Treatment
Treatment for patients with ALL and AML can be subdivided into two or three phases. Induction chemotherapy is the initial treatment designed to clear the marrow of overt leukemia. This phase usually involves multiple drugs that cause pancytopenia for 2 to 3 weeks.
The purpose of consolidation therapy is to further reduce the residual leukemic burden in patients who are in morphologic remission. Molecular markers of residual disease can often be detected after induction chemotherapy, which indicates the need for further treatment. The intensity of consolidation therapy varies, depending on the risk of relapse (based primarily on cytogenetic or molecular risk groups) and patient age, or comorbid conditions.
Maintenance chemotherapy using low-dose oral chemotherapy for 18 to 24 months has been shown to prolong relapse-free survival in pediatric patients with ALL and in adults with APL. Its value is less clear in adults with ALL; maintenance is used much less frequently in AML.
Acute lymphoblastic leukemia
Induction therapy
The initial goal of therapy is to rapidly reduce the leukemic burden to a level undetectable by conventional methods of light microscopy and flow cytometry, a state that is deemed a complete remission (CR). Two standard induction regimens have been used in adults with ALL—the Hoelzer regimen, developed by the BFM multicenter group, and the Larson regimen, developed by the CALGB. Along with the standard induction schemas, two newer regimens, the Hyper-CVAD (high-dose cyclophosphamide(Drug information on cyclophosphamide), vincristine, Adriamycin [doxorubicin], dexamethasone(Drug information on dexamethasone)) regimen from M. D. Anderson and the Linker regimen (2002 version), which have an induction drug dosing simil ar to that of the older regimens but include much higher doses of antimetabolites (cytarabine [Ara-C] and methotrexate(Drug information on methotrexate)) and etoposide(Drug information on etoposide) for dose-dense consolidations, are outlined in Table 3 along with the standard induction schemas. All of these induction regimens consist of treatment with one cycle each of two regimens with differing mechanisms of cytotoxicity. Overall, CRs are obtained in 80% to 94% of adults younger than age 60 treated with any of these regimens. The incidence of death during induction therapy for these trials was low (2%–9%). Cytokines (such as filgrastim(Drug information on filgrastim) [Neupogen]) may be used to shorten the period of cytopenia during ALL therapy.
ALL induction and consolidation therapy
L-asparaginase has been a major agent in pediatric trials in both induction and consolidation therapies. Although L-asparaginase is used during induction therapy in adults younger than age 50 with ALL (except in the M. D. Anderson Hyper-CVAD regimen), it is rarely used in consolidation therapy. The potential importance of this drug was emphasized by observations on L-asparaginase depletion during induction therapy in the most recent CALGB trial, which showed a median survival of 31 months in patients who were depleted vs 13 months for those who were not depleted. They also showed improved depletion using the pegylated form of L-asparaginase (pegaspargase [Oncaspar]), which has a longer half-life. In most clinical trials, a single dose of pegasparaginase (2,000 IU/m2) is now used to replace multiple doses of L-asparaginase. Several pediatric trials have also compared outcomes based on steroid regimens (prednisone vs dexamethasone) and have shown better event-free survival in the dexamethasone arms (81% to 85%) compared to 75% to 79% in the prednisone(Drug information on prednisone) arms. The improvement was more prominent in the high-risk patient populations. However, this improvement came at the price of higher risk of infections, myopathy, and avascular necrosis. The bone abnormalities were most obvious in teens and young adults and uncommon in children under 10 years of age.
Assessment of outcomes for young adults (< 30 years) treated on either pediatric or adult regimens has shown comparable remission rates but significant differences in long-term disease-free survival. As a rule, the pediatric regimen contains higher and more frequent doses of L-asparaginase as well as stricter adherence to a tight dose schedule. All three US adult cooperative groups are now collaborating on a trial using the most recent COG high-risk arm for adult patients (18–40 years) to see if results comparable to those reported by COG can be achieved. The most recent trial of Total Therapy published by St. Jude's showed a 5-year event-free survival of 86% in 45 adolescents ages 15–18 vs 87% for the 453 younger patients. The current regimen maximizes vincristine, steroids, and asparaginase(Drug information on asparaginase) and reduces anthracyclines and alkylators in hopes of reducing late second malignancies (Table 3).
