T-cell Acute Lymphoblastic Leukemia
        Treatment options under clinical evaluation
        Current Clinical Trials
Infants With Acute Lymphoblastic Leukemia
        Treatment options under clinical evaluation
Adolescent Patients with ALL
Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia
        Current Clinical Trials

T-cell Acute Lymphoblastic Leukemia

Historically, patients with T-cell acute lymphoblastic leukemia (ALL) have had a worse prognosis than children with precursor B-cell ALL. With current treatment regimens, outcomes for children with T-cell ALL are now approaching those achieved for children with precursor B-cell ALL. For example, the 5-year event-free survival (EFS) for children with T-cell ALL treated on the Dana-Farber Cancer Institute (DFCI) Consortium ALL protocols was 75% compared with 84% for children with precursor B-cell ALL.[1]

Protocols of the former Pediatric Oncology Group (POG) treated children with T-cell ALL distinctly from children with B-lineage ALL. The POG-9404 protocol for patients with T-cell ALL was designed to evaluate the role of high-dose methotrexate and the role of the cardioprotectant dexrazoxane. The multiagent chemotherapy backbone for this protocol was based on the DFCI 87-001 regimen. Results of an interim analysis of the POG protocol led investigators to conclude that the addition of high-dose methotrexate to the DFCI-based chemotherapy regimen results in significantly improved EFS, due in large measure to a decrease in the rate of central nervous system (CNS) relapse.[2] This POG study was the first clinical trial to provide convincing evidence that high-dose methotrexate can improve outcome for children with T-cell ALL. High-dose asparaginase and doxorubicin were also important components of this regimen.[1,2]

Protocols of the former Children’s Cancer Group (CCG) treated children with T-cell ALL on the same treatment regimens as children with precursor B-cell ALL, basing protocol and treatment assignment on the patients' clinical characteristics (e.g., age and white blood cell count [WBC]) and the disease response to initial therapy. Most children with T-cell ALL meet National Cancer Institute (NCI) high-risk criteria. Results from CCG-1961 showed that an augmented Berlin-Frankfurt-Munster (BFM) regimen with a single delayed intensification course produced the best results for patients with morphologic rapid response to initial induction therapy.[3] Almost 60% of events in this group, however, were isolated CNS relapses. Overall results from POG-9404 and CCG-1961 were similar, though POG-9404 used cranial radiation for every patient while CCG-1961 used cranial radiation only for patients with slow morphologic response.[4,2] Among children with NCI standard-risk T-cell ALL, the EFS for children treated on CCG-1952 and CCG-1991 studies was inferior to the EFS for children treated on the POG-9404 study.[5]

In the Children’s Oncology Group (COG), children with T-cell ALL are no longer treated on the same protocols as children with precursor B-cell ALL. All patients with T-cell ALL are considered high risk regardless of age and WBC count. Pilot studies from this group have demonstrated the feasibility of incorporating nelarabine (a nucleoside analog with demonstrated activity in patients with relapsed and refractory T-cell lymphoblastic disease) [6,7] in the context of a BFM backbone for patients with newly diagnosed T-cell ALL; efficacy will be evaluated in the current trial.[8]

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG protocol AALL0434 is a phase III trial for patients aged 1 to 30 years with T-cell ALL utilizing a hemi-augmented BFM backbone. Patients are classified into one of three risk groups (low, intermediate, or high) based on NCI age/leukocyte criteria, CNS status at diagnosis, morphologic marrow response on days 15 and 29, and minimal residual disease (MRD) level at day 29. The objectives of the trial are 1) to determine the safety and efficacy of adding nelarabine to the augmented BFM regimen in high and intermediate risk patients, 2) to determine the relative safety and efficacy of high-dose versus Capizzi dose methotrexate during interim maintenance, and 3) to test the efficacy of treating low-risk T-cell ALL patients without cranial radiation.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with T-cell childhood acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

Infant ALL is uncommon, representing approximately 2% to 4% of cases of childhood ALL.[9] Because of their distinctive biological characteristics and their high risk for leukemia recurrence, infants with ALL are treated on protocols specifically designed for this patient population. Despite intensification of therapy, long-term EFS rates from recent trials remain below 50%, and for those infants with MLL gene rearrangement the EFS rates continue to be in the 30% to 40% range.[10-13] 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.[11,13,14]

Treating infants with and without MLL gene rearrangements with different treatment protocols has been evaluated in a Japanese study. A favorable outcome was obtained with antimetabolite-based therapy for MLL-germline (nonrearranged) patients, while outcome remained unfavorable, despite intensive chemotherapy, for infants with MLL gene rearrangements.[10] An additional study from Japan confirms the good outcome of infants without MLL gene rearrangements.[10] This raises the question whether infants with B-lineage immunophenotype and germline MLL configuration should be treated on the same protocols as similar patients older than 1 year, although infants without MLL gene rearrangements treated on the Interfant-99 also had favorable outcome (4-year EFS of 74%).[13]

