Several studies presented at the 2008 American Society of Hematology (ASH) meeting focused on improving the outcome of acute lymphoblastic leukemia (ALL) in children and adults.
Acute Lymphoblastic Leukemia in Children
Dexamethasone or Prednisone?
Remission induction therapy for standard-risk children with ALL currently consists of administering three drugs: vincristine, prednisone, or dexamethasone, and L-asparaginase or PEG-L-asparaginase. The relative effectiveness of dexamethasone compared with prednisone in induction of childhood ALL has not been extensively studied.
Researchers affiliated with the European AIEOP-BFM ALL 2000 trial have reported that dexamethasone in the induction regimen for childhood acute lymphoblastic leukemia (ALL) reduces the relapse rate compared with prednisone.1 In this study 3,655 patients with ALL were randomly allocated to receive dexamethasone or prednisone in the induction regimen. After consolidation 98.8% of patients achieved a complete remission. The median follow-up of this study is 4.4 years. Table 1 summarizes the main findings of this randomized trial:
Table 1: Dexamethasone Versus Prednisone in Childhood ALL
Non-fatal infectious complications were more common in the dexamethasone group. These authors concluded that dexamethasone “can eliminate one third of all relapses in childhood ALL.” These authors also speculated that more intensive clinical monitoring and early intervention for infections could further improve the advantage of dexamethasone over prednisone. The above results were in contrast to a study presented by researchers affiliated with EORTC Trial 58951 who found no difference between dexamethasone and prednisolone in the induction regimen.2 It should be noted that the dose of dexamethasone in the AIE-BFM trial was 10 mg per sq meter compared to 6 mg per sq meter in the EORTC study, while the dose of prednisone was the same in both studies.
Effects of Pulsed Vincristine and Steroids
Researchers affiliated with the EORTC Randomized Phase III Trial 58951 reported that pulses of vincristine and corticosteroids (dexamethasone or prednisone) during continuation therapy improves disease-free survival in average risk ALL.3 These authors concluded: “In future, for [average risk] patients treated according to the BFM protocol, pulses should become a standard component of therapy.” These authors found that dexamethasone decreased the five-year CNS relapse rate by 2% but was associated with an increase in non-CNS relapses by 1.5%. The death rate in CR was 0.6% higher in the dexamethasone group, and there were more infections. They concluded that at the doses administered in this study, dexamethasone and prednisiolone were comparable in effectiveness. However, they also stated, “The optimal dosage of either glucocorticoid, compatible with acceptable toxicity, remains to be determined.”
Effects of Methotrexate
Researchers affiliated with the FRALLE93B Study reported that high-dose methotrexate benefited patients with standard-risk B-cell precursor (BCP) phenotype who had a good response to chemotherapy.4 Patients were randomly allocated to be treated with high- or low-dose methotrexate. High-dose methotrexate had no impact on outcomes of patients with low- or high-risk disease. High-dose methotrexate appeared to benefit only those patients with average-risk ALL who had clearing of blasts on day 21 with improvement in five-year overall survival from 89% to 95%. Researchers affiliated with Children’s Oncology Group Study 1991 also reported that increasing dosage of intravenous methotrexate without leucovorin rescue was superior to oral methotrexate during interim maintenance for children with standard-risk ALL.5
Effects of Allogeneic Stem Cell Transplantation in ALL in Children
Researchers from Europe have reported that children with poor-risk ALL have an improved survival following allogeneic stem cell transplantation in first complete remission compared with continued chemotherapy.6 Results from a 2002 analysis by the International Bone Marrow Transplant Registry (IBMTR) reported that allogeneic stem cell transplants from unrelated donors produce similar results to related transplants in children with ALL in second remission.7 In this study the five-year survival was 22%. However, a more recent analysis of IBMTR data shows a 62% survival for children with ALL in second remission and 33% survival for those transplanted with more advanced disease; this suggests significant progress between the two reports.8 This study also showed that results of unrelated donor transplants were better when bone marrow was used as a source of stem cells rather than peripheral blood stem cells, which is more commonly used in adults.
