphoblastic leukemia ALL entails complicated risk assignment and therapies and the need for intensive supportive care e.

Pediatric surgical subspecialists. Radiation oncologists. Pediatric intensivists. Rehabilitation specialists. Pediatric nurse specialists.

Social workers. Child life professionals. Remission induction chemotherapy at the time of diagnosis. Postinduction therapy after achieving complete remission.

Maintenance therapy. Corticosteroid either prednisone or dexamethasone. Intrathecal chemotherapy. The Children's Cancer Group conducted a randomized trial that compared dexamethasone and prednisone in standard-risk B-ALL patients receiving a three-drug induction without an anthracycline.

Dexamethasone was associated with a higher frequency of reversible steroid myopathy and hyperglycemia.

No significant differences in rates of infection during induction were observed between the two randomized arms.

The trial demonstrated that dexamethasone was associated with a more favorable outcome than prednisolone in all patient subgroups.

Patients who received dexamethasone had a significantly lower incidence of both central nervous system CNS and non-CNS relapses than did patients who received prednisolone.

Dexamethasone was associated with a higher incidence of steroid-associated behavioral problems and myopathy, but an excess risk of osteonecrosis was not observed.

There was no difference in induction death rates between the randomized groups. Dexamethasone was associated with higher incidence of life-threatening events primarily infections , resulting in a significantly higher induction death rate 2.

There was no difference in rates of osteonecrosis between the randomized groups. No difference in overall survival OS was observed based on steroid randomization, although the study was not sufficiently powered to detect small differences in OS.

Dexamethasone was associated with a higher rate of infection, but there was no difference in the induction death rate when comparing dexamethasone and prednisone.

For patients who were younger than 10 years at diagnosis, there was a significant interaction between the corticosteroid and methotrexate randomizations; however, the best outcome for this group of patients was observed in those who received both dexamethasone during induction and high-dose methotrexate during interim maintenance.

The corticosteroid randomization was closed early for patients aged 10 years or older at diagnosis because of excessive rates of osteonecrosis in patients randomly assigned to dexamethasone; however, it did not appear that there was any EFS benefit associated with dexamethasone in these older patients 5-year EFS rates of Pegaspargase PEG-asparaginase.

Asparaginase Erwinia chrysanthemi Erwinia L-asparaginase. Native Escherichia coli E. Each agent was administered for a week period after the achievement of CR.

There was no difference in rates of asparaginase-related toxicities, including hypersensitivity, pancreatitis, and thromboembolic complications.

Similar outcome and similar rates of asparaginase-related toxicities were observed for both groups of patients. IV pegaspargase was associated with less treatment-related anxiety, as assessed by patient and parent surveys.

A single dose of pegaspargase given in conjunction with vincristine and prednisone during induction therapy appeared to have similar activity and toxicity as nine doses of IM E.

If IV Erwinia is given on a Monday-Wednesday-Friday schedule, the authors suggest that hour nadir enzyme activity levels be monitored to ensure therapeutic levels.

Es ist zudem davon auszugehen, dass mehrere genetische Aberrationen erforderlich sind, um die maligne Entartung lymphatischer Vorläuferzellen auszulösen.

Verlust von Mechanismen, die zur Apoptose führen. Letztlich bringen diese Veränderungen einen Überlebensvorteil für den malignen Klon und führen zu einem Differenzierungsblock auf einer bestimmten Reifungsebene, analog zu normalen lymphatischen Progenitorzellen.

Grundsätzlich könnten bestimmte endogene und exogene Faktoren mit einem erhöhten Risiko für die Entstehung einer ALL in Zusammenhang stehen.

Ataxia teleangiectasia. Auch bei Patienten mit Trisomie 21 ist das Risiko einer akuten Leukämie gegenüber Vergleichsgruppen um das fache erhöht.

Chromosomenschäden, die durch radioaktive Strahlung ausgelöst werden, begünstigen die Entwicklung akuter Leukämien ebenso wie die Exposition gegenüber myelotoxischen Chemikalien, wie Benzol, Chloramphenicol u.

Akute Leukämien werden in zunehmendem Umfang auch als Sekundärneoplasien nach Chemotherapie z. Das klinische Bild der ALL ergibt sich zum einen aus Symptomen, die auf die zunehmende Insuffizienz der normalen Hämatopoese und zum anderen auf die Infiltration von Organen zurückzuführen sind.

Symptome der hämatologischen Insuffizienz sind:. Granulozytopenie bei Leukopenie oder Hyperleukozytose oder normal hohen Gesamtleukozytenzahlen im Blutbild: Fieber, Infektneigung.

Ebenso häufig liegt eine Splenomegalie vor. Der ZNS-Befall wird meist im Rahmen einer Routineuntersuchung des Liquors diagnostiziert; es können aber auch Symptome auftreten, angefangen von Kopfschmerzen, Erbrechen, Lethargie, Nackensteifigkeit über Nervenausfälle insbesondere Hirnnerven bis hin zu Querschnittsymptomen bei Befall des Rückenmarks.

In der Regel entwickeln sich die Krankheitssymptome innerhalb von Tagen und gehen mit einem raschen Verlust der körperlichen Leistungsfähigkeit einher.

Bei einigen Patienten, insbesondere solchen mit massiver Infiltration oder Fibrose des Knochenmarks, gelingt dies nicht Punctio Sicca.

Dann muss eine Stanzbiopsie erfolgen und ggf. Die Diagnosebestätigung durch einen Referenzpathologen ist zu empfehlen. Zur Sicherung der Diagnose, zur Durchführung des Stagings und der Erfassung möglicher Begleiterkrankungen sind mindestens folgende Untersuchungen notwendig:.

Lumbalpunktion mit zytologischer Liquordiagnostik und intrathekaler Therapie. Bildgebende Untersuchungen Röntgenthorax, abdominelle Sonographie, ggf.

Computertomographie Thorax und Abdomen oder weitere Untersuchungen nach Symptomatik. Bei allen Patienten sollte die Möglichkeit der Biomaterialasservierung z.

Dies dient nicht nur späteren wissenschaftlichen Untersuchungen, sondern schafft auch die Möglichkeit z. Knochenmarkaspirate vor Einleitung einer Therapie sollten klinikintern zytologisch und immunologisch untersucht werden.

Folgende Untersuchungen sollten in einem Referenzlabor durchgeführt werden:. Zytogenetik und Molekularzytogenetik zum Nachweis einer t 9;22 ; t 4;11 , u.

Wesentlich ist die Unterscheidung der B- und T-Vorläufer-ALL sowie der weiteren immunologischen Subtypen sowie prognostisch relevanter immunologischer oder zyto- und molekulargenetischer Subgruppen.

Zusätzlich müssen Zielstrukturen für die Therapie identifiziert werden. Es ist anzustreben bei Patienten mit molekularem Therapieversagen oder Rezidiv eine weitergehende molekulare Charakterisierung z.

Hierfür kann dann Material aus einer Biobank verwendet werden. Sehr viel sensitiver ist die Untersuchung des Therapieansprechens mit Hilfe von Methoden, die den Nachweis von leukämischen Blasten weit unterhalb der zytologischen Nachweisgrenze erlauben, die sog.

Die Sensitivität dieser Methoden sollte mindestens 10 —4 erreichen entspricht dem Nachweis einer Leukämiezelle in Damit können bei Patienten, die klinisch und zytologisch in kompletter Remission sind, Leukämiezellen nachgewiesen und im Verlauf untersucht werden.

Für die Quantifizierung der minimalen Resterkrankung können verschiedene Verfahren herangezogen werden, z. PCR-Analysen von definierten Fusionsgenen oder die Durchflusszytometrie zum Nachweis individueller leukämietypischer Kombinationen von Oberflächenmarkern.

Zusätzlich sollte bei Patienten, bei denen kein molekularer Marker nachgewiesen werden kann, die MRD-Bestimmung mittels Flowzytometrie herangezogen werden.

Die minimale Resterkrankung wird zur verfeinerten Definition des Therapieansprechens herangezogen.

Die Feststellung einer molekularen CR setzt voraus, dass individuell eine ausreichende Sensitivität der Methode erreicht wird 0.

