Azacitidine after allo-SCT: the good without the bad?

Mohty, Mohamad; Chevallier, Patrice

doi:10.1182/blood-2012-02-406678

Cited by 16 publications

(17 citation statements)

References 11 publications

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“…Another strategy used to prevent AML relapse after alemtuzumab-based RIC has been based on the pre-emptive administration of azacitidine which can likely favor the GVT effect without excessive GVHD. 36,37 Besides the impact of in vivo T-cell depletion on outcomes, this study also confirmed the negative impact of poor risk cytogenetics, 23,38,39 of being transplanted with a female donor in case of male recipients, 40 and of being transplanted in low-activity centers 18,22 on OS and PFS, as previously observed by our group 18,22,38,41 and by other groups of investigators. 39,40 Further, in contrast to what was observed in a recent CIBMTR study, 39 current data suggest that older patient age at transplantation is associated with higher NRM translating to worse LFS and OS in multivariate analyses.…”

Section: Discussionsupporting

confidence: 77%

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Baron

Labopin

Blaise³

et al. 2014

Bone Marrow Transplant

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The impact of in vivo T-cell depletion on transplantation outcomes in patients transplanted with reduced-intensity conditioning (RIC) remains controversial. This study assessed the outcome of 1250 adult patients with de novo AML in first CR (CR1) given PBSC from HLA-identical siblings after chemotherapy-based RIC. A total of 554 patients did not receive any form of in vivo T-cell depletion (control group), whereas antithymocyte globulin (ATG) and alemtuzumab were given in 444 and 252 patients, respectively. The incidences of grade II-IV acute GVHD were 21.4, 17.6 and 10.2% in control, ATG and alemtuzumab patients, respectively (Po0.001).In multivariate analysis, the use of ATG and the use of alemtuzumab were each associated with a lower risk of chronic GVHD (Po0.001 each), but a similar risk of relapse, and of nonrelapse mortality, and similar leukemia-free survival and OS. Further, among patients given BU-based RIC, the use of o6 mg/kg ATG did not increase the risk of relapse (hazard ratio, HR ¼ 1.1), whereas there was a suggestion for higher relapse risk in patients given X6 mg/kg ATG (HR ¼ 1.4, P ¼ 0.08). In summary, these data suggest that a certain amount of in vivo T-cell depletion can be safely used in the conditioning of AML patients in CR1 given PBSC after chemotherapy-based RIC. INTRODUCTIONThe use of PBSC instead of BM in patients receiving grafts from HLA-matched donors after myeloablative conditioning has been associated with faster hematological recovery, lower relapse risk in patients with advanced disease (due to higher immune-mediated graft-versus-tumor (GVT) effects), but also higher incidence extensive chronic GVHD. 1-4 These observations prompted several groups of investigators to study in vivo T-cell depletion of the graft with antithymocyte globulin (ATG) or alemtuzumab as a way to reduce severe GVHD in patients given PBSC after highdose myeloablative conditioning regimen. [5][6][7] These studies demonstrated that the use of ATG or alemtuzumab was successful at preventing severe GVHD without apparently increasing the relapse incidence (RI). [5][6][7] In contrast to patients given grafts after myeloablative conditioning who benefit from both the high-dose chemo/radiotherapy given as part of the conditioning regimen and the GVT effect for tumor eradication,

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Section: Discussionsupporting

confidence: 77%

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Baron

Labopin

Blaise³

et al. 2014

Bone Marrow Transplant

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“…26 Furthermore, it is likely that maintenance therapies should be considered in most of these patients in order to achieve long-term disease control after transplant. 27 In conclusion, this analysis suggests that allo-SCT may be of some benefit as salvage therapy in specific subgroups of adult patients with active or progressive disease at the time of transplant. Increasing disease control with novel agents as a bridge to transplant, 28,29 and the use of maintenance strategies after allo-SCT, may allow for further optimizing the results of these highly poor-risk patients.…”

