Non-myeloablative conditioning with allogeneic hematopoietic cell transplantation for the treatment of high-risk acute lymphoblastic leukemia

Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., Seattle, WA 98109, USA.
Haematologica (Impact Factor: 5.81). 04/2011; 96(8):1113-20. DOI: 10.3324/haematol.2011.040261
Source: PubMed


Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients with acute lymphoblastic leukemia. However, the majority of older adults with acute lymphoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-myeloablative preparative regimen is a reasonable treatment option for this group. We sought to determine the outcome of non-myeloablative conditioning and allogeneic transplantation in patients with high-risk acute lymphoblastic leukemia.
Fifty-one patients (median age 56 years) underwent allogeneic hematopoietic cell transplantation from sibling or unrelated donors after fludarabine and 2 Gray total body irradiation. Twenty-five patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. Eighteen of these patients received post-grafting imatinib.
With a median follow-up of 43 months, the 3-year overall survival was 34%. The 3-year relapse/progression and non-relapse mortality rates were 40% and 28%, respectively. The cumulative incidences of grades II and III-IV acute graft-versus-host disease were 53% and 6%, respectively. The cumulative incidence of chronic graft-versus-host disease was 44%. Hematopoietic cell transplantation in first complete remission and post-grafting imatinib were associated with improved survival (P=0.005 and P=0.03, respectively). Three-year overall survival rates for patients with Philadelphia-negative acute lymphoblastic leukemia in first remission and beyond first remission were 52% and 8%, respectively. For patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first remission who received post-grafting imatinib, the 3-year overall survival rate was 62%; for the subgroup without evidence of minimal residual disease at transplantation, the overall survival was 73%.
For patients with high-risk acute lymphoblastic leukemia in first complete remission, non-myeloablative conditioning and allogeneic hematopoietic cell transplantation, with post-grafting imatinib for Philadelphia chromosome-positive disease, can result in favorable long-term survival.

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Available from: Ron Ram
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    • "A single center study from the University of Minnesota showed a trend toward improved outcome in patients who could be treated with IM in the pre- and post-transplant period following myeloablative conditioning [40]. Ram et al. also reported that IM given for a median duration of 1 year after RIC-SCT had good tolerability and was associated with an improved outcome, although the effect on relapse was not statistically significant [41]. In a Chinese study, IM treatment was scheduled for 3–12 months after SCT, until BCR-ABL transcript levels were negative at least for 3 consecutive tests or molecular remission was sustained for at least 3 months. "
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    ABSTRACT: New genetic markers for adult acute lymphoblastic leukemia (ALL) have been found to have prognostic impact, such as the lymphoid transcription factor gene IKZF1 alterations, which are associated with a high rate of leukemic relapse in B-ALL. Although complete remission rates by induction chemotherapy in ALL are now high, the long-term survival is still disappointing. Improvements in the survival outcome of ALL have been observed in young adults as a result of the use of pediatric inspired regimens and the broadening of the number of patients who are eligible for allogeneic SCT. Development of new and less toxic agents also provide promise to improve the outcome in adult ALL, such as tyrosine kinase inhibitors in Ph-positive ALL, rituximab in CD20-positive disease, blinatumomab in precursor B-ALL and nelarabine in T-lineage ALL. Challenges for the future are to implement genomic profiling into the clinical setting to guide risk stratification and providing novel targets for tailored therapies.
    Full-text · Article · Jun 2013 · Journal of Hematology & Oncology
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    • "The majority of older adults with ALL are candidates for a reduced-intensity or a non-myeloablative conditioning regimen [10], [11]. Combining allo-HSCT with TKIs could maximize antileukemic activity against Ph chromosome-positive leukemias [12]. In addition to BCR-ABL, imatinib and nilotinib inhibit c-Kit, the receptor for the stem cell factor (SCF). "
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    ABSTRACT: The availability of tyrosine kinase inhibitors (TKIs) has considerably changed the management of Philadelphia chromosome positive leukemia. The BCR-ABL inhibitor imatinib is also known to inhibit the tyrosine kinase of the stem cell factor receptor, c-Kit. Nilotinib is 30 times more potent than imatinib towards BCR-ABL in vitro. Studies in healthy volunteers and patients with chronic myelogenous leukemia or gastrointestinal stromal tumors have shown that therapeutic doses of nilotinib deliver drug levels similar to those of imatinib. The aim of this study was to compare the inhibitory effects of imatinib and nilotinib on proliferation, differentiation, adhesion, migration and engraftment capacities of human cord blood CD34(+) cells. After a 48-hour cell culture with or without TKIs, CFC, LTC-IC, migration, adhesion and cell cycle analysis were performed. In a second time, the impact of these TKIs on engraftment was assessed in a xenotransplantation model using NOD/SCID/IL-2Rγ (null) mice. TKIs did not affect LTC-IC frequencies despite in vitro inhibition of CFC formation due to inhibition of CD34(+) cell cycle entry. Adhesion of CD34(+) cells to retronectin was reduced in the presence of either imatinib or nilotinib but only at high concentrations. Migration through a SDF-1α gradient was not changed by cell culture in the presence of TKIs. Finally, bone marrow cellularity and human chimerism were not affected by daily doses of imatinib and nilotinib in a xenogenic transplantation model. No significant difference was seen between TKIs given the equivalent affinity of imatinib and nilotinib for KIT. These data suggest that combining non-myeloablative conditioning regimen with TKIs starting the day of the transplantation could be safe.
    Full-text · Article · Dec 2012 · PLoS ONE
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    • "This study showed that a better EFS was observed in young patients with Ph+ ALL in the ALL-Ph-08 trial (which included reduction of chemotherapy and a concomitant increase in the imatinib dose) compared with that observed in the historical CSTIBES02 trial. Imatinib together with chemotherapy followed by either myeloablative or non-myeloablative SCT (Ram et al, 2011; Kebriaei et al, 2012) is considered as the standard of care for young patients with Ph+ ALL. The systematic use of tyrosine kinase inhibitors after allogeneic SCT and their possible combination with other agents is a matter of investigation (Nishiwaki et al, 2010; Pfeiffer et al, 2011). "
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    ABSTRACT: The main outcomes of the Programa Español para Tratamiento de Hemopatías (PETHEMA)-acute lymphoblastic leukaemia (ALL)-Ph-08 trial were described and compared with those of the historical PETHEMA-CSTIBES02 trial. The trials differed in imatinib dose (600 vs. 400 mg/d) and amount of chemotherapy (one vs. two consolidation cycles) before stem cell transplantation (SCT). All patients (n = 29) enrolled in the ALL-Ph-08 trial achieved complete remission (CR) (vs. 90% in CSTIBES02), and SCT was performed in CR in 90% (vs. 78%). The reduction in early death, relapse before SCT and transplant-related mortality observed in the ALL-Ph-08 trial resulted in an improved 2-year event-free survival (63% vs. 37%, P = 0·009).
    Full-text · Article · Jul 2012 · British Journal of Haematology
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