At ASH 2008 researchers from Germany reported that there has been a significant reduction in transplant-related mortality associated with allogeneic stem cell transplant for children and adolescents with ALL over the past 12 years.9 This analysis included 185 patients transplanted in first CR and 218 after first relapse from 1996 to 2003; this group was compared to 109 patients transplanted in first CR and 135 after first relapse after 2003. Transplant-related mortality was reduced from 20% to 12% during these two time periods. This reduction occurred despite the fact that there was a larger number of older patients in the latter period and more unrelated and mismatched donors. Thus, allogeneic stem cell transplant may become a more attractive alternative strategy for subsets of patients with ALL.
Philadelphia Chromosome-Positive (Ph+) ALL in Children
Researchers affiliated with the International Childhood Acute Lymphoblastic Leukemia Study Group presented the results of treating 640 children with Ph+ ALL between 1995 and 2005 who had not received tyrosine kinase inhibitors.10 The previous report by this group was published in 2000 in the New England Journal of Medicine and involved outcomes of 267 children with Ph+ ALL.11 In this report event-free survival was 25% and overall survival was 36%. Approximately half of patients with the best prognosis survived disease-free compared with 30% for intermediate-risk patients and 20% for poor-risk patients. The best outcomes were for those receiving an allogeneic stem cell transplant. In the current ASH presentation, event-free survival was 31% and overall survival was 44%, representing an overall improvement in outcomes since the previous report. Two hundred sixty-four patients underwent an allogeneic stem cell transplant in first CR with a disease-free survival of 44%. However, there were not differences in overall survival at seven years between those transplanted in first remission and those receiving chemotherapy alone, suggesting that salvage therapies, including stem cell transplantation after relapse, were effective.
Acute Lymphoblastic Leukemia in Adults
A combined U.S. (Eastern Cooperative Oncology Group) and UK study has confirmed that an allogeneic stem cell transplant in first complete remission is the best option for patients with standard- and high-risk ALL who were 65 years of age or younger.12 Only a minority of patients with adult ALL will have a related donor and must resort to using an unrelated donor or umbilical cord blood. Researchers affiliated with the European Bone Marrow Transplant (EBMT) Registry have reported that, for adults with ALL in first remission, allogeneic stem cell transplants from unrelated donors result in similar outcomes to those observed following related allogeneic stem cell transplants.13 These authors reported that the disease-free survival for patients with ALL in first complete remission was 45% following a related donor transplant and 42% following an unrelated donor transplant.
Allogeneic stem cell transplantation from a related or unrelated donor or by using umbilical cord blood also offers the best chance of long-term disease-free survival in patients with relapsed ALL. A large study recently reported that patients with adult ALL who receive a related or unrelated donor stem cell transplant in other than first complete remission have a long-term disease-free survival of 27%.14
At ASH 2008 researchers affiliated with the Acute Leukemia Working Party of the EBMT reported a comparison of reduced-intensity conditioning with myeloablative conditioning in patients receiving an allogeneic stem cell transplant for ALL.15 This study compared reduced-intensity conditioning in 97 patients with myeloablative conditioning in 504 patients. The cumulative incidence of non-relapse mortality was 24% for reduced-intensity regimens versus 32% for myeloablative regimens. The relapse rate was 12% higher following reduced intensity regimens. These authors concluded that reduced-intensity regimens were still valid for patients over the age of 45 years or with significant co-morbidities that preclude intensive conditioning.
Philadelphia Chromosome-Positive (Ph+) ALL in Adults
Up to 40% of adults with ALL have Ph+ ALL, which connotes an adverse prognosis. This abnormality increases with age, making the treatment of older patients difficult. Adults with Ph+ ALL usually receive Gleevec® (imatinib) in the induction regimen. Current treatment of adult patients with Ph+ ALL is aggressive multi-agent chemotherapy and Gleevec. The goal of therapy in younger individuals is to induce a complete remission prior to allogeneic stem cell transplantation. For patients not suitable for allogeneic transplantation due to age or significant health problems, long-term maintenance therapy with Gleevec is administered.
