Treatment of AML and MDS relapsing after reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation

Oran, Betül; Giralt, Sergío; Couriel, Daniel R.; Hosing, Chitra; Shpall, Elizabeth J.; Meis, Ernesto de; Khouri, Issa F.; Qazilbash, Muzaffar H.; Anderlini, Paolo; Kebriaei, Partow; Popat, Uday; Carrasco-Yalán, Antonio A.; Champlin, Richard E.; Lima, Marcos de

doi:10.1038/sj.leu.2404828

Cited by 58 publications

(59 citation statements)

References 7 publications

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“…This finding is consistent with data from other reports on relapse after RIC. 33,34 Kishi et al 31 and Mrsic et al 35 demonstrated that acute leukaemia in remission before the second transplant is a factor clearly correlated with better outcome. Kedmi et al 36 retrospectively analysed the outcome after second or subsequent allogeneic transplantation for different indications, and found that factors indicating higher likelihood for survival were a non-malignant disease, full HLA-matching, the use of RIC and a non-relapse indication.…”

Section: Outcomementioning

confidence: 99%

Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes

Vrhovać

Labopin

Ciceri³

et al. 2015

Bone Marrow Transplant

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Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 4225 days, presence of CR at RIC2, patient's Karnofsky performance status 480 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.

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Section: Outcomementioning

confidence: 99%

Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes

Vrhovać

Labopin

Ciceri³

et al. 2015

Bone Marrow Transplant

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“…132 Reported relapse rates have exceeded 40 or 50% with low-intensity regimens 27 or high-risk disease characteristics. 120,133 The median interval to AML relapse after RIC SCT is short-3-7 months, 27,119,134,135 and the median survival following relapse is 3-6 months. 135,136 The EBMT identified three factors that predicted better survival after relapse-long interval from transplant to relapse, low percentage of BM blasts and absence of acute GvHD.…”

Section: Relapse After Ric Sctmentioning

confidence: 99%

“…Responses to DLI, after either RIC or myeloablative transplants, are observed in approximately one-third of patients, but do not always translate into long-term survival. 132,134,135,[137][138][139][140][141] The high relapse rate after RIC SCT has stimulated the development of prophylactic approaches that can be applied to high-risk patients. 5-Azacitidine has a favorable safety profile and good antileukemic activity in patients with low disease burden.…”

Section: Relapse After Ric Sctmentioning

confidence: 99%

Reduced-intensity conditioned allogeneic SCT in adults with AML

Reshef

Porter

2015

Bone Marrow Transplant

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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 ...

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“…1 In most series, the median time to relapse after HCT is 4-6 months, 2,3 suggesting that identifying patients with a higher risk of relapse early after HCT is important to tailor transplant and post-transplant management strategies with an aim to reduce the relapse incidence (RI). 4 Cytogenetic and molecular abnormalities detected at diagnosis are important prognostic factors for RI, leukemia-free survival (LFS) and overall survival (OS).…”

Section: Introductionmentioning

confidence: 99%

Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia

et al. 2016

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Treatment of AML and MDS relapsing after reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation

Cited by 58 publications

References 7 publications

Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes

Second reduced intensity conditioning allogeneic transplant as a rescue strategy for acute leukaemia patients who relapse after an initial RIC allogeneic transplantation: analysis of risk factors and treatment outcomes

Reduced-intensity conditioned allogeneic SCT in adults with AML

Pre-transplantation minimal residual disease with cytogenetic and molecular diagnostic features improves risk stratification in acute myeloid leukemia

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