Management of B-Cell Acute Lymphoblastic Leukemia
The University of Texas MD Anderson Cancer Center, Houston, TX, USA
1. What is the standard of care for front-line management of Philadelphia chromosome–negative (Ph−) acute lymphoblastic leukemia (ALL)?
The front-line strategy for the management of adult ALL is similar to that in pediatrics, and it involves induction chemotherapy, multiple rounds of consolidation, a prolonged maintenance phase, as well as central nervous system (CNS) prophylaxis. Most protocols call for approximately 3 years of therapy in total. There are several accepted regimens employed in the United States, and most involve the same key agents, which include vincristine, anthracycline (e.g., doxorubicin or daunorubicin), and corticosteroids (e.g., prednisone or dexamethasone), with or without some form of L-aspariginase. One such regimen is hyperCVAD, which employs the combination of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine. Cycles are repeated approximately monthly for eight cycles, at which point patients move to the maintenance portion of the regimen with daily mercaptopurine, monthly vincristine, weekly methotrexate, and monthly pulses of prednisone (POMP).
L-asparaginase, an enzyme used to deprive lymphoblasts of the non-essential amino acid asparagine, is considered an important component in pediatric ALL regimens. It is also included in several of the commonly used adult regimens, but the cumulative dose is generally less than that of the pediatric programs. A pegylated form of the drug allows for continuous exposure over a period of weeks, reducing the number of infusions or injections that a patient would be subjected to if receiving the conventional preparation. More recently, a study from the German Multicenter Study Group for Adult ALL (GMALL) was presented, indicating that intensifying the dose of pegylated asparaginase during induction and consolidation improved the survival of younger patients with standard risk disease at baseline. In this regimen, the drug was tolerated well, although there was a significant increase in the incidence of grades 3/4 hyperbilirubinemia. This led to treatment interruptions that were found to have a prognostic impact on the outcome. Other potential toxicities that pose a problem include pancreatitis, thrombosis, allergic reaction, hyperglycemia, and hypofibrinogenemia, among others. This makes it highly important to determine the optimal dose and timing of drug administration to prevent or avoid adverse effects that may compromise further antileukemic therapy. If the pegylated formulation is used, these problems can be delayed, arising typically 1 to 2 weeks after a dose is given. A detailed review of asparaginase toxicity and its management has recently been published by a group of experts.
2. What is the role of anti-CD20 immunotherapy in the treatment of B-lineage ALL (B-ALL)?
Approximately 50% of patients’ leukemic blasts express the CD20 antigen. The prognostic role of CD20 expression in ALL is controversial, but it is a marker against which targeted therapies have been developed. Recently, data from the MD Anderson Cancer Center has indicated that the addition of rituximab, a monoclonal antibody against CD20, to the hyperCVAD regimen improves overall survival (OS) in younger patients. These results were confirmed by a European study that also evaluated the role of monoclonal antibody therapy added to conventional chemotherapy. Although rituximab was incorporated when CD20 expression was 20% or greater, anti-CD20 therapy may be beneficial regardless of CD20 expression at diagnosis. Ofatumumab is another CD20-targeted monoclonal antibody currently approved for the management of relapsed and refractory chronic lymphocytic leukemia (CLL). Ofatumumab is being evaluated in combination with the hyperCVAD regimen in adults with newly diagnosed ALL.
3. What are the options for front-line management of Philadelphia chromosome–positive (Ph+) ALL?
Ph+ ALL continues to pose a major challenge for the adult population. Allogeneic stem cell transplantation (allo-SCT) is regarded as the only curative intervention for this subset of patients. Recently, the incorporation of small-molecule tyrosine kinase inhibitors (TKIs) has improved the outcome of these patients. The addition of a TKI to chemotherapy, including anthracyclines, vincristine, and cytarabine, may produce synergistic effects. Although the optimal schedule of TKIs has yet to be determined in ALL, early initiation and prolonged treatment courses have been implicated to provide the best outcomes.
Imatinib
Imatinib combined with conventional chemotherapy has been proven to be superior to chemotherapy alone in several trials that have been published or presented to date. A major mechanism of secondary resistance to imatinib appears to be related to the acquisition of point mutations within the BCR–ABL kinase domain, over 30 of which have been documented, including the gatekeeper mutation T315I, which causes resistance to imatinib as well as the second-generation TKIs. Other BCR–ABL-independent mechanisms of resistance include decreased drug influx and activation of other downstream or parallel cell-signaling pathways that promote cell proliferation and survival, such as the Src family of kinases (SFKs).