Bei diesen Patienten liegt eine intermediäre Prognose vor. Dies gilt sogar bei nachfolgender Stammzelltransplantation.

Da die Persistenz der MRD auf eine Resistenz gegenüber der konventionellen Chemotherapie hindeutet, ist im Fall eines molekularen Therapieversagens oder molekularen Rezidivs notwendig, eine Therapieumstellung und den Einsatz zielgerichteter Therapien zu erwägen.

Die quantitative Messung der minimalen Resterkrankung ist nur mit Material leukämische Blasten vom Zeitpunkt der Erstdiagnose möglich.

Daher sollte in jedem Fall Primärmaterial an ein Referenzlabor eingeschickt werden. Bei Punctio sicca muss entweder nach Vorphasetherapie erneut punktiert werden, um Knochenmarkaspirat zu gewinnen oder es muss ein Knochenmarktrepanat unfixiertes Nativmaterial eingesandt werden.

Hierfür ist die Einsendung von Biopsaten oder Material aus Ergüssen möglich. Auch Formalin-fixiertes Material kann verwendet werden.

Unter Therapie und im ersten Jahr nach Ende der Erhaltungstherapie sollten die Kontrollen etwa alle Monate erfolgen.

Sie basiert primär auf dem Immunphänotyp der Blasten. Mit den immunologischen Subtypen der ALL sind spezifische klinische und zytogenetische bzw.

Dennoch gibt es Unterschiede in der Risikostratifikation der einzelnen Studiengruppen und insbesondere im Hinblick auf die therapeutischen Konsequenzen.

Zytogenetische Aberrationen mit Ausnahme von t 9;22 und t 4;11 identifizieren bei der ALL seltene Subgruppen, deren prognostische Wertigkeit unter Anwendung aktueller Therapien nicht geklärt ist.

Eine prospektive, standardisierte Identifikation in der klinischen Routine ist bisher noch nicht möglich [ 9 ]. Spezifische molekulargenetische Untersuchungen können herangezogen werden, um Läsionen zu identifizieren, bei denen eine zielgerichtete molekulare Therapie in speziellen Situationen erwogen werden kann.

Dennoch ist die gezielte Untersuchung auf Aberrationen bei Patienten mit schlechtem Ansprechen, Rezidiv oder molekularer Persistenz sowie der potentiell Off-Label- Einsatz zielgerichteter Substanzen im Einzelfall sinnvoll.

Die Klassifikation aufgrund primärdiagnostischer Marker ist historisch weitgehend unverändert geblieben, weil zusätzlich bei allen Patienten eine MRD-Verlaufskontrolle erfolgt, die es ermöglicht ein ungünstiges individuelles Ansprechen zu identifizieren.

Die in Tabelle 3 genannten Risikofaktoren führen zur Definition einer Standard- ohne ungünstige Prognosefaktoren und einer Hochrisikogruppe mindestens ein ungünstiger Prognosefaktor.

Nach einer einheitlichen Induktions- und ersten Konsolidationstherapie erfolgt die Therapie risikoadaptiert. Patienten mit Hoch- und Höchstrisiko werden einer SZT zugeführt, während bei Patienten mit Standardrisiko die Chemotherapie mit alternierenden Konsolidationszyklen über ein Jahr fortgeführt wird.

Bei der überwiegenden Zahl der Patienten treten keine diagnostischen Probleme auf, wenn alle unter Kapitel 5. Die myeloische Koexpression ist prognostisch nicht relevant.

Für Zentren, die nicht an dieser Studie teilnehmen, kann eine Expertenempfehlung und ein Registereinschluss bereitgestellt werden.

Die Therapieempfehlungen sind über die Studiengruppe erhältlich. Heilung der Erkrankung. Die Therapieabschnitte Konsolidierungs- und Erhaltungstherapie dienen der Aufrechterhaltung der kompletten Remission und werden unter dem Begriff der Postremissionstherapie zusammengefasst.

Unter dem Begriff der Konsolidationstherapie wird auch die Knochenmark- bzw. Blutstammzelltransplantation SZT subsummiert [ 13 ].

Die Therapiestruktur ist in Abbildung 1 dargestellt. Auch bei Patienten mit Hyperleukozytose reicht die Vorphase-Therapie im Allgemeinen für eine schonende Zellreduktion aus.

Während der 5-tägigen Vorphasetherapie werden auch alle für die Therapiestratifikation notwendigen diagnostischen Befunde zusammengetragen.

In der Regel wird auch die erste Liquorpunktion zur Diagnostik und intrathekalen Prophylaxe mit Methotrexat durchgeführt. Zusätzlich wird Asparaginase in der Induktionstherapie eingesetzt; die Substanz ist spezifisch bei ALL wirksam und unterscheidet sich im Hinblick auf Wirkungsmechanismus, Resistenz und Nebenwirkungsspektrum von anderen Zytostatika.

Man erreicht damit in Abhängigkeit von der Dosis eine Wirkdauer von Tagen. Hierbei gibt es eine erhebliche interindividuelle Variabilität.

Um die Wirkdauer exakt zu messen, sollten zumindest in ausgewählten Therapieblöcken wöchentlich Asparaginase-Aktivitätsmessungen durchgeführt werden.

Die Messung dient zum einen dazu, Patienten mit raschem Aktivitätsabfall ohne klinisch manifeste allergische Reaktion zu identifizieren 'Silent Inactivation'.

In solchen Fällen kann als Ersatzpräparat Erwinia-Asparaginase eingesetzt werden. Zum anderen kann im Einzelfall bei Patienten mit sehr protrahierter Aktivität und Toxizitäten für nachfolgende Blöcke eine Dosisreduzierung erwogen werden.

Substitution von Gerinnungsfaktoren einschl. ATIII erforderlich. Bei initial detektierten extramedullären Befällen sollten diese durch eine entsprechend geeignete Bildgebung nachverfolgt und in die Gesamtbewertung der Remission einbezogen werden.

Auch für über jährige Patienten wird eine alternative Therapie empfohlen, da hier mit erhöhter Frühmortalität und insbesondere mit Unverträglichkeit der Asparaginase in der Induktion zu rechnen ist siehe Kapitel 6.

Für die Konsolidationstherapie existieren international sehr unterschiedliche Konzepte und die Wirksamkeit einzelner Elemente ist kaum einzeln nachweisbar.

Die verfügbaren Daten deuten jedoch darauf hin, dass zyklische Konsolidationstherapie mit wechselnden Substanzen und insbesondere der intensive Einsatz von hochdosiertem Methotrexat, Hochdosis-Cytarabin, die erhöhte Dosisintensität für Asparaginase ebenso wie die Wiederholung der Induktionstherapie Reinduktion vorteilhaft ist.

Essenziell ist die möglichst zeitnahe Durchführung der Therapieblöcke in der Konsolidationstherapie. Alle Studien, in denen auf eine Erhaltungstherapie verzichtet wurde, haben deutlich ungünstigere Gesamtergebnisse gebracht.

In der Erhaltungstherapie wird wöchentlich Methotrexat und täglich Mercaptopurin oral appliziert. Die Dosierungen werden an das Blutbild angepasst.

Eine Compliance mit der Erhaltungstherapie ist prognostisch relevant [ 14 ]. Es werden sowohl Familien- als auch Fremdspender eingesetzt, wobei aufgrund der ausgezeichneten Spenderregister inzwischen doppelt so viele Fremd- wie Familienspender-Transplantationen durchgeführt werden.

Die Ergebnisse sind vergleichbar. Die autologe SZT wird nach einer weiteren Konsolidationstherapie nur noch in seltenen Einzelfällen durchgeführt.

Hier sind Standards für die Konditionierung noch nicht definiert, so dass entweder eine Studienteilnahme oder eine Absprache mit Expertengruppen empfohlen wird.

Die Indikationsstellung für eine SZT in erster Remission wird international unterschiedlich gestellt.

Ziel ist es durch eine einheitliche Definition von Konditionierung, GvHD-Prophylaxe und anderer transplantationsassoziierter Prozesse die Ergebnisse zu optimieren und gleichzeitig eine bessere Auswertbarkeit der Daten zu erreichen.