A previous study from France reported that Gleevec and methylprednisone alternated with chemotherapy improves outcomes of elderly patients with Ph+ ALL.16 This study included patients who were 55 years of age or older. A complete remission was achieved in 90% of patients. These results are significantly better than for patients not treated with Gleevec. Researchers from the M. D. Anderson Cancer have treated 54 patients with Ph+ ALL with hyper-CVAD and Gleevec.17 All patients received Gleevec for the first 14 days of induction and continuously through courses 2-8 with indefinite maintenance. The complete remission rate was 93% and the complete molecular complete remission rate was 52%.
At ASH 2008 researchers affiliated with the GRAAPH-2005 study reported the results of a randomized trial comparing induction therapy of adult patients with Ph+ ALL with one of the following:
- Gleevec, vincristine, and dexamethasone
- Gleevec plus HyperCVAD
Complete hematologic remissions were observed in 100% of patients in the less intensive regimen and 95% in the HyperCVAD group. The HyperCVAD regimen was more effective in producing a negative minimal residual disease (MRD) state. After consolidation patients in this study received an allogeneic stem cell transplant or an autologous stem cell transplant. After allogeneic stem cell transplantation, the two-year overall survival was 62%, which was better than observed in historical controls. Two-year overall survival was 68% in those induced with less intensive therapy and 54% for those induced with HyperCVAD. Disease-free survival was 43% for the less intensive induction regimen and 32% for the HyperCVAD group. These authors suggest that “imatinib and chemotherapy allows a majority of patients to have consolidation with stem cell transplantation.” This study raises questions about whether the HyperCVAD regimen predisposes to increased transplant-related mortality. More information of this issue is needed.
Sprycel for First-line Therapy of Philadelphia Chromosome-positive (Ph+) ALL
Sprycel® (dasatinib) is a newly developed tyrosine kinase inhibitor that is 325-fold more active than Gleevec for inhibition of Bcr-Abl. Sprycel is active in patients who are resistant or intolerant to Gleevec. On June 29, 2006, the U.S. Food and Drug Administration (FDA) announced the approval of Sprycel for the treatment of patients with Ph+ ALL who are resistant to or intolerant of Gleevec. German researchers reported at 58% complete cytogenetic remission rate in patients with Ph+ ALL resistant to Gleevec.18
Two studies presented at ASH 2008 suggest that Sprycel is effective for first-line therapy of Ph+ ALL. Researchers from Italy reported that Sprycel monotherapy resulted in a 100% complete hematologic remission rate in 36 patients with newly diagnosed Ph+ ALL. 19 This is the first trial to evaluate Sprycel as up-front therapy for newly diagnosed patients with Ph+ ALL. The median age of this group was 54 years, with the oldest patients being 76 years of age. This trial enrolled 48 patients, and data were presented on 34. In this trial patients received steroids seven days prior to starting Sprycel and all received intrathecal therapy. All 34 patients had a complete hematologic remission. Nine patients have relapsed and PCR studies of MRD were positive in seven of these patients. These authors state that complete remissions can be produced with Sprycel or Gleevec in most if not all cases. They suggest that elderly patients do not need chemotherapy for remission induction and that future research should focus on postremission strategies.
Researchers affiliated with the European Working Group on Adult ALL (EWALL) reported a 100% complete hematologic remission rate for 22 patients with newly diagnosed Ph+ ALL treated with Sprycel plus chemotherapy.20 The median age of this group was 71 years. One patient died during induction, and the remainder achieved a CR. Molecular CR was achieved in 33%. One relapse occurred during consolidation, and there have been no other relapses. There were three non-leukemic deaths in CR. These are interesting data that show that Sprycel is very active for the treatment of Ph+ ALL. Optimal incorporation of Sprycel into a tolerable regimen for consolidation and maintenance therapies will need further studies. Presumably the intensity of chemotherapy required for “cure” can be monitored by PCR.