Dasatinib
Dasatinib is a second-generation TKI that is approximately 325-fold more potent against the BCR–ABL protein compared to imatinib, and it has the ability to block the SFKs (dual BCR–ABL and SRC kinase inhibitor). The SRC kinases have been implicated as being required for the development of Ph+ ALL. Dasatinib also retains activity against most known tyrosine kinase domain mutations that confer resistance to imatinib. Recently, dasatinib was found to be superior to imatinib for the initial treatment of chronic myeloid leukemia (CML) in the chronic phase. These favorable characteristics made it appropriate to test combination chemotherapy with the addition of dasatinib in the front-line setting for adult ALL. On a clinical trial recently published, 35 patients with newly diagnosed Ph+ ALL were treated with hyperCVAD and dasatinib. Dasatinib was administered at 100 mg once daily for the first 14 days during the induction and consolidation cycles. If patients completed the consolidation portion, they went on to receive monthly vincristine and prednisone while continuing on dasatinib 100 mg once daily. Ninety-four percent of patients achieved complete remission (CR), and the estimated 2-year survival was 64%. A very low percentage of patients proceeded with upfront allo-SCT (4 of 36); it will be important to assess whether dasatinib therapy modifies the conventional notion that a transplant is absolutely indicated for all patients who are fit for such a procedure and have an adequate stem cell source. Nevertheless, additional follow-up is required before that will be determined. In another recent report on older patients with Ph+ ALL (age >55 years), Rousselot and colleagues (2009) used induction treatment with steroids, vincristine, and dasatinib followed by consolidation cycles of dasatinib, and chemotherapy, which resulted in a CR rate of 97%. With a median follow-up of 12.4 months, median event-free survival and OS were not reached. Dasatinib is currently not US Food and Drug Administration (FDA) approved for front-line therapy of Ph+ ALL patients.
Nilotinib
Nilotinib is a second-generation TKI, derivative of imatinib, with an increased and more selective binding affinity to the adenosine triphosphate pocket of the BCR–ABL oncoprotein, resulting in activity that is 20–50 times higher than the inhibitory activity of imatinib. It has demonstrated activity against most kinase domain mutations, with the exception of T315I and P-loop mutations. It is currently approved for use in the treatment of newly diagnosed patients with CML and patients with chronic-phase CML who are resistant to or are intolerant of imatinib. Nilotinib is not approved for use in patients with Ph+ ALL. Kantarjian et al. (2006) first reported positive results in a phase I dose-escalation study of nilotinib in imatinib-resistant CML or Ph+ ALL, which included 33 patients in the blast phase. Based on the encouraging results of a phase II trial in the relapsed setting, Kim et al. (2011) reported on the use of nilotinib in combination with chemotherapy for front-line treatment of patients with newly diagnosed Ph+ ALL, with a 90% hematologic remission rate and a 54% complete molecular remission (CMR) rate. With a median follow-up of 17.4 months, the estimated recurrence-free survival and OS at 2 years were 71% and 66%, respectively.
Ponatinib
Although the results of second-generation TKIs combined with chemotherapy are quite encouraging, patients still relapse, and there are specific kinase domain mutations that are not sensitive to any first- or second-generation TKIs. The most notorious mutation for any Ph+ malignancy is T315I, which confers resistance to imatinib, dasatinib, as well as nilotinib. Patients with Ph+ ALL receiving dasatinib in a European study appeared to develop this mutation at a relatively high frequency, making it important to develop and examine options to combat this problem. One strategy might be to utilize a TKI that has activity against T315I-mutated disease, such as ponatinib. Ponatinib is a rationally designed molecule that has activity against nearly all known BCR–ABL kinase domain mutations. Of note, ponatinib was approved in December 2012 for the treatment of adult patients with chronic-phase, accelerated-phase, or blast-phase CML that is resistant or intolerant to previous TKI therapy or Ph+ ALL that is resistant or intolerant to previous TKI therapy. Approval was based on a trial of 449 patients with various phases of CML and Ph+ ALL. In this study, 41% of patients with Ph+ ALL achieved a major hematologic response (HR) for a median duration of 3.2 months. Importantly, ponatinib is active against all mutations, including T315I. It is currently being evaluated as a front-line strategy in combination with the hyperCVAD regimen. Preliminary results from the combination of ponatinib and hyperCVAD were presented at the 2013 American Society of Clinical Oncology (ASCO) meeting.
The National Comprehensive Cancer Network (NCCN) guidelines recommend similar approaches to those described here. Available data indicate that it is important to start a TKI as soon as the presence of the Philadelphia chromosome is confirmed. Moreover, the guidelines do not specify a preference for which TKI is initiated in the front-line setting (e.g., imatinib versus dasatinib). Despite the fact that outcomes appear to be improving with current therapies, the NCCN appropriately recommends first and foremost that patients be considered for ongoing clinical trials.
4. What are the potential strategies for salvage therapy in patients with relapsed B-ALL?
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