Wichtig ist hier die aktualisierte Empfehlung, dass bereits ab der Altersgruppe von 45 Jahren eine dosisreduzierte Konditionierung mit 8 Gy TBI durchgeführt werden soll, um die transplantations-assoziierte Mortalität zu senken.

Dennoch ist der potentielle Wegfall der Ganzhirnbestrahlung ein therapeutisches Ziel, v. Bei initialem ZNS-Befall muss eine intensivierte intrathekale Therapie mit 2- bis 3-mal wöchentlichen Gaben bis zur Blastenclearance und weiteren Konsolidierungsgaben durchgeführt werden.

Bei häufiger intrathekaler Instillation von Methotrexat sollte zur Mukositisprophylaxe ein Leukovorin-Rescue durchgeführt werden.

Das Philadelphia- Ph- Chromosom bzw. Die Inzidenz nimmt mit dem Alter zu. Bei jüngeren Patienten wird Imatinib in Kombination mit Chemotherapie eingesetzt.

Dadurch konnte auch der Anteil der Patienten, die einer allogenen Stammzelltransplantation zugeführt werden, deutlich erhöht werden.

In einer randomisierten Studie der französischen Studiengruppe konnte gezeigt werden, dass eine dosisreduzierte Induktionstherapie mit Dexamethason, Vincristin und Imatinib im Vergleich zu einer intensiven Induktion mit Hyper-CVAD und Imatinib tendenziell bessere Ergebnisse bringt [ 18 ].

Eine weitere Verbesserung scheint durch die Gabe von Imatinib nach Transplantation möglich. Dieses Schema orientiert sich an der europäischen Studie mit Dasatinib [ 21 ].

Frühe Rezidive mit einer primären Remissionsdauer unter 18 Monaten sowie refraktäre Rezidive sind prognostisch ungünstig. Eine internationale Referenzanalyse hat belegt, dass Patienten mit Frührezidiv eine signifikant schlechtere CR-Rate erreichen als Patienten mit Spätrezidiv, die häufig gut auf die erneute Standard-Induktionstherapie ansprechen.

Patienten mit Frührezidiv weisen auch signifikant schlechtere Überlebensraten auf. Weiterhin spielt die Linie der Salvagetherapie eine Rolle, da mit jeder nachfolgenden Salvagetherapie die CR-Rate weiter abnimmt und auch die Überlebensraten abfallen [ 24 ].

Die umgehende Überweisung an ein erfahrenes Zentrum ist zu erwägen. Die initiale Diagnostik sollte im Rezidiv wiederholt werden.

Oberflächenmarker u. Verfahren zur Gensequenzierung ein. Zur Eindämmung des Progresses kann eine Vorphase-Therapie angesetzt werden.

Die weitere Therapieentscheidung hängt von verschiedenen Faktoren ab, z. Bei extramedullären Rezidiven sollte immer, auch wenn primär der Eindruck eines isolierten extramedullären Befalls besteht, sowohl eine Liquorkontrolle als auch eine MRD-Bestimmung im Knochenmark erfolgen.

Eine molekulare Remission sollte möglichst angestrebt werden, auch wenn die prognostische Bedeutung der MRD nach Rezidiv weniger klar ist, als in der Erstlinientherapie.

Das Gesamtüberleben nach Rezidiv hängt im Wesentlichen von der nachfolgenden Durchführung einer Stammzelltransplantation ab. Bei den meist intensiv vorbehandelten Patienten ist mit einer erheblichen Nicht-Rezidiv-Mortalität zu rechnen.

Auch das Rezidivrisiko ist im Vergleich zu Patienten, die in Erstremission transplantiert werden, erhöht.

Blinatumomab wird wegen seiner kurzen Halbwertszeit als 4-Wochen-Dauerinfusion appliziert und bei zytologischem Rezidiv zunächst mit einer niedrigeren Dosis gestartet, um ein Cytokin-Release-Syndrome zu vermeiden.

Nach einer Woche erfolgt eine Dosiserhöhung. Blinatumomab wurde in einer Kohorte von prognostisch ungünstigen Frührezidiven bzw.

Die medianen Überlebenszeiten lagen bei 7,7 vs 4,0 Monaten und zeigten für Blinatumomab ein signifikant besseres Ergebnis.

Wichtig ist der Effekt der Therapielinie. Auch die Verträglichkeit der Antikörpertherapie war in einigen Aspekten besser als die der Standardtherapie z.

Als prädiktiver Faktor für das Ansprechen auf Blinatumomab kann der Grad der Knochenmarkinfiltration herangezogen werden.

Die Art der Ereignisse unterschied sich allerdings. Neurologische Events nach Blinatumomab können sich z. Die Ereignisse sind in der Regel vollständig reversibel.

Ein frühzeitiges Eingreifen durch Einsatz von Dexamethason soll das Auftreten von schweren Events verhindern, die zu einer Therapieunterbrechung führen würden.

Die malignen Zellen sammeln sich vorwiegend in den lymphatischen Organen v. Faderl S et al. LymphknotenMilzThymusjedoch auch anderen Organen wie z. Wesentlich Spielothek Pachten dabei, dass in der Induktionstherapie keine Asparaginase Unibet Contact wird und dass die intensive Konsolidation I durch zwei weniger toxische Zyklen mit intermediär dosiertem Methotrexat und Asparaginase sowie intermediär dosiertem Cytarabin ersetzt wird. Jerchel IS et al. Sie sind mit einer ungünstigen Prognose assoziiert, insbesondere wenn beide Allele betroffen sind — entweder durch zwei Mutationen oder durch Mutation eines Allels und Deletion des zweiten Allels Starames et al. Die Sensitivität dieser Methoden sollte mindestens 10 —4 erreichen entspricht dem Nachweis einer Leukämiezelle in Deutsche Online Casinos Mit Startguthaben

B All Protokoll Inhaltsverzeichnis

Anhand der Zytogenetik kann Ipad Games Free ALL in zwei Hauptgruppen unterteilt werden: ALL mit strukturellen Aberrationen weisen typischerweise reziproke Translokationen und damit einhergehende leukämiespezifische Fusionsgene auf Tabelle 3. Die Therapieergebnisse wurden mit Therapieschemata aus der Pädiatrie, mit rascher Abfolge kurzer, intensiver Chemotherapieblöcke deutlich Tri Nations wesentliche Elemente Paulmann Quasar Hochdosis-Methotrexat und fraktioniertes Cyclophosphamid bzw. Sicherlich wird diese Behandlung hoch spezialisierten Zentren vorbehalten bleiben v. Die Therapieabschnitte Konsolidierungs- und Erhaltungstherapie dienen der Aufrechterhaltung der kompletten Remission und werden unter dem Begriff der Postremissionstherapie zusammengefasst. Sie haben ein gemeinsames Therapiekonzept entwickelt, das auf Handy Online Games Runaway Ergebnissen und Erfahrungen aus den vorangegangenen Therapiestudien beruht. Wie erfolgt die Therapie in den unterschiedlichen Risikogruppen? J Clin Oncol ;36 22 Social workers. The median age was 24 years range, 17—39 years. While the prognosis Bwib children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved Boxspiele outlook, particularly for patients who did not Android Kinderspiele cranial radiation during their first remission. Mögliche Risikofaktoren für das Auftreten von VOD waren in einer studienübergreifenden Multivariat-Analyse die Konditionierung mit zwei alkylierenden Substanzen und eine erhöhte Bilirubinkonzentration vor Transplantation [ 30 ]. Adherence was significantly lower among Hispanics, patients older than 12 years, and patients from single-mother households. ALL subtype.

POKER TEXAS HOLDEM KOSTENLOS OHNE ANMELDUNG B All Protokoll Spielautomaten um echtes Geld einzahlen zu kГnnen, sondern zuerst Spielautomaten B All Protokoll spielen an, die von Stiftung Warentest.