Allogeneic Stem Cell Transplantation for Ph+ ALL
Ph+ ALL represents 40% of ALL cases in patients over the age of 40 years. For adults with Ph+ ALL, survival at three years does not exceed 20% in most studies. Most studies are based on the observation that recipients of allogeneic transplant from related or unrelated donors have improved survivals with up to 40-50% of patients being long-term survivors. More recently there has been great interest in evaluating Gleevec and other tyrosine kinase inhibitors, which have markedly improved the remission rate of patients with Ph+ ALL.
Researchers from Japan have reported a three-year relapse-free survival of 53% for patients receiving an allogeneic stem cell transplant from related, unrelated, or cord blood donors in first CR of Ph+ ALL.22Researchers involved in the current study have previously reported a 96% complete remission rate and a 72% complete molecular remission rate in patients with Ph+ ALL treated with Gleevec and chemotherapy.22 Allogeneic stem cell transplantation in first CR was performed in 48 of 77 patients in this study. The study presented at ASH 2008 reported the outcomes of 60 patients who underwent allogeneic stem cell transplantation in first CR; 24 from HLA identical siblings, six from mismatched related donors, 21 from matched unrelated donors, and ninw from umbilical cord blood. Patients less than 55 years received myeloablative regimens, and those over this age received reduced intensity regimens. The median follow-up was 2.6 years. Transplant-related mortality was 15%, and 25% relapsed. The probability of overall survival was 64% and 53% for relapse-free survival. Patients younger than 40 years of age had a better outcome than patients between the ages of 40 and 54. All eight patients aged 55 or over who received reduced-intensity regimens survive in remission. These authors suggest that these data are superior to historical controls at their institution. They also suggest that reduced-intensity regimens should be given to patients over the age of 40 years rather than only to those over 55 years of age. By utilizing unrelated and cord blood, virtually all patients should have a source of stem cells for allogeneic stem cell transplantation.
There appears to be major progress in the development of new drugs and new strategies for the treatment of patients with ALL, which should be reflected in improved survival in the future.
1 Schrappe M, Zimmermann M, Moricke A, et al. Dexamethasone in induction can eliminate one third of all relapses in childhood acute lymphoblastic leukemia (ALL): Results of an international randomized trial in 3655 patients (Trial AIEOP-BFM ALL 2000). Blood. 2008;112:9, abstract number 7.
2 Bertrand Y, Suciu S, Benoit y, et al. Dexamethasone (DEX) (6mg/sm/d) and prednisolone (PRED) (60mg/sm/d) in induction therapy of childhood ALL are equally effective: Results of the 2nd interim analysis of EORTC Trial 58951. Blood 2008;112:9, abstract number 8.
3 Suciu S, Bertrand Y, Mazingue F, et al. Improved outcome of pulses of vincristine and steroids in continuation therapy in children with average risk acute lymphoblastic leukemia (ALL) and non Hodgkin lymphoma (NHL): Final report of the EORTC Randomized Phase III Trial 58951. Blood 2008;112:10, abstract number 11.
4 Leblanc T, Landman-Parker J, Auclerc M-F, et al. High-dose methotrexate seems to benefit only to standard-risk BCP-ALL patients with good early response to chemotherapy: Final analysis of the FRALL93B Study. Blood 2008;112:10, abstract 10.
5 Bosrom BC, Hunger SP, Angiolillo AL, et al. Escalating dose intravenous methotrexate without leucovorin rescue during interim maintenance is superior to oral methotrexate for children with standard risk acute lymphoblastic leukemia (SR-ALL): Children’s Oncology Group Study 1991. Blood 2008;112:9, abstract 9.
