Risk factors for outcome in refractory acute myeloid leukemia patients treated with a combination of fludarabine, cytarabine, and amsacrine followed by a reduced-intensity conditioning and allogeneic stem cell transplantation

Pfrepper, Christian; Klink, Anne; Behre, Gerhard; Schenk, Thomas; Franke, Georg‐Nikolaus; Jentzsch, Madlen; Schwind, Sebastian; Al-Ali, Haifa Kathrin; Hochhaus, Andreas; Niederwieser, Dietger; Sayer, Herbert G.

doi:10.1007/s00432-015-2050-y

Cited by 22 publications

(25 citation statements)

References 22 publications

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“…Our results showing a 2‐year OS of about 40% compared favorably with previous series of MAC and sequential HSCT in relapsing or refractory AML . Patients from two groups did not differ in regards to their major characteristics, especially the distribution between refractory and relapsed leukemia.…”

Section: Discussionsupporting

confidence: 76%

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Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

et al. 2018

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Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18-50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty-eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow-up of 48 months, 2-year overall survival was 39%, 95% confidence interval (CI) (24-53) in the myeloablative group versus 33%, 95% CI (21-45) in the sequential groups (P = .39), and 2-year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II-IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21-0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.

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Section: Discussionsupporting

confidence: 76%

“…That is lower than previously reported in the experience of the German group . However, in most studies of SEQ transplant, prophylactic DLI did not exceed 25%, due to early transplant mortality, early relapse or GVHD occurrence, actually showing the poor feasibility of this strategy.…”

Section: Discussioncontrasting

confidence: 57%

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

et al. 2018

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“…This sequential strategy, employing a T‐cell depleted transplant platform to reduce toxicity and planned donor lymphocyte infusion (DLI) to strengthen donor immune graft‐versus‐leukaemia (GvL) effects, resulted in improved outcomes for patients with relapsed/refractory AML and high‐risk MDS. Subsequently, several other groups have reported successful application of sequential chemotherapy and AHST using a variety of RIC regimens, confirming the utility of this approach (Liu et al , ; Cluzeau et al , ; Buchholz et al , ; Chemnitz et al , ; Saure et al , ; Krejci et al , ; Schneidawind et al , ; Pfrepper et al , ). However, all used T‐cell depletion with anti‐thymocyte globulin, which increases viral infection after AHST (Hamadani et al , ) and may increase relapse after RIC regimens (Soiffer et al , ).…”

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confidence: 78%

“…A major potential advantage for using a T‐replete transplant platform is that high levels of donor chimerism, particularly T‐cell chimerism, can be achieved spontaneously without DLI, whereas persistent split chimerism, particularly in the T‐cell lineage, is common after T‐cell depleted approaches and DLI is more frequently required to augment chimerism levels (Dey et al , ; Shaw et al , ). Previous early AHST or sequential AHST strategies for relapsed/refractory AML have used T‐cell depletion either for all patients (Schmid et al , ; Cluzeau et al , ; Buchholz et al , ; Chemnitz et al , ; Krejci et al , ; Pfrepper et al , ) or for patients receiving transplants from unrelated donors (Platzbecker et al , ; Liu et al , ; Saure et al , ; Stolzel et al , ; Schetelig et al , ) with the majority administering planned DLI. In contrast, almost all of our assessable patients achieved full donor chimerism spontaneously despite the truly non‐myeloablative conditioning employed.…”

Section: Discussionmentioning

confidence: 99%

Durable graft‐versus‐leukaemia effects without donor lymphocyte infusions – results of a phase II study of sequential T‐replete allogeneic transplantation for high‐risk acute myeloid leukaemia and myelodysplasia

et al. 2017

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Allogeneic haematopoietic stem-cell transplantation remains the only curative treatment for relapsed/refractory acute myeloid leukaemia (AML) and high-risk myelodysplasia but has previously been limited to patients who achieve remission before transplant. New sequential approaches employing T-cell depleted transplantation directly after chemotherapy show promise but are burdened by viral infection and require donor lymphocyte infusions (DLI) to augment donor chimerism and graft-versus-leukaemia effects. T-replete transplantation in sequential approaches could reduce both viral infection and DLI usage. We therefore performed a single-arm prospective Phase II clinical trial of sequential chemotherapy and T-replete transplantation using reduced-intensity conditioning without planned DLI. The primary endpoint was overall survival. Forty-seven patients with relapsed/refractory AML or high-risk myelodysplasia were enrolled; 43 proceeded to transplantation. High levels of donor chimerism were achieved spontaneously with no DLI. Overall survival of transplanted patients was 45% and 33% at 1 and 3 years. Only one patient developed cytomegalovirus disease. Cumulative incidences of treatment-related mortality and relapse were 35% and 20% at 1 year. Patients with relapsed AML and myelodysplasia had the most favourable outcomes. Late-onset graft-versus-host disease protected against relapse. In conclusion, a T-replete sequential transplantation using reduced-intensity conditioning is feasible for relapsed/refractory AML and myelodysplasia and can deliver graft-versus-leukaemia effects without DLI.

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“…24,25 The regimen consisted of fludarabine, cytarabine and amsacrine, followed after 3 days of rest and then by a 4-Gy TBI, cyclophosphamide and ATG-based reduced-intensity conditioning and allotransplant from related or unrelated donors. In the original study by Schmid et al, 23 patients who did not develop GVHD by post-transplant day +120 received a prophylactic donor lymphocyte infusion (DLI).…”

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confidence: 99%

Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy

Gyurkocza

Lazarus

Giralt

2017

Bone Marrow Transplant

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Patients with acute myeloid leukemia (AML) who fail to achieve complete remission (CR) have a dismal prognosis. Although data suggest that durable remissions can be achieved in approximately 30% of patients with refractory or relapsed AML after allogeneic hematopoietic cell transplantation (HCT), only a small fraction of those patients are offered this therapeutic option. Importantly, patients with primary refractory AML have distinctly better outcomes following allogeneic HCT than those with refractory relapse. Access to suitable donors could be one of the main barriers in these situations. However, with recent developments in the field of allogeneic HCT, such as alternative donor sources, high-resolution HLA-typing, reduced intensity conditioning regimens and improvements in supportive care, this approach has the potential to offer long-term survival for patients with refractory and relapsed AML and should be considered as early after diagnosis as possible. Incorporating novel agents into the conditioning regimen or as post-transplant maintenance therapy could further improve outcomes and render older or medically infirm patients with refractory or relapsed AML eligible for allogeneic HCT. In this review, we summarize existing data on allogeneic HCT in patients with refractory or relapsed AML and explore novel approaches with the potential to improve outcomes in this patient population.

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Risk factors for outcome in refractory acute myeloid leukemia patients treated with a combination of fludarabine, cytarabine, and amsacrine followed by a reduced-intensity conditioning and allogeneic stem cell transplantation

Abstract: FLAMSA-RIC shows long-term survival in refractory AML patients. Factors for favorable outcome are <20 % bone marrow blasts prior to HCT, <3 lines of pretreatment and complete donor chimerism after HCT.

Cited by 22 publications

References 22 publications

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Durable graft‐versus‐leukaemia effects without donor lymphocyte infusions – results of a phase II study of sequential T‐replete allogeneic transplantation for high‐risk acute myeloid leukaemia and myelodysplasia

Allogeneic hematopoietic cell transplantation in patients with AML not achieving remission: potentially curative therapy

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