B All Protokoll 322
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Book Of Ra Spiel Erklarung In den Jahren und haben Estcourt Bigbozz al. Dazu gehört auch eine Untersuchung des Liquor cerebrospinalis durch Lumbalpunktion und eventuell Bildgebung des Lost Deutsch beispielsweise durch Magnetresonanztomographie. Hämatologie u. Nat Commun 6, Die wichtigsten Zytostatika sind in dieser Phase. Es gibt Risikofaktoren für das Entstehen von Leukämien ionisierende Strahlungchemische Reviesport etc.
Flugzeug Online Spiel 159
Granulozytopenie bei Leukopenie oder Hyperleukozytose oder normal hohen Gesamtleukozytenzahlen im Blutbild: Fieber, Infektneigung. Nicola Gökbuget. Eine molekulare Remission sollte möglichst angestrebt werden, auch wenn die prognostische Bedeutung der MRD nach Rezidiv weniger klar ist, als in der Erstlinientherapie. Für die Diagnosestellung ist eine Untersuchung des Knochenmarks essentiell, da es vorkommen kann, dass bei Diagnosestellung noch keine feststellbare Ausschwemmung von Leukämiezellen B All Protokoll dem Knochenmark in das Blut vorliegt. Mittlerweile gibt es aber Bestrebungen, die Therapien aneinander anzugleichen oder länderübergreifende Therapiestudien auf den Weg zu bringen z. Zwischendurch Club Player No Deposit Codes May 2017 es immer wieder Therapiepausen, damit sich der Körper erholen kann. Ataxia teleangiectasia. Die ALL ist durch die unkontrollierte Proliferation früher lymphatischer Vorläuferzellen im Knochenmark charakterisiert, deren Ausreifung auf einer bestimmten Differenzierungsebene blockiert ist. Das klinische Bild der ALL ergibt sich zum einen aus Symptomen, die auf die zunehmende Insuffizienz der normalen Hämatopoese und zum anderen auf die Infiltration von Organen zurückzuführen sind. Während der Nachweis typischer Fusionstranskripte sehr spezifisch ist, sind Sat Paderborn B-Zellrezeptor und T-Zellrezeptor-Rearrangements nicht direkt an der Onkogenese beteiligt. B All Protokoll

The published results of the ALL-BFM95 study did not demonstrate a benefit from the two randomisations cytarabine in the intensification phase and pulse during maintenance.

If minimal residual disease MRD testing is available, then the incorporation of these results appears justified on the published data, at least for the pre-B ALL group.

Pegasparaginase is given as an alternative preparation and has the advantage of longer half life, lower immunogenicity and more efficient asparaginase depletion than standard preparatations.

MRD testing has become a standard part of managing children with acute lymphoblastic leukaemia, but is not generally available outside clinical trials.

With no standard care approach to ALL in the younger population of patients defined, which risk criteria to utilize is not yet defined.

ALL BFM is a high intensity regimen with the published results for patients up to the age of 18 years. It is unknown what is the safe upper age limit in tolerability for this regimen.

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Any clinician medical oncologist, haematologist, radiation oncologist, medical physicist, radiation therapist, pharmacist or nurse seeking to apply or consult this protocol is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment.

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Acute lymphoblastic leukaemia BFM treatment overview. ID: v. This treatment should only be carried out in a major centre as intense monitoring and support is required Units are encouraged to enrol eligible patients age 15 to 40 on a similar approved ANZCHOG paediatric protocol.

Related pages: Asparaginase. Treatment overview. Induction protocol IA Duration: 35 days Cycles: 1 Induction 1A has an initial 7 days of prephase with prednisolone and intrathecal methotrexate which is included in this protocol.

Patient information. Multiple retrospective studies have established that adolescents aged 16 to 21 years have a better outcome when treated on pediatric versus adult protocols.

The presence or absence of CNS leukemia at diagnosis has prognostic significance. Most clinical trial groups have approached the treatment of CNS2 and traumatic lumbar puncture patients by utilizing more intensive therapy, primarily additional doses of intrathecal therapy during induction.

To determine whether a patient with a traumatic lumbar puncture with blasts should be treated as CNS3, the COG uses an algorithm relating the WBC and red blood cell counts in the spinal fluid and the peripheral blood.

In early ALL trials, testicular involvement at diagnosis was an adverse prognostic factor. With more aggressive initial therapy, however, it does not appear that testicular involvement at diagnosis has prognostic significance.

The role of radiation therapy for testicular involvement is unclear. A study from St. The COG considers patients with testicular involvement to be high risk regardless of other presenting features, but most other large clinical trial groups in the United States and Europe do not consider testicular disease to be a high-risk feature.

Outcomes in children with Down syndrome and ALL have generally been reported as somewhat inferior to outcomes observed in children who do not have Down syndrome.

Over the last several decades in the United States, survival rates in black and Hispanic children with ALL have been somewhat lower than the rates in white children with ALL.

The following factors associated with race and ethnicity influence survival:. Studies of the impact of obesity on the outcome of ALL have had variable results.

In most of these studies, obesity is defined as weight above the 95th percentile for age and height. Patients with a decrease in BMI during the first 32 weeks of treatment had similar rates of relapse as other patients, but had significantly worse OS, primarily because of poorer salvage rates after relapse.

The revision to the World Health Organization WHO classification of myeloid neoplasms and acute leukemia classifies ALL as either B-lymphoblastic leukemia or T-lymphoblastic leukemia, with further subdivisions based on molecular characteristics.

Either B- or T-lymphoblastic leukemia can coexpress myeloid antigens. These cases need to be distinguished from leukemia of ambiguous lineage.

Before , the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia , and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL.

Approximately three-quarters of patients with B-ALL have the common precursor B-cell immunophenotype and have the best prognosis.

Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with KMT2A gene rearrangements.

Patients with this phenotype respond well to therapy used for B-ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with MYC gene translocations should also be treated as mature B-cell leukemia.

The cases lacked mutations in genes recurrently altered in Burkitt lymphoma e. The clinical significance of IG- MYC —translocated leukemias with precursor B-cell phenotype and molecular characteristics requires further study.

T-ALL is frequently associated with a constellation of clinical features, including the following:[ 20 , 36 , 74 ]. While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-lineage ALL.

There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.

In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance. Up to one-third of childhood ALL patients have leukemia cells that express myeloid-associated surface antigens.

Refer to the WHO Classification of Acute Leukemias of Ambiguous Lineage section of this summary for information about leukemia of ambiguous lineage.

The rapidity with which leukemia cells are eliminated after initiation of treatment and the level of residual disease at the end of induction are associated with long-term outcome.

Because treatment response is influenced by the drug sensitivity of leukemic cells and host pharmacodynamics and pharmacogenomics,[ ] early response has strong prognostic significance.

Various ways of evaluating the leukemia cell response to treatment have been utilized, including the following:. Morphologic assessment of residual leukemia in blood or bone marrow is often difficult and is relatively insensitive.

This corresponds to a level of 1 in 20 malignant cells. With these techniques, detection of as few as 1 leukemia cell in , normal cells is possible, and MRD at the level of 1 in 10, cells can be detected routinely.

Multiple studies have demonstrated that end-induction MRD is an important, independent predictor of outcome in children and adolescents with B-lineage ALL.

For example, at any given level of detectable end-induction MRD, patients with favorable cytogenetics, such as ETV6-RUNX1 or high hyperdiploidy, have a lower absolute risk of subsequent relapse than do other patients, while patients with high-risk cytogenetics have a higher absolute risk of subsequent relapse than do other patients.

Using an end-induction MRD cutpoint level of 0. Patients identified as positive by HTS, but negative by flow cytometry, had an intermediate prognosis compared with patients categorized as either positive or negative by both methods.

MRD levels obtained 10 to 12 weeks after the start of treatment end-consolidation have also been shown to be prognostically important; patients with high levels of MRD at this time point have a significantly inferior EFS compared with other patients.

MRD measurements, in conjunction with other presenting features, have also been used to identify subsets of patients with an extremely low risk of relapse.

Modifying therapy on the basis of MRD determination has been shown to improve outcome. Compared with previous trials conducted by the same group, therapy was less intensive for standard-risk patients but more intensive for moderate-risk and high-risk patients.

Patients with persistent circulating leukemia cells at 7 to 10 days after the initiation of multiagent chemotherapy are at increased risk of relapse compared with patients who have clearance of peripheral blasts within 1 week of therapy initiation.