A recent Canadian study using a modified pediatric regimen with weekly high-dose L-asparaginase for 30 weeks during intensification in adults aged 18 to 60 years showed an overall survival of 63% and a disease-free survival of 71% at 5 years. Adverse predictors of outcome included age > 35 years, MLL gene rearrangement, high WBC count, and < 80% planned L-asparaginase dose. The regimen was associated with significant morbidity, however, including infections (47%), avascular necrosis of major joints (32%), thromboembolic events (23%), and peripheral neuropathy (22%).
T-cell ALL There is evidence that patients with T-cell ALL may benefit from early treatment with Ara-C and cyclophosphamide. Pharmacologic studies show high levels of Ara-C triphosphate accumulation in T lymphoblasts and synergy between cyclophosphamide and Ara-C in cell lines of T-cell malignancies. T lymphocytes also have a lower expression of polyglutamate synthetase than pre-B blasts. Randomized trials in children with T-cell ALL showed that the use of high-dose methotrexate (up to 5 g/m2) also improved outcome.
Adults with T-cell ALL treated on the recent MRC UKALL XII/ECOG 2993 trial had a 94% CR rate and a 48% 5-year survival. Patients with complex cytogenetics, however, had a very poor outcome, with a survival of 19% at 5 years.
Mature B-cell ALL Patients with the more mature B-cell ALL (Burkitt-cell leukemia) experienced an improvement in survival when high doses of cyclophosphamide, methotrexate, and Ara-C were incorporated early in the treatment course (HyperCVAD regimen; Table 3). The probability of leukemia-free survival improved from 35% with standard ALL induction to 60% to 70% with these newer regimens. Rituximab(Drug information on rituximab) (Rituxan) is also being added in patients whose blasts express CD20.
Ph+ ALL The development of imatinib(Drug information on imatinib), a selective BCR-ABL protein kinase inhibitor, provided a potent new agent in the treatment of Ph+ ALL. As a single agent, it produced CRs in 30% of patients with relapsed Ph+ disease. Several centers have reported improved remission rates of 90% to 95% when imatinib (600 mg/d) was added to initial induction therapy (usually in regimens lacking L-asparaginase) without additional toxicity. With continuation of imatinib through consolidation therapy, 50% to 60% of patients will achieve a molecular remission by 60 days post induction. Patients who achieve a molecular remission and continue on imatinib therapy have an improved disease-free survival of 62% at 3 years, compared with 14% at 1 year in the pre-imatinib era. Clinical trials are being designed to incorporate new, more potent TKIs (eg, dasatinib(Drug information on dasatinib) [Sprycel], nilotinib(Drug information on nilotinib) [Tasigna]); both of these agents have shown activity in the relapse setting.
Consolidation therapy
The BFM, CALGB, Linker (2002), and Hyper-CVAD COG regimens for ALL are outlined in Table 3. There is a CALGB Intergroup Study regimen for adults age 30 or younger which uses more dose-intensive consolidation with asparaginase usage (for more information about this, visit www.ClinicalTrials.gov and search for trial NCT 00558519). As yet, no randomized trials have compared these regimens. However, in sequential studies from Memorial Sloan-Kettering Cancer Center, BFM group, and the Linker study, use of multiple cycles of non–cross-resistant drugs for 3 to 8 cycles after remission followed by maintenance with methotrexate and mercaptopurine(Drug information on mercaptopurine) (Purinethol) resulted in overall long-term DFS rates of 38% to 52%.
Long-term outcome data of 282 patients treated with Hyper-CVAD showed an 81% CR rate after cycle 1A and a 92% rate after receiving both cycles 1A and 1B (see Table 3); a 5% overall death rate during induction was noted, although treatment-related mortality reached 15% in patients older than age 60 despite the use of G-CSF (granuolocyte colony-stimulating factor). At a median follow-up of 63 months, the 5-year DFS was 38%, similar to that reported in the BFM and CALGB trials. In this series, adverse prognostic factors for DFS were age ≥ 45 years, poor performance status, WBC count > 50,000/, Ph+ cytogenetics, more than 1 cycle to achieve a CR, or > 5% residual blasts at day 14. Patients with none or one of these factors had a 52% 5-year DFS rate, vs 37% for patients with two or three factors and only 10% for patients with at least four risk factors.