The role of bone marrow transplantation in infants with MLL-rearranged ALL remains controversial. Case series have suggested that allogeneic transplants in first remission may be effective;[15-17] in a retrospective analysis of 256 patients initially treated between 1983 and 1995, however, no benefit was observed for any type of allogeneic stem cell transplant compared with intensive chemotherapy without transplant.[18] Similarly, in the Interfant-99 study after adjusting for waiting time to transplantation, high-risk patients who underwent hematopoietic stem cell transplantation had 4-year disease-free survival (DFS) rates that did not significantly differ from those of high-risk patients treated with chemotherapy alone.[13] A COG study of infants with ALL observed that patients with MLL gene rearrangements who underwent transplantation in first remission as per protocol had outcome inferior to a comparable group of infants who completed treatment with chemotherapy.[11]

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• The Interfant-06 Study Group is conducting an international collaborative randomized trial (including sites in the United States) to test whether an ALL/AML hybrid regimen might improve outcomes for infants with MLL-rearranged ALL. The role of allogeneic transplantation in first remission is also being assessed in high-risk patients (defined as MLL-rearranged, younger than 6 months, and WBC >300,000 u/L).

Older children and adolescents (10 years or older) with ALL more frequently present with adverse prognostic factors at diagnosis, including T-cell immunophenotype, and a lower incidence of favorable cytogenetic abnormalities.[19,20] These patients have a less favorable outcome than children aged 1 to 9 years at diagnosis, and more aggressive treatments are generally employed for them.[21] A study from France of 15- to 20-year-old patients diagnosed between 1993 and 1999, demonstrated superior outcome for patients treated on a pediatric trial (67%; 5-year EFS) compared with patients treated on an adult trial (41%; 5-year EFS).[22] Other studies have confirmed that older adolescent patients fare better on pediatric rather than adult regimens.[20,23,24] For instance, the DFCI ALL Consortium reported a 5-year EFS of 78% in adolescents aged 15 to 18 years.[23] The reason for this difference is not known, although possible explanations include treatment setting (i.e., site experience in treating ALL), adherence to protocol therapy, and the components of protocol therapy.[23] Adolescents with ALL appear to be at higher risk than younger children for developing therapy-related complications, including osteonecrosis, deep venous thromboses, and pancreatitis.[20,25-27] High body mass index is also a risk factor for osteonecrosis,[28] and may be associated with a higher relapse rate in older patients.[29]

Hematopoietic stem cell transplantation (HSCT) from a matched sibling donor is the treatment of choice for patients with Philadelphia chromosome–positive (Ph+) ALL.[30-32] In a retrospective, multigroup analysis of children and young adults with Ph+ ALL, HSCT from a matched sibling donor improved outcome compared with standard chemotherapy.[33] In this retrospective analysis, Ph+ ALL patients undergoing HSCT from an unrelated donor had a very poor outcome. More rigorous human leukocyte antigen (HLA) matching by molecular high-resolution typing, however, has significantly improved outcome for patients receiving matched unrelated donor transplants.[34] Patients with Ph+ ALL who show a rapid morphologic response to induction therapy have an improved outcome compared with patients who show a slow response.[35] Following MRD by reverse transcription polymerase chain reaction for the BCR-ABL fusion transcript may provide a means to predict which patients will benefit from allogeneic HSCT.[36,37]

Imatinib mesylate is a selective inhibitor of the BCR-ABL protein kinase. Phase I and II studies of single-agent imatinib in children and adults with relapsed or refractory Ph+ ALL have demonstrated relatively high response rates, although these responses tended to be of short duration.[38,39] Clinical trials in adults with Ph+ ALL have demonstrated the feasibility of administering imatinib mesylate in combination with multiagent chemotherapy.[40] Preliminary outcome for results also demonstrated higher rates of complete remission in adult Ph+ ALL patients receiving imatinib mesylate.[40] The COG AALL0031 study evaluated whether imatinib mesylate could be incorporated into an intensive chemotherapy regimen for children with Ph+ ALL. Patients received imatinib mesylate in conjuction with chemotherapy during postinduction therapy. Some children proceeded to allogeneic stem cell transplant after two cycles of consolidation chemotherapy with imatinib mesylate, while other patients received imatinib mesylate in combination with chemotherapy throughout all treatment phases. Continuous dosing of imatinib mesylate in combination with intensive chemotherapy blocks appeared to be feasible without any additional significant toxicities observed. Efficacy results from this trial are pending longer follow-up.[41]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with Philadelphia chromosome positive childhood precursor acute lymphoblastic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

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41. Schultz KR, Aledo A, Bowman WP, et al.: Minimal toxicity of imatinib mesylate in combination with intensive chemotherapy for Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) in children: a report of the Childrens Oncology Group (COG) AALL0031 protocol for very high risk ALL. [Abstract] Blood 108 (11): A-283, 2006. 
    
    

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