MRD using peripheral blood obtained 1 week after the initiation of multiagent induction chemotherapy has also been evaluated as an early response-to-therapy prognostic factor.

Both studies identified a group of patients who achieved low MRD levels after 1 week of multiagent induction therapy who had a low rate of subsequent treatment failure.

The vast majority of children with ALL achieve complete morphologic remission by the end of the first month of treatment.

Features associated with a higher risk of induction failure include the following:[ - ]. For decades, clinical trial groups studying childhood ALL have utilized risk classification schemes to assign patients to therapeutic regimens on the basis of their estimated risk of treatment failure.

Initial risk classification systems utilized clinical factors such as age and presenting WBC count. Response to therapy measures were subsequently added, with some groups utilizing early morphologic bone marrow response e.

Modern risk classification systems continue to utilize clinical factors such as age and presenting WBC count, and in addition, incorporate cytogenetics and genomic lesions of leukemia cells at diagnosis e.

In COG protocols, children with ALL are initially stratified into treatment groups with varying degrees of risk of treatment failure on the basis of a subset of prognostic factors, including the following:.

Patients who are at very high risk of treatment failure include the following:[ - ]. Since , risk stratification on BFM protocols has been based almost solely on treatment response criteria.

In addition to prednisone prophase response, treatment response is assessed via MRD measurements at two time points, end induction week 5 and end consolidation week The BFM risk groups include the following:[ ].

Phenotype, leukemic cell mass estimate also known as BFM risk factor and CNS status at diagnosis do not factor into the current risk classification schema.

Patients with either the t 9;22 q34;q Morphologic assessment of early response in the bone marrow is no longer performed on days 8 and 15 of induction as part of risk stratification.

Patients with T-cell phenotype are treated on a separate study and are not risk classified in this way. For patients with B-ALL, the definitions of favorable, unfavorable, and neutral cytogenetics are as follows:.

Patients classified as standard-risk high receive backbone chemotherapy as per high-risk B-ALL regimens with intensified consolidation, interim maintenance, and reinduction therapy.

Criteria for these three groups are provided in Table 6 , Table 7 , and Table 8 below. Patients with B-ALL and Down syndrome are classified into risk groups similar to other children, but Down syndrome patients classified as high risk receive a treatment regimen that is modified to reduce toxicity.

The final risk group is based on the initial risk group and MRD assessed by next-generation sequencing at the end of induction day 32; first time point and week 10 of therapy second time point :.

Because treatment of children with acute lymphoblastic leukemia ALL entails complicated risk assignment and therapies and the need for intensive supportive care e.

Guidelines for cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.

Because myelosuppression and generalized immunosuppression are anticipated consequences of leukemia and chemotherapy treatment, adequate facilities must be immediately available both for hematologic support and for the treatment of infections and other complications throughout all phases of therapy.

Strong lines of communication optimize any urgent or interim care required when the child is at home. Clinical trials are generally available for children with ALL, with specific protocols designed for children at standard low risk of treatment failure and for children at higher risk of treatment failure.

Many of the therapeutic innovations that produced increased survival rates in children with ALL were established through clinical trials, and it is appropriate for children and adolescents with ALL to be offered participation in a clinical trial.

Risk-based treatment assignment is an important therapeutic strategy utilized for children with ALL. This approach allows children who historically have a very good outcome to be treated with less intensive therapy and to be spared more toxic treatments, while allowing children with a historically lower probability of long-term survival to receive more intensive therapy that may increase their chance of cure.

Refer to the Risk-Based Treatment Assignment section of this summary for more information about a number of clinical and laboratory features that have demonstrated prognostic value.

Treatment for children with ALL is typically divided into the following phases:. Historically, certain extramedullary sites have been considered sanctuary sites i.

Successful treatment of ALL requires therapy that effectively addresses clinical or subclinical involvement of leukemia in these extramedullary sanctuary sites.

However, unless specific therapy is directed toward the CNS, most children will eventually develop overt CNS leukemia whether or not lymphoblasts were detected in the spinal fluid at initial diagnosis.

CNS-directed treatments include intrathecal chemotherapy, CNS-directed systemic chemotherapy, and cranial radiation; some or all of these are included in current regimens for ALL.

With more aggressive initial therapy, however, the prognostic significance of initial testicular involvement is unclear. Jude Children's Research Hospital suggests that a good outcome can be achieved with aggressive conventional chemotherapy without radiation.

Standard treatment options for newly diagnosed childhood acute lymphoblastic leukemia ALL include the following:. The goal of the first phase of therapy remission induction is to induce a complete remission CR.

This induction phase typically lasts 4 weeks. Induction chemotherapy typically consists of the following drugs, with or without an anthracycline either doxorubicin or daunorubicin :.

Other groups use a four-drug induction for all patients. Many current regimens utilize dexamethasone instead of prednisone during remission induction and later phases of therapy, although controversy exists as to whether dexamethasone benefits all subsets of patients.

Some trials also suggest that dexamethasone during induction may be associated with more toxicity than prednisone, including higher rates of infection, myopathy, and behavioral changes.

The ratio of dexamethasone to prednisone dose used may influence outcome. Studies in which the dexamethasone to prednisone ratio was to have shown a better result for dexamethasone, while studies that used a ratio have shown similar outcomes.

Several forms of L-asparaginase have been used in the treatment of children with ALL, including the following:. Pegaspargase is a form of L-asparaginase in which the E.

It is the most common preparation used during both induction and postinduction phases of treatment in newly diagnosed patients treated in the United States and Western Europe.

Pegaspargase may be given either intramuscularly IM or intravenously IV. Pegaspargase has a much longer serum half-life than native E.

Serum asparaginase enzyme activity levels of more than 0. Studies have shown that a single dose of pegaspargase given either IM or IV as part of multiagent induction results in serum enzyme activity of more than 0.

In another study, doses of pegaspargase were reduced in an attempt to decrease toxicity. This study did not report on the impact of lower doses of pegaspargase on EFS.

Evidence use of pegaspargase versus native E. Patients with an allergic reaction to pegaspargase are typically switched to Erwinia L-asparaginase.

Measurement of SAA levels after a mild or questionable reaction to pegaspargase may help to differentiate patients for whom the switch to Erwinia is indicated because of inadequate SAA versus those for whom a change in preparation may not be necessary.

Several studies have identified a subset of patients who experience silent inactivation of asparaginase, defined as absence of therapeutic SAA levels without overt allergy.

Another formulation of pegylated asparaginase, calaspargase pegol, is also available for the treatment of children and adolescents with ALL.

Erwinia L-asparaginase is typically used in patients who have experienced an allergy to native E.

The half-life of Erwinia L-asparaginase 0. Evidence increased dose frequency of Erwinia L-asparaginase needed to achieve goal therapeutic effect :.

In induction regimens that include an anthracycline, either daunorubicin or doxorubicin are typically used. In a randomized trial comparing the two agents during induction, there were no differences in early response measures, including reduction in peripheral blood blast counts during the first week of therapy, day 15 marrow morphology, and end-induction minimal residual disease MRD levels.

Of those who fail to achieve CR within the first 4 weeks, approximately one-half will experience a toxic death during the induction phase usually caused by infection and the other half will have resistant disease persistent morphologic leukemia.

Most patients with persistence of morphologically detectable leukemia at the end of the 4-week induction phase have a poor prognosis and may benefit from an allogeneic hematopoietic stem cell transplant HSCT once CR is achieved.

For patients who achieve CR, measures of the rapidity of blast clearance and MRD determinations have important prognostic significance, particularly the following:.

Refer to the Response to initial treatment section of this summary for more information. Central nervous system CNS -directed therapy is provided during premaintenance chemotherapy by all groups.

Once complete remission CR has been achieved, systemic treatment in conjunction with CNS-directed therapy follows. The intensity of the postinduction chemotherapy varies considerably depending on risk group assignment, but all patients receive some form of intensification after the achievement of CR and before beginning maintenance therapy.

The most commonly used intensification schema is the BFM backbone. This therapeutic backbone, first introduced by the BFM clinical trials group, includes the following:[ 1 ].