In the 2002 Linker trial, which intensifies the consolidation with alternating cycles of higher-dose Ara-C (histone deacetylase [HDAC]) and etoposide alternating with cycles of high-dose methotrexate, the 5-year relapse-free survival rate was 52% overall and 60% for patients with standard-risk features. Prognostic features that were associated with a poor outcome in this study included pre-B ALL with > 100,000/μL WBC count at diagnosis, cytogenetic abnormalities involving chromosome 11q23 or t(9;22), and time to remission > 30 days. Without either allogeneic or autologous transplantation, all high-risk patients relapsed within a short time (1 to 9 months). A recent update of the Ph− pre-B ALL subgroup showed a 3-year DFS rate of 60% and an overall survival rate of 50%.
The French LALA-94 trial of 922 patients was designed to look at postremission therapy that was stratified by risk of relapse. The standard-risk patients who achieved CR with 1 cycle of induction therapy were randomized to receive either conventional cyclophosphamide, Ara-C, and mercaptopurine or early intensification with intermediate-dose Ara-C (1 g/m2 × 8 doses) and mitoxantrone(Drug information on mitoxantrone).
In this study, there was no difference in 5-year DFS (33% conventional vs 37% early intensification, with an OS at 5 years of 44%). High-risk patients included those with defined cytogenetic risks (excluding Ph+), WBC count > 30,000/μL, and CNS disease at diagnosis or who required more than 35 days to achieve CR. Patients with a sibling donor received allogeneic transplant in CR, with the remainder randomized to receive either the early intensification chemotherapy or autologous transplant. The 5-year DFS was 45% for those receiving allogeneic transplant and 23% for those without a donor. There was no significant difference in OS with chemotherapy vs autologous transplant, but there was a different pattern of relapse, with fewer late relapses in the autologous patients.
High-risk patients Although the BFM regimen is now standard therapy for standard-risk patients (aged 30 to 55 years), high-risk patients are being selected for dose-intensive therapies, including HDAC and methotrexate or etoposide, high-dose methotrexate, L-asparaginase, or TKIs such as imatinib or dasatinib in the case of Ph+ ALL. Patients with high-risk features including Ph+ have DFS of 50%–60% when allogeneic stem cell transplant is performed in CR1 (first CR) for adults.
The presence of minimal residual disease using PCR-based probes or multicolor flow cytometry at end of double induction in pediatric series or at 16 to 22 weeks from the start of therapy in adults has been the strongest predictor of relapse and should inform choices regarding intensified therapy or allogeneic transplant.
Allogeneic hematopoietic cell transplantation (HCT)
Myeloablative allogeneic HCT combines dose-intensive chemotherapy and radiation therapy with the immunotherapeutic aspects of graft-vs-leukemia effect from donor antitumor surveillance. Relapse rates following allogeneic HCT for high-risk patients are significantly lower (15% to 20% vs 50% to 65%) for nontransplant recipients, but transplant-related mortality is also high (20% to 30%) and increases with age. Several studies have shown improved survival for high-risk patients receiving allogeneic transplants in first CR. Results from the ECOG/MRC trial also showed improved disease-free survival (62% vs 52%) at 5 years for standard-risk patients transplanted from a sibling donor. Three sequential French ALL trials as well as the ECOG/MRC trial failed to show any survival advantage for autologous HCT compared with 2.5 to 3 years of consolidation and maintenance chemotherapy.
For patients with Ph+ ALL, imatinib has provided a means to achieve molecular remission in approximately half of these very high-risk patients; this has allowed physicians more time to identify an unrelated donor. Studies that will assess the impact of molecular remission pre-HCT on the risk of relapse are in progress. Imatinib (at 400 mg/day orally) is also studied in the post-HCT phase. Patients who remain molecularly positive or revert to a positive state are at high risk of relapse and should be considered for treatment with second-generation TKIs such as dasatinib or nilotinib. (See chapter on CML for further details.)
CNS prophylaxis
CNS relapse occurs at a much higher frequency in patients with ALL than in those with AML. The rate of CNS relapse was 20% in the first year in a pediatric ALL trial in which the CNS therapy was attenuated to a subtherapeutic level. Patients with ALL require preemptive therapy for occult CNS disease with intrathecal methotrexate and/or Ara-C preferably combined with regimens employing high-dose systemic Ara-C or methotrexate. Pediatric trials showed that regimens which used dexamethasone at a daily dose of at least 6 mg/m2 had lower rates of CNS relapse (3.7%) than regimens which used prednisone 40 mg/m2 (7.1% ) due to higher CNS penetration and longer retention. This has changed the pediatric practice to omit cranial radiation as a component of CNS prophylaxis, thus minimizing risks for late neurocognitive problems in children. Specific use of intrathecal liposomal Ara-C should not be used concomitantly with high-dose systemic chemotherapy such as Ara-C, methotrexate, or etoposide, which cross the blood-brain barrier, due to a high risk (15%–20%) of serious neurotoxicity (seizures, cauda equina syndrome, and encephalitis).
