Back to the Future! The Evolving Role of Maintenance Therapy after Hematopoietic Stem Cell Transplantation

Hourigan, Christopher S.; McCarthy, Philip L.; Lima, Marcos de

doi:10.1016/j.bbmt.2013.11.017

Cited by 36 publications

(20 citation statements)

References 107 publications

(97 reference statements)

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“…(13–15) They showed that azacitidine (AZA) can be safely administered to heavily pretreated post-transplant patients and may prolong event-free and overall survival. In addition, recent studies have shown that AZA, followed by DLI, is well tolerated when administered for early AML/MDS relapse after alloHSCT.…”

Section: Introductionmentioning

confidence: 99%

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Pusic

Choi

Fiala

et al. 2015

Biology of Blood and Marrow Transplantation

152

102

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Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD) and facilitate a graft-versus-leukemia effect by enhancing the effect of T-regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplant started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10 and 15 mg/m2/day x 5 days every 6 weeks, for maximum 8 cycles. The Maximum Tolerated Dose (MTD) was defined as the maximum dose at which ≤25% of people experience dose limiting toxicities (DLT) during the 1st cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose-levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3/4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose-level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients have died due to: relapse (n=4), infectious complications (n=3) and GVHD (n=2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; one patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in post-allotransplant setting. Although MTD was not reached, the dose of 10 mg/m2 for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m2, where most hematological toxicities occurred.

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Section: Introductionmentioning

confidence: 99%

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Pusic

Choi

Fiala

et al. 2015

Biology of Blood and Marrow Transplantation

152

102

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“…The use of post-transplant therapy after ASCT is attractive. 48 Maintenance therapy post ASCT was introduced in adult ALL by the Royal Marsden team in the UK; 27 of 71 patients in CR 120 days after ASCT, those receiving two or three maintenance agents had significantly lower RI and superior LFS compared with those receiving one or none. In the Russian ALL study group, 40 which used the BEAM regimen in patients with ALL who underwent ASCT in CR1, patients also received maintenance therapy for 2 years post transplant.…”

mentioning

confidence: 99%

Autologous stem cell transplantation for adult acute leukemia in 2015: time to rethink? Present status and future prospects

Gorin

Giebel

Labopin

et al. 2015

Bone Marrow Transplant

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The use of autologous stem cell transplantation (ASCT) as consolidation therapy for adult patients with acute leukemia has declined over time. However, multiple randomized studies in the past have reported lower relapse rates after autologous transplantation compared with chemotherapy and lower non-relapse mortality rates compared with allogeneic transplantation. In addition, quality of life of long-term survivors is better after autologous transplantation than after allogeneic transplantation. Further, recent developments may improve outcomes of autograft recipients. These include the use of IV busulfan and the busulfan+melphalan combination, better detection of minimal residual disease (MRD) with molecular biology techniques, the introduction of targeted therapies and post-transplant maintenance therapy. Therefore, ASCT may nowadays be reconsidered for consolidation in the following patients if and when they reach a MRD-negative status: good-and at least intermediate-1 risk acute myelocytic leukemia in first CR, acute promyelocytic leukemia in second CR, Ph-positive acute lymphocytic leukemia. Conversely, patients with MRDpositive status or high-risk leukemia should not be considered for consolidation with ASCT.

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“…The “number needed to test” for cost-neutrality would likely be highly favorable given the considerable economic consequences of preventing an inappropriate transplant for example. Furthermore, given the rising costs of drug development and efficiency in the conduct of clinical trials required for drug approval [71] and increased focus on targeted relapse prevention with maintenance therapy [72] having quantifiable evidence of efficacy for interventions performed in the remission setting is likely to have benefit.…”

Section: What Are the Constraints That Impact Aml Mrd And Its Adoptiomentioning

confidence: 99%

Advancing the Minimal Residual Disease Concept in Acute Myeloid Leukemia

Hokland

Ommen

Mulè

et al. 2015

Seminars in Hematology

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The criteria to evaluate response to treatment in acute myeloid leukemia (AML) have changed little in the past sixty years. It is now possible to use higher sensitivity tools to measure residual disease burden in AML. Such minimal or measurable residual disease (MRD) measurements provide a deeper understanding of current patient status and allow stratification for risk of subsequent clinical relapse. Despite these obvious advantages, and after over a decade of laboratory investigation and pre-clinical validation, MRD measurements are not currently routinely used for clinical decision-making or drug development in non-APL AML. We review here some potential constraints that may have delayed adoption including a natural hesitancy of end users, economic impact concerns, misperceptions regarding the meaning of and need for assay sensitivity, the lack of one single MRD solution for all AML patients and finally the need to involve patients in decision making based on such correlates. It is our opinion that none of these issues represent insurmountable barriers and our hope is that by providing potential solutions we can help map a path forward to a future where our patients will be offered personalized treatment plans based on the amount of AML they have left remaining to treat.

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Back to the Future! The Evolving Role of Maintenance Therapy after Hematopoietic Stem Cell Transplantation

Cited by 36 publications

References 107 publications

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Maintenance Therapy with Decitabine after Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

Autologous stem cell transplantation for adult acute leukemia in 2015: time to rethink? Present status and future prospects

Advancing the Minimal Residual Disease Concept in Acute Myeloid Leukemia

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