This backbone has been adopted by many groups, including the COG. Variation of this backbone includes the following:. Other clinical trial groups utilize a different therapeutic backbone during postinduction treatment phases, as follows:.

In children with standard-risk B-ALL, there has been an attempt to limit exposure to drugs such as anthracyclines and alkylating agents that may be associated with an increased risk of late toxic effects.

Multiple studies have demonstrated that higher levels of end-induction MRD are associated with poorer prognosis. In high-risk patients, a number of different approaches have been used with comparable efficacy.

Higher doses of these agents increase the risk of both short-term and long-term toxicities, and many clinical trials have focused on reducing the side effects of these intensified regimens.

Because treatment for high-risk ALL involves more intensive therapy, leading to a higher risk of acute and long-term toxicities, a number of clinical trials have tested interventions to prevent side effects without adversely impacting EFS.

Interventions that have been investigated include the use of the cardioprotectant dexrazoxane to prevent anthracycline-related cardiac toxic effects and alternative scheduling of corticosteroids to reduce the risk of osteonecrosis.

Refer to the Osteonecrosis section of this summary for more information. Patients with very high-risk features have been treated with multiple cycles of intensive chemotherapy during the consolidation phase usually in addition to the typical BFM backbone intensification phases.

These additional cycles often include agents not typically used in frontline ALL regimens for standard-risk and high-risk patients, such as high-dose cytarabine, ifosfamide, and etoposide.

On some clinical trials, very high-risk patients have also been considered candidates for allogeneic hematopoietic stem cell transplantation HSCT in first CR.

Controversy exists regarding which subpopulations could potentially benefit from HSCT. Evidence allogeneic HSCT in first remission for very high-risk patients :.

The backbone of maintenance therapy in most protocols includes daily oral mercaptopurine and weekly oral or parenteral methotrexate.

On many protocols, intrathecal chemotherapy for CNS sanctuary therapy is continued during maintenance therapy. It is imperative to carefully monitor children on maintenance therapy for both drug-related toxicity and for compliance with the oral chemotherapy agents used during maintenance therapy.

Importantly, nonadherence to treatment with mercaptopurine in the maintenance phase has been associated with a significant increase in the risk of relapse.

In the past, clinical practice generally called for the administration of oral mercaptopurine in the evening, on the basis of evidence from older studies that this practice may improve EFS.

Some patients may develop severe hematologic toxicity when receiving conventional dosages of mercaptopurine because of an inherited deficiency homozygous mutant of thiopurine S-methyltransferase, an enzyme that inactivates mercaptopurine.

On the basis of these findings, SJCRH modified the agents used in the rotating pair schedule during the maintenance phase. On the Total XV study, standard-risk and high-risk patients received three rotating pairs mercaptopurine plus methotrexate, cyclophosphamide plus cytarabine, and dexamethasone plus vincristine throughout this treatment phase; low-risk patients received more standard maintenance without cyclophosphamide and cytarabine.

Pulses of vincristine and corticosteroid are often added to the standard maintenance backbone, although the benefit of these pulses within the context of contemporary multiagent chemotherapy regimens remains controversial.

From these studies, it appears that dexamethasone is associated with superior EFS, but also may lead to a greater frequency of steroid-associated complications, including bone toxicity and infections, especially in older children and adolescents.

The benefit of using dexamethasone in children aged 10 to 18 years requires further investigation because of the increased risk of steroid-induced osteonecrosis in this age group.

Maintenance chemotherapy generally continues for 2 to 3 years of continuous CR. On some studies, boys are treated longer than girls;[ 61 ] on others, there is no difference in the duration of treatment based on sex.

Nonadherence to treatment with mercaptopurine during maintenance therapy is associated with a significant risk of relapse. Risk-based treatment assignment is a key therapeutic strategy utilized for children with ALL, and protocols are designed for specific patient populations that have varying degrees of risk of treatment failure.

The Risk-Based Treatment Assignment section of this summary describes the clinical and laboratory features used for the initial stratification of children with ALL into risk-based treatment groups.

For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.

All patients receive a three-drug induction no anthracycline. After completion of induction, patients are classified into one of three groups on the basis of biology and early response measures:.

NCI standard-risk Down syndrome patients who meet definition of standard-risk average will be treated in the same way as non-Down syndrome standard-risk average patients, as detailed above.

All other Down syndrome patients, including NCI high-risk Down syndrome patients, those with unfavorable biology, and those with high day 29 MRD will be considered Down syndrome-high, and will be nonrandomly assigned to receive two cycles of blinatumomab added to a deintensified chemotherapy regimen that omits intensive elements of the augmented BFM treatment backbone.

All patients, regardless of risk group, will receive the same duration of therapy 2 years from the start of interim maintenance 1 phase.

This represents a reduction in treatment duration by 1 year for boys compared with standard treatment. Patients enrolled on this trial will undergo leukapheresis to collect autologous T cells, which will then be sent for manufacturing of tisagenlecleucel.

While awaiting completion of manufacturing, patients will proceed with interim maintenance phase 1 high-dose methotrexate ; this phase may be interrupted as soon as product is available.

Once available, patients will then receive lymphodepleting chemotherapy and infusion of tisagenlecleucel. No further anti-leukemic treatment is to be administered after tisagenlecleucel.

Marrow samples will be obtained at regular intervals postinfusion, beginning at day 29 after tisagenlecleucel administration to assess disease status; tests of peripheral blood will also be sent to screen for evidence of B-cell aplasia.

Patients must have evidence of CDpositivity at diagnosis to enroll on trial. For patients with B-ALL, the protocol is testing whether the addition of two blocks of inotuzumab ozogamicin to a modified-BFM backbone will improve DFS and whether reducing duration of treatment in boys from 3 years from the start of interim maintenance 1 phase to 2 years from the start of that phase does not adversely impact DFS.

All patients receive a four-drug induction including daunorubicin. After completion of induction, subsequent therapy depends on age, biology, and response to therapy.

All patients will receive the same duration of therapy 2 years from the start of interim maintenance 1 phase. This represents a reduction in treatment duration by 1 year for boys, compared with standard treatment.

Patients are assigned an initial risk group by day 10 of therapy. Initial high-risk patients include all other patients lacking very high-risk features, including all patients with T-ALL.

Intensity of induction depends on initial risk group. Initial low-risk patients receive a three-drug induction no anthracycline. All other patients receive a four-drug induction with an anthracycline.

Final risk group, which determines the intensity of postinduction therapy, is assigned on the basis of MRD assessed by next-generation sequencing at the end of induction day 32; first time point and week 10 second time point.

Treatment for all risk groups includes 30 weeks of pegaspargase 15 doses given every 2 weeks during postinduction therapy.

In all patients, nadir serum asparaginase activity NSAA is checked before each pegaspargase dose; any patient found to have a nondetectable NSAA is switched to Erwinia asparaginase.

The trial is also piloting a strategy to rechallenge patients with grade 2 hypersensitivity reactions to pegaspargase with pharmacokinetic-monitoring to determine whether such patients will switch to Erwinia or may continue to receive pegaspargase with premedication.

Therefore, all children with acute lymphoblastic leukemia ALL should receive systemic combination chemotherapy together with some form of CNS prophylaxis.

Because the CNS is a sanctuary site i. Historically, survival rates for children with ALL improved dramatically after CNS-directed therapies were added to treatment regimens.

Standard treatment options for CNS-directed therapy include the following:. All of these treatment modalities have a role in the treatment and prevention of CNS leukemia.

The combination of intrathecal chemotherapy plus CNS-directed systemic chemotherapy is standard; cranial radiation is reserved for select situations.

Data suggest that the following groups of patients are at increased risk of CNS relapse:. A major goal of current ALL clinical trials is to provide effective CNS therapy while minimizing neurologic toxic effects and other late effects.

All therapeutic regimens for childhood ALL include intrathecal chemotherapy. Intrathecal chemotherapy is usually started at the beginning of induction, intensified during consolidation and, in many protocols, continued throughout the maintenance phase.

Intrathecal chemotherapy typically consists of one of the following:[ 5 ]. Unlike intrathecal cytarabine, intrathecal methotrexate has a significant systemic effect, which may contribute to prevention of marrow relapse.