Section: Discussionmentioning

confidence: 99%

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Chevallier

Labopin

Milpied

et al. 2013

Bone Marrow Transplant

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for the SFGM-TC Previous data suggested that allo-SCT might be an effective therapy in the setting of chemo-refractory/relapsed diseases because of the potent long-term immune-mediated tumor control. This retrospective study aimed to analyze the outcome of adult patients who received allo-SCT in a chemo-refractory/relapsed status. The series included 840 patients with active or progressive disease at the time of transplant. Median age was 50 years. With a median follow-up of 40 months, 3-year OS, disease-free survival (DFS), and non-relapse mortality rates were 29 ± 2, 23 ± 2, and 30 ± 2%, respectively. At the last follow-up, 252 patients (30%) were still alive (of whom 201 were in CR (24%). In a Cox multivariate analysis, the use of a reduced-intensity conditioning (RIC) before allo-SCT and use of an HLA-identical sibling donor remained independently associated with a better OS (hazard ratio (HR) ¼ 0.82; 95% confidence interval (CI), 0.69-0.98, P ¼ 0.03; and HR ¼ 0.79; 95% CI, 0.66-0.93, P ¼ 0.006, respectively). Also, a diagnosis of myelodysplastic syndrome/myeloproliferative disorder, Hodgkin lymphoma and non-Hodgkin lymphoma compared with acute leukemia had a favorable impact on OS (HR ¼ 0.55; 95% CI, 0.45-0.68, Po0.0001; HR ¼ 0.49; 95% CI, 0.31-0.75, P ¼ 0.001; and HR ¼ 0.47; 95% CI, 0.35-0.63, Po0.0001, respectively). In conclusion, this study suggests that allo-SCT may be of benefit in some subgroups of patients with active or progressive hematological malignancies at the time of allo-SCT.

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“…AZA also has the capacity to up-regulate the expression of epigenetically silenced tumor antigens, and can induce a CD8 + T-cell response to tumor antigens post transplant, raising the possibility that it may have the potential to augment a graft-versus-leukemia (GvL) response. 8,9 A number of small series have reported that AZA can induce remissions in patients who relapse after an allogeneic transplant, raising the possibility that this agent represents a potential new treatment strategy in this challenging patient population. [10][11][12] Furthermore, it has been suggested in single arm studies that AZA may augment the anti-tumor activity of DLI in patients who relapse after an allograft.…”

Section: Clinical Activity Of Azacitidine In Patients Whomentioning

confidence: 99%

“…Prospective studies to confirm optimal treatment options in this challenging patient population are required. relapse after allogeneic stem cell transplantation for acute myeloid leukemia Charles Craddock, 1 Myriam Labopin, 2 Marie Robin, 3 Juergen Finke, 4 Patrice Chevallier, 5 Ibrahim Yakoub-Agha, 6 Jean Henri Bourhis, 7 Henrik Sengelov, 8 Didier Blaise, 9 Thomas Luft, 10 Michael Hallek, 11 Nicolaus Kröger, 12 Arnon Nagler, *13 and Mohamad Mohty developing effective treatment options for patients with recurrent disease after allogeneic SCT, and the great majority remain destined to die of resistant disease. 3 Although a small number of patients with disease recurrence can survive long term after a second transplant or donor lymphocyte infusion (DLI), the success of both these treatment modalities is contingent on the prior acquisition of morphological remission with salvage therapy.…”

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confidence: 99%

Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

et al. 2016

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Disease relapse is the most common cause of treatment failure after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndromes, yet treatment options for such patients remain extremely limited. Azacitidine is an important new therapy in high-risk myelodysplastic syndromes and acute myeloid leukemia but its role in patients who relapse post allograft has not been defined. We studied the tolerability and activity of azacitidine in 181 patients who relapsed after an allograft for acute myeloid leukemia (n=116) or myelodysplastic syndromes (n=65). Sixtynine patients received additional donor lymphocyte infusions. Forty-six of 157 (25%) assessable patients responded to azacitidine therapy: 24 (15%) achieved a complete remission and 22 a partial remission. Response rates were higher in patients transplanted in complete remission (P=0.04) and those transplanted for myelodysplastic syndromes (P=0.023). In patients who achieved a complete remission, the 2-year overall survival was 48% versus 12% for the whole population. Overall survival was determined by time to relapse post transplant more than six months (P=0.001) and percentage of blasts in the bone marrow at time of relapse (P=0.01). The concurrent administration of donor lymphocyte infusion did not improve either response rates or overall survival in patients treated with azacitidine. An azacitidine relapse prognostic score was developed which predicted 2-year overall survival ranging from 3%-37% (P=0.00001). We conclude that azacitidine represents an important new therapy in selected patients with acute myeloid leukemia/myelodysplastic syndromes who relapse after allogeneic stem cell transplantation. Prospective studies to confirm optimal treatment options in this challenging patient population are required.

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Azacitidine after allo-SCT: the good without the bad?

Cited by 16 publications

References 11 publications

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Impact of in vivo T-cell depletion on outcome of AML patients in first CR given peripheral blood stem cells and reduced-intensity conditioning allo-SCT from a HLA-identical sibling donor: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation

Outcomes of adults with active or progressive hematological malignancies at the time of allo-SCT: a survey from the Société Française de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)

Clinical activity of azacitidine in patients who relapse after allogeneic stem cell transplantation for acute myeloid leukemia

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