Maintenance therapy
Maintenance therapy with daily mercaptopurine and weekly methotrexate for 18 to 24 months beyond consolidation remains the standard of care for children with ALL. In adults, the benefit of maintenance therapy is less certain. In low-risk adults, who may have an outcome more similar to that in the pediatric population, maintenance therapy would appear to be justified (see Table 3 for maintenance regimens). In individuals who have mature B-cell ALL, it is unlikely that maintenance therapy has any effect. In other high-risk adult populations, more than half of patients relapse while on maintenance therapy, indicating the need for other strategies to eradicate minimal residual disease.
Treatment of relapse
Treatment of relapsed adult ALL is a major challenge. Because most protocols for initial treatment incorporate 6 to 11 agents with different cytotoxic mechanisms, a selection process for drug resistance has occurred. The overall remission rate for relapse therapy is 30% to 40%, with a median duration of remission of 6 months. In the MRC/ECOG trial, the 5-year overall survival for adults who relapsed was 7% in the absence of allogeneic transplant.
Salvage strategies include reinduction with the initial regimen in patients with late relapse or high-dose antimetabolites (Ara-C or methotrexate [see Hyper-CVAD regimen, Table 3]) in those who relapse early. Monoclonal antibodies such as epratuzumab directed at CD22 and alemtuzumab(Drug information on alemtuzumab) (Campath) directed at CD52 are being studied in the subset of patients whose blasts express those antigens. Other drugs currently being studied for relapsed disease include the purine analog clofarabine, proteosome inhibitors such as bortezomib(Drug information on bortezomib) and novel tyrosine kinase inhibitors such as dasatinib. Allogeneic transplantation remains a mainstay of salvage therapy.
Clofarabine (Clolar) has been approved for treatment of relapsed refractory ALL in children. Of 61 patients, 12 achieved CR, including children who had relapsed following allogeneic transplantation. The maximum tolerated dose was 52 mg/m2 infused over 2 hours daily for 5 days. Significant toxic effects include febrile neutropenia, anorexia and nausea, capillary leak syndrome, hepatotoxicity, and rash. A small, phase I trial combined clofarabine, etoposide, and cyclophosphamide in patients with relapsed ALL (n = 20) or AML (n = 5). Nine of 13 pre-B-cell ALL patients achieved CR, as compared with 1 of 5 of those with T-cell ALL. Four patients developed severe liver toxicity, including veno-occlusive disease of the liver in patients with prior stem cell transplantation or hepatitis. Clofarabine is now also being integrated into preparative regimens for allogeneic transplantation in combination with either busulfan or melphalan(Drug information on melphalan) for reduced intensity conditioning. Liposomal vincristine also has been explored in combination with dexamethasone for relapsed ALL. In one trial, 7 of 36 patients achieved CR. A rate-limiting toxicity was neuropathy.
Nelarabine (Arranon) has been approved for the treatment of T-cell lymphoblastic disease. In a recommended dose of 1,500 mg/m2 on days 1, 3, and 5, this agent has produced response rates of 30% to 50% in heavily pretreated patients. Vinorelbine has produced remission in 50% of adults with relapsed ALL in a small pilot study.
In individuals with Ph+ ALL or CML in lymphoid blast crisis, imatinib (400 to 800 mg orally daily) can induce remissions in up to 30% of patients. These remissions are short-lived but may control the leukemia long enough for a donor to be identified, thus providing an option for an allogeneic transplant in second remission. Nilotinib, which has been recently approved by the US Food and Drug Administration, is an imatinib analog with high binding affinity to BCR-ABL. It has been shown to overcome imatinib resistance in approximately 30% of Ph+ ALL patients.
Dasatinib, which is a kinase inhibitor of multiple targets including BCR-ABL, c-Kit, SRC, and PDGFR (platelet-derived growth factor receptor), can provide short-term salvage therapy for patients whose disease progresses while receiving combinations of imatinib and chemotherapy. Dasatinib has a higher propensity for complications related to serositis, with significant pleural and peritoneal effusion. There is some evidence of CNS penetration for dasatinib compared with imatinib. Patients with Ph+ ALL who develop active CNS disease should be switched to dasatinib in conjunction with intrathecal chemotherapy.