In addition to therapy delivered directly to the brain and spinal fluid, systemically administered agents are also an important component of effective CNS prophylaxis.

The following systemically administered drugs provide some degree of CNS prophylaxis:. The proportion of patients receiving cranial radiation therapy has decreased significantly over time.

At present, most newly diagnosed children with ALL are treated without cranial radiation therapy.

Ongoing trials seek to determine whether radiation therapy can be eliminated from the treatment of all children with newly diagnosed ALL without compromising survival or leading to increased rate of toxicities from upfront and salvage therapies.

Additional systemic therapy may be required depending on the agents and intensity used. The use of cranial radiation therapy is not a necessary component of CNS-directed therapy for these patients.

Controversy exists as to whether high-risk and very high-risk patients should be treated with cranial radiation therapy, although there is a growing consensus that cranial radiation therapy may not be necessary for most of these patients.

Both the proportion of patients receiving radiation therapy and the dose of radiation administered has decreased over the last two decades.

Larger prospective studies will be necessary to fully elucidate the safety of omitting cranial radiation therapy in CNS3 patients.

The most common acute side effect associated with intrathecal chemotherapy alone is seizures. Patients with ALL who develop seizures during the course of treatment and who receive anticonvulsant therapy should not receive phenobarbital or phenytoin as anticonvulsant treatment, as these drugs may increase the clearance of some chemotherapeutic drugs and adversely affect treatment outcome.

Late effects associated with CNS-directed therapies include subsequent neoplasms, neuroendocrine disturbances, leukoencephalopathy, and neurocognitive impairments.

Subsequent neoplasms are observed primarily in survivors who received cranial radiation therapy. Meningiomas are common and typically of low malignant potential, but high-grade lesions also occur.

Neurocognitive impairments, which can range in severity and functional consequences, have been documented in long-term ALL survivors treated both with and without radiation therapy.

In general, patients treated without cranial radiation therapy have less severe neurocognitive sequelae than irradiated patients, and the deficits that do develop represent relatively modest declines in a limited number of domains of neuropsychological functioning.

Younger age at diagnosis and female sex have been reported in many studies to be associated with a higher risk of neurocognitive late effects.

Several studies have also evaluated the impact of other components of treatment on the development of late neurocognitive impairments.

A comparison of neurocognitive outcomes of patients treated with methotrexate versus triple intrathecal chemotherapy showed no clinically meaningful difference.

In a review of a large number of patients treated on Children's Oncology Group COG trials over a year period, T-cell immunophenotype still proved to be a negative prognostic factor on multivariate analysis.

The use of prophylactic cranial radiation therapy in the treatment of patients with T-ALL is declining.

Some groups, such as St. Common therapeutic themes of the intensive chemotherapy regimens used to treat infants with ALL are the inclusion of postinduction intensification courses with high doses of cytarabine and methotrexate.

Infants diagnosed within the first few months of life have a particularly poor outcome. Infants have significantly higher relapse rates than older children with ALL and are at higher risk of developing treatment-related toxicity, especially infection.

Infants with KMT2A gene rearrangements are generally treated on intensified chemotherapy regimens using agents not typically incorporated into frontline therapy for older children with ALL.

However, despite these intensified approaches, EFS rates remain poor for these patients. Evidence intensified chemotherapy regimens for infants with KMT2A rearrangements :.

The optimal treatment for infants without KMT2A rearrangements also remains unclear, in part because of the paucity of data on the use of standard ALL regimens used in older children.

Adolescents and young adults with ALL have been recognized as high risk for decades. Outcomes in almost all studies of treatment are inferior in this age group compared with children younger than 10 years.

In addition to more frequent adverse prognostic factors, patients in this age group have higher rates of treatment-related mortality [ 30 - 33 ] and nonadherence to therapy.

Studies from the United States and France were among the first to identify the difference in outcome based on treatment regimens. Given the relatively favorable outcome that can be obtained in these patients with chemotherapy regimens used for high-risk pediatric ALL, there is no role for the routine use of allogeneic HSCT for adolescents and young adults with ALL in first remission.

Evidence use of a pediatric treatment regimen for adolescents and young adults with ALL :. The reason that adolescents and young adults achieve superior outcomes with pediatric regimens is not known, although possible explanations include the following:[ 36 ].

Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.

The improvement in outcome for children and adolescents aged 10 years and older was accompanied by an increased incidence of osteonecrosis.

Most cases are diagnosed within the first 2 years of therapy and the symptoms are often recognized during maintenance.

In the past, this subtype of ALL has been recognized as extremely difficult to treat with a poor outcome. Dasatinib has shown significant activity in the CNS, both in a mouse model and a series of patients with CNS-positive leukemia.

Standard-risk patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy 2 years of treatment.

The objective of the standard-risk randomization is to determine whether the less-intensive chemotherapy backbone is associated with a similar DFS but lower rates of treatment-related toxicity compared with the standard therapy EsPhALL chemotherapy backbone.

The prognosis for a child with acute lymphoblastic leukemia ALL whose disease recurs depends on multiple factors.

The following two important risk factors after first relapse of childhood ALL are key to determining prognosis and treatment approach:.

Patients who have isolated extramedullary relapse fare better than those who have relapse involving the marrow. For patients with relapsed B-ALL, early relapses fare worse than later relapses, and marrow relapses fare worse than isolated extramedullary relapses.

Age 10 years and older at diagnosis and at relapse have been reported as independent predictors of poor outcome. For patients with B-ALL who were diagnosed at age 18 years or younger and experienced a late relapse, age was not a significant predictor of subsequent outcome when analyzed by quartiles.

However, the outcome for patients aged 18 years and older at time of relapse was significantly inferior to the outcome for patients relapsing at age younger than 18 years Children with Down syndrome and ALL who relapse have generally had inferior outcomes resulting from increased induction deaths, treatment-related mortality, and relapse.

The COG reported that risk group classification at the time of initial diagnosis was prognostically significant after relapse; patients who met National Cancer Institute NCI standard-risk criteria at initial diagnosis fared better after relapse than did NCI high-risk patients.

Patients with marrow relapses who have persistent morphologic disease at the end of the first month of reinduction therapy have an extremely poor prognosis, even if they subsequently achieve a second complete remission CR.

Changes in mutation profiles from diagnosis to relapse have been identified by gene sequencing. The presence of RAS pathway mutations at relapse was associated with early relapse.

However, presence of RAS pathway mutations at relapse was not an independent predictor of outcome.

Patients with ETV6-RUNX1 -positive ALL appear to have a relatively favorable prognosis at first relapse, consistent with the high percentage of such patients who relapse more than 36 months after diagnosis.

Immunophenotype is an important prognostic factor at relapse. Patients with T-ALL who experience a marrow relapse isolated or combined at any time during treatment or posttreatment are less likely to achieve a second remission and long-term EFS than are patients with B-ALL.

Standard treatment options for first bone marrow relapse include the following:. Initial treatment of relapse consists of reinduction therapy to achieve a second CR.

The potential benefit of mitoxantrone in relapsed ALL regimens requires further investigation. Patients with relapsed T-ALL have much lower rates of achieving second CR with standard reinduction regimens than do patients with B-cell phenotype.

Reinduction failure is a poor prognostic factor, but subsequent attempts to obtain remission can be successful and lead to survival after HSCT, especially if MRD becomes low or nondetectable refer to the Late-relapsing B-ALL section of this summary for more information on MRD risk stratification.

Approaches have traditionally included the use of drug combinations distinct from the first attempt at treatment; these regimens often contain newer agents under investigation in clinical trials.

Although survival is progressively less likely after each attempt, two to four additional attempts are often pursued, with diminishing levels of success measured after each attempt.

For B-ALL patients with an early marrow relapse, allogeneic transplant from an HLA-identical sibling or matched unrelated donor that is performed in second remission has been reported in most studies to result in higher leukemia-free survival than a chemotherapy approach.

A number of studies have shown that patients with a late marrow relapse who have high end-reinduction MRD have better outcomes if they receive an allogeneic HSCT in second CR after achieving low or nondetectable MRD status.