6 Balduzzi A, Valsecchi MG, Uderzo C, et al. Chemotherapy versus allogeneic transplantation for very-high-risk childhood acute lymphoblastic leukemia in first complete remission: comparison by genetic randomization in an international prospective study. Lancet 2005; Aug 20-26;366(9486):635-42.
8 MacMillan ML, Davies SM, Nelson GO, et al. Twenty years of unrelated donor bone marrow transplantation for pediatric acute leukemia facilitated by the National Marrow Donor Program. Biology of Blood and Marrow Transplantation 14:16-22.
9 Schrauder A, Schrappe M, Stackelberg A, et al. Significant reduction of treatment related mortality after stem cell transplantation in 647 children and adolescents with ALL within BFM trials during the last 12 years: A long term analysis from 1996 to 2007. Blood 2008;112:213, abstract number 567.
10 Schrappe M, Hungar S, Carroll WL. Et al. Clinical outcome of 640 with newly diagnosed Philadelphia chromosome positive acute lyphoblastic leukemia between 1995 and 2005. Blood 2008;112:213, abstract number 568.
12 Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia the greatest benefit is achieved from a matched allogeneic transplant in first complete remission and an autologous transplant is less effective than conventional consolidation/maintenance chemotherapy in all patients: Final results of the International ALL Trial (MRC UKAII/ECOG E2993). Blood 2008;111:1827-1833.
13 Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared to unrelated transplant in first complete remission. Journal of Clinical Oncology 2004;22:2816-2825.
14 Kiehl MG, Kraut L, Schwerdtfeger R, et al. Outcome of allogeneic hematopoietic stem-cell transplantation in adult patients with acute lymphoblastic leukemia: No difference in related compared to unrelated transplant in first complete remission. Journal of Clinical Oncology 2004;22:2816-2825.
15 Reduced intensity versus conventional myeloablatic conditioning (RIC vs MAC) allogeneic stem cell transplantation (Allo-SCT) for patients with acute lymphoblastic leukemia (ALL): A survey from the Acute Leukemia Working Party of EBMT. Blood 2008;112:294, abstract number 793.
16 Delannoy A, Delabesse E, Lheritier V, et al. Imatinib and methylprednisolone alternated with chemotherapy improve outcomes of elderly patients with Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukemia: results of the GRAALL AFR09 study. Leukemia. 2006;20:1526-1532.
17 Thomas DA, Kantarjian HM, Cortes JE, et al. Outcome after frontline therapy with the hyper-CVAD and imatinib mesylate regimen for adults with de novo or minimally treated Philadelphia (PH) positive acute lymphoblastic leukemia (ALL). Journal of Clinical Oncology. 2008;26:abstract 7019.
18 Ottmann O, Dombret H, Martinelli G, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood 2007;110:23092315.
19 Foa R, Vitale A, Guarini A, et al. Dasatinib monotherapy effective and feasible as first-line treatment of adult Philadelphia-chromosome positive acute lymphoblastic leukemia: Final results of the GIMEMA LAL1205 study. Blood 2008;112:119, abstract number 305.
20 Cayuela J-M, Recher C, Leguay T, et al. Dasatinib (Sprycel®) and chemotherapy for first-line treatment of elderly patients with de Novo Philadelphia Positive ALL: Results of the first 22 patients included in the EWALL-PH-01 Trial (on behalf of the European Working Group on Adult ALL (EWALL). Blood2008;112:1004, abstract 2920.
21 Yanada Nm Sugiura, Yagaski F, et al. Efficacy of allogeneic hematopoietic stem cell transplantation during first complete remission following imatinib-combined chemotherapy in patients with Philadelphia Chromosome positive-acute lymphoblastic leukemia. Blood 2008;112:178, abstract number 462.
22 Yanada M, Takeuchi J, Sugiura I, et al. High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. Journal of Clinical Oncology.20;2006:460-466.