Reduced-intensity conditioned allogeneic SCT in adults with AML

Abstract

AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. ( Bone Marrow Transplantation THE RATIONALE FOR RIC IN AMLTraditional myeloablative transplants are effective in part due to a potent immunologic GVL effect independent of the conditioning regimen. The GVL response has been repeatedly demonstrated in allo-SCT 1,2 and through the use of DLI. 3,4 The ability to harness GVL yet minimize toxicity is highly relevant in AML, which is common in older patients and often incurable with chemotherapy alone. In 2013, AML was the most common indication for allo-SCT, 35% of AML transplants were in patients over age 60 and over 40% were performed with reduced-intensity conditioning (RIC) regimens (data from CIBMTR-Center for International Blood and Marrow Transplant Research).Data from animal models 5,6 and clinical observations regarding GVL activity [1][2][3][4]7 facilitated the development of RIC regimens. The success of initial attempts to use low-dose (2 Gy) TBI alone as conditioning was hindered by frequent graft rejections. The addition of fludarabine to low-dose TBI promoted engraftment with encouraging outcomes. [8][9][10][11][12] This supported a conceptual shift in allo-SCT away from dose intensity toward less myelotoxic regimens that rely on a potent GVL response. EFFICACY-IS THERE AN IDEAL CONDITIONING REGIMEN?The definition of RIC has been a moving target. The term 'reduced intensity' describes regimens characterized by lower rates of toxicities compared with myeloablative transplants. RIC regimens can be further classified as non-myeloablative when they result in minimal cytopenias. These regimens presumably have minimal or no direct effect on leukemic cells, relying solely on the GVL response. 13 The CIBMTR defines a RIC regimen ...

Expanding transplant options to patients over 50 years. Improved outcome after reduced intensity conditioning mismatched-unrelated donor transplantation for patients with acute myeloid leukemia: a report from the Acute Leukemia Working Party of the EBMT

“…3,4,11,12 Reduced-intensity conditioning (RIC) regimens have further extended the use of allogeneic HCT to older patients and those with significant pre-transplant comorbidities. 9,13,14 Several previous studies comparing the clinical outcomes of RIC and MAC regimens after matched related or unrelated donor HCT in AML have shown similar outcomes; [13][14][15][16] however, it is unknown in patients receiving mismatched unrelated donor (MM-URD) HCT. Therefore, we explored whether there were outcome differences for adults with AML after RIC or MAC regimens in the setting of MM-URD HCT using data reported to the European Society for Blood and Marrow Transplantation (EBMT).…”

Peripheral blood stem cell graft compared to bone marrow after reduced intensity conditioning regimens for acute leukemia: a report from the ALWP of the EBMT

“…11,12 Moreover, outcomes for unrelated donor HCT after RIC regimens appear comparable to those seen with sibling donor RIC HCT. 3,[13][14][15] Here we report on transplant outcomes after related or unrelated donor BMT (n=837) versus PBSCT (n=9011) in the setting of reduced intensity conditioning for the treatment of adults with acute leukemia using data reported to the ALWP of the EBMT from 2000 to 2012.…”

“…1,2 Furthermore, following the introduction of reduced intensity conditioning (RIC) regimens, individuals with co-morbidities and those 65 years of age and older are now eligible to undergo HCT. [3][4][5] The use of peripheral blood stem cells (PB) has largely replaced bone marrow (BM) as the main stem cell source for HCT in adults with hematologic malignancies. 1 However, limited data are available on the impact of the stem cell source (related or unrelated donor) in the setting of RIC HCT, [6][7][8][9][10] including our small previous European Group for Blood and Marrow Transplantation (EBMT) series.…”

Prophylactic donor lymphocyte infusion in patients with high-risk acute myeloid leukemia: ready for prime time?

“…2 In an attempt to extend the use of allo-HCT to older patients and those with medical comorbid conditions, several groups of investigators have carried out allo-HCT after reduced intensity (RIC) or truly nonmyeloablative conditioning regimens. 4,5 These regimens rely on graft-versus-AML effects rather than on chemo/radiotherapy for tumor eradication. 3,6 Remarkably, a recent study by the HOVON/SAKK group demonstrated that RIC/nonmyeloablative allo-HCT improved overall survival (OS) in older (60 years of age or older) patients with intermediate or high-risk AML in comparison with those not transplanted.…”