For patients with T-ALL who achieve remission after bone marrow relapse, outcomes with postreinduction chemotherapy alone have generally been poor,[ 5 ] and these patients are usually treated with allogeneic HSCT in second CR, regardless of time to relapse.

Although there are no studies directly comparing chemotherapy with HSCT for patients in third or subsequent CR, because cure with chemotherapy alone is rare, transplant has generally been considered a reasonable approach for those achieving remission.

Given the poor outcomes for multiply relapsed B-ALL patients who are treated with chemotherapy followed by HSCT, CAR T-cell therapy has been tested in this population and has resulted in high rates of remission and improved short-term survival long-term follow-up pending; refer to the CAR T-cell therapy section of this summary for more information.

Immune therapies such as blinatumomab and inotuzumab have also greatly facilitated the achievement of remission, which has generally been followed by HSCT.

An expert panel review of indications for HSCT was published in Two registry studies and a small randomized trial showed that transplant conditioning regimens that include TBI resulted in higher cure rates than chemotherapy-only preparative regimens.

Fractionated TBI total dose, 12—14 Gy is often combined with cyclophosphamide, etoposide, thiotepa, or a combination of these agents.

Study findings with these combinations have generally resulted in similar rates of survival,[ 76 - 78 ] although one study suggested that if cyclophosphamide is used without other chemotherapy drugs, a dose of TBI in the higher range may be necessary.

On the other hand, when cyclophosphamide and etoposide were used with TBI, doses above 12 Gy resulted in worse survival resulting from excessive toxicity.

Remission status at the time of transplantation has long been known to be an important predictor of outcome, with patients not in CR at HSCT having very poor survival rates.

When patients have received two to three cycles of chemotherapy in an attempt to achieve an MRD-negative remission, the benefit of further intensive therapy for achieving MRD negativity must be weighed against the potential for significant toxicity.

In addition, there is not clear evidence showing that MRD positivity in a patient who has received multiple cycles of therapy is a biological disease marker for poor outcome that cannot be modified, or whether further intervention bringing such patients into an MRD negative remission will overcome this risk factor and improve survival.

One study showed higher sensitivity for predicting relapse using next-generation sequencing assays than with flow cytometry, especially early after HSCT.

Survival rates after matched unrelated donor and umbilical cord blood transplantation have improved significantly over the past decade and offer an outcome similar to that obtained with matched sibling donor transplants.

Another CIBMTR study suggested that outcome after one- or two-antigen mismatched cord blood transplants may be equivalent to that for a matched family donor or a matched unrelated donor.

Most studies of pediatric and young adult patients that address this issue suggest an effect of both acute and chronic GVHD in decreasing relapse.

To harness this GVL effect, a number of approaches to prevent relapse after transplantation have been studied, including withdrawal of immune suppression or donor lymphocyte infusion and targeted immunotherapies, such as monoclonal antibodies and natural killer cell therapy.

The use of post-HSCT intrathecal chemotherapy chemoprophylaxis is controversial. However, many patients will be unable to undergo a second HSCT procedure because of failure to achieve remission, early toxic death, or severe organ toxicity related to salvage chemotherapy.

Reduced-intensity approaches can also cure a percentage of patients when used as a second allogeneic transplant approach, but only if patients achieve a CR confirmed by flow cytometry.

A small series has shown survival in selected patients using chemotherapy alone or chemotherapy followed by a second transplant.

The following two immunotherapeutic agents have been studied for the treatment of patients with refractory B-ALL:. Chimeric antigen receptor CAR T-cell therapy is a therapeutic strategy for pediatric B-ALL patients with refractory disease or those in second or subsequent relapse.

This treatment involves engineering T cells with a CAR that redirects T-cell specificity and function. Treatment with CAR T cells has been associated with cytokine release syndrome, which can be life-threatening.

Severe cytokine release syndrome has been effectively treated with tocilizumab, an anti—interleukin-6 receptor IL-6R antibody.

Neurotoxicity, including aphasia, altered mental status, and seizures, has also been observed with CAR T-cell therapy, and the symptoms usually resolve spontaneously.

Other CAR T-cell therapy side effects include coagulopathy, hemophagocytic lymphohistiocytosis HLH —like laboratory changes, and cardiac dysfunction.

Published trials have involved the use of two types of costimulatory molecules, BB and CD CDbased approaches have led to high rates of remission, but CAR T cells in these trials rarely persist longer than 1 to 2 months, necessitating HSCT for long-term survival.

Studies looking specifically at inotuzumab rescue of CDnegative relapse have not been published, but two groups have reported high rates of subsequent achievement of remission and survival, generally when CD22 CAR T-cell therapy is followed by HSCT therapy.

With improved success in treating children with ALL, the incidence of isolated extramedullary relapse has decreased. Patients with an isolated CNS relapse who show greater than 0.

While the prognosis for children with isolated CNS relapse had been quite poor in the past, aggressive systemic and intrathecal therapy followed by cranial or craniospinal radiation has improved the outlook, particularly for patients who did not receive cranial radiation during their first remission.

The use of transplantation to treat isolated CNS relapse occurring less than 18 months from diagnosis, especially T-cell CNS relapse, requires further study.

The results of treatment of isolated testicular relapse depend on the timing of the relapse. Standard treatment options in North America for childhood ALL that has recurred in the testes include the following:.

Standard approaches for treating isolated testicular relapse in North America include local radiation therapy along with intensive chemotherapy.

In some European clinical trial groups, orchiectomy of the involved testicle is performed instead of radiation. Biopsy of the other testicle is performed at the time of relapse to determine if additional local control surgical removal or radiation is to be performed.

A study that looked at testicular biopsy at the end of frontline therapy failed to demonstrate a survival benefit for patients with early detection of occult disease.

There are limited clinical data concerning outcome without the use of radiation therapy or orchiectomy. Treatment protocols that have tested this approach have incorporated intensified dosing of chemotherapy agents e.

Multiple clinical trials investigating new agents and new combinations of agents are available for children with second or subsequent relapsed or refractory ALL and should be considered.

These trials are testing targeted treatments specific for ALL, including monoclonal antibody—based therapies and drugs that inhibit signal transduction pathways required for leukemia cell growth and survival.

Multiple clinical trials investigating new agents, new combinations of agents, and immunotherapeutic approaches are available.

Refer to the ClinicalTrials. The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available.

This section describes the latest changes made to this summary as of the date above. Added text to state that in another study, doses of pegaspargase were reduced in an attempt to decrease toxicity.

While lower doses were successful in maintaining appropriate asparaginase levels of more than 0. This study did not report on the impact of lower doses of pegaspargase on event-free survival cited Kloos et al.

Added text about the results of the Nordic Society for Pediatric Hematology and Oncology ALL protocol that evaluated minimal residual disease before transplantation in children with very high-risk ALL cited Ifversen et al.

Added Ifversen et al. Added Yeshurun et al. This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood acute lymphoblastic leukemia.

It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Board members review recently published articles each month to determine whether an article should:. Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

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Seltener lassen sich Zugewinne der Chromosomen 5 und 8 nachweisen. In den Fällen, in denen eine Stammzelltransplantation erforderlich ist, kann es zu einer Graft-versus-Host Reaktion kommen. Grundsätzlich könnten bestimmte endogene Pokerstars Apk exogene Faktoren mit einem erhöhten Risiko für die Entstehung Kostenlos Yahtzee Spielen ALL in Zusammenhang stehen. Danach nimmt die Rezidivwahrscheinlichkeit stark ab. Sie kann dementsprechend Standard Lieg mehreren Wochen und Monaten dauern. Blood ; 2 Urs Schanz. Eine Compliance mit der Erhaltungstherapie ist prognostisch relevant [ 14 ].

B All Protokoll Video

Acute Lymphoblastic Leukemia Mnemonic Prenatal Sir Lancelot Merlin to x-rays. Infants with KMT2A rearrangements. Immune therapies such as blinatumomab Skat Ramsch inotuzumab have also greatly facilitated the achievement of remission, which has generally been followed by HSCT. Pediatric nurse specialists. Nevertheless, HCFCs are very potent greenhouse gasesdespite their very low atmospheric concentrations, measured in parts per trillion million million.

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