Impact of FLT3 Internal Tandem Duplication on the Outcome of Related and Unrelated Hematopoietic Transplantation for Adult Acute Myeloid Leukemia in First Remission: A Retrospective Analysis

Brunet, Salut; Labopin, Myriam; Esteve, Jordi; Cornelissen, Jan J.; Socié, Gérard; Iori, Anna Paola; Verdonck, Leo F.; Volin, Liisa; Gratwohl, Aloïs; Sierra, Jorge; Mohty, Mohamad; Rocha, Vanderson

doi:10.1200/jco.2011.36.9868

Cited by 258 publications

(223 citation statements)

References 33 publications

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“…The lack of significant association between conventional cytogenetics or FLT3 mutations and prognosis in our series, contrary to AML cohorts after first allo-SCT, 26,27 suggests the selection of other adverse biologic factors in these very high-risk patients. Such defects, like the loss of HLA heterozygosity in leukaemic blasts, were recently demonstrated by more sensitive methods, such as genome-wide profiling.…”

Section: Discussioncontrasting

confidence: 40%

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML

Christopoulos

Schmoor

Waterhouse

et al. 2013

Bone Marrow Transplant

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A second allograft was offered to 58 relapsed AML patients after conditioning with fludarabine 90-150 mg/m 2 and thiotepa 15 mg/kg, in most cases with active disease. Median age was 53 years (range 23-69), median time to relapse after the first allo-SCT was 326 (47-2189) days and median follow-up was 6.7 years. GVHD prophylaxis consisted mainly of CsA and alemtuzumab. Response rates at 1 month were CR in 50 and persistent disease in 3/53 evaluable patients. At 3 years, the relapse incidence (95% confidence interval) was 56 (45-71)%, the TRM 31 (21-46)%, the OS rate was 18 (9-29)% and the EFS rate was 13 (5-23)%. OS improved with younger patient age, longer relapse-free interval after the first allo-SCT and the development of chronic GVHD. Patients p65 years old who relapsed 412 months after the first allograft (n ¼ 20) had a 3-year OS rate of 41 (19-62)%. Conventional cytogenetics and FLT3 mutation status did not affect outcome. Our regimen is feasible and provides at least for a subgroup of patients with AML recurrence after allo-SCT a reasonable therapeutic option in an otherwise fatal situation. Further modifications and a better understanding of the underlying biology could help lower the risk of relapse. INTRODUCTIONFor patients with AML, relapsing after allo-SCT prognosis is very poor. A second allograft is currently the only therapeutic approach capable of inducing long-term remissions in patients who cannot be salvaged with DLI. 1,2 This approach has, however, two main limitations. First, many of these patients cannot tolerate a second allo-SCT because of accumulated organ toxicities and opportunistic infections, which increase the risk for TRM and severe GVHD. 3,4 Second, despite high TRM and GVHD rates, relapse remains the main cause of death in this very high-risk patient population. [5][6][7][8] The concept of allo-SCT with reduced-intensity conditioning (RIC) is based on the notion that the GVL contributes significantly to the curative potential. This permits dose reductions of preparative chemotherapy or radiation with a lower overall toxicity. 9 In 2008, we reported the results of a phase II RIC trial using fludarabine 5 Â 30 mg/m 2 and thiotepa 3 Â 5 mg/kg in patients with recurrent or persistent haematological malignancies after a previous auto-or allo-SCT. 3 In this series, a TRM (95% confidence interval) of 29 (14-44)% at 2 years despite heavy pretreatment demonstrated the feasibility of our regimen, but the low number of patients in each diagnostic subgroup and the relatively short follow-up precluded a thorough evaluation of efficacy.Here we analyse the long-term outcome of a larger, homogeneous patient cohort with AML at relapse after first allo-SCT treated in a similar manner.

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Section: Discussioncontrasting

confidence: 40%

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML

Christopoulos

Schmoor

Waterhouse

et al. 2013

Bone Marrow Transplant

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“…(1) AML patients with FLT3 gene internal tandem duplication (ITD) have a poor outcome, with a median overall survival of 13.1 months. (2) Although AML patients with FLT3-ITD benefit from allogeneic HSCT in first complete remission (CR1), (3) it has been shown that this subset of patients are at increased risk of relapse after HSCT. (3,4) Post-transplant relapsed AML is associated with a high mortality rate.…”

Section: Introductionmentioning

confidence: 99%

“…(2) Although AML patients with FLT3-ITD benefit from allogeneic HSCT in first complete remission (CR1), (3) it has been shown that this subset of patients are at increased risk of relapse after HSCT. (3,4) Post-transplant relapsed AML is associated with a high mortality rate. The use of chemotherapy followed by donor lymphocyte infusion (DLI) can provide long-term remission in less than 20% of patients.…”

Section: Introductionmentioning

confidence: 99%

Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases

Campregher

Mattos

Salvino

et al. 2017

Einstein (São Paulo)

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This content is licensed under a Creative Commons Attribution 4.0 International License.Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases ABSTRACTAcute myeloid leukemia is a hematopoietic stem cell neoplastic disease associated with high morbidity and mortality. The presence of FLT3 internal tandem duplication mutations leads to high rates of relapse and decreased overall survival. Patients with FLT3 internal tandem duplication are normally treated with hematopoietic stem cell transplantation in first complete remission. Nevertheless, the incidence of post-transplant relapse is considerable in this group of patients, and the management of this clinical condition is challenging. The report describes the outcomes of patients with FLT3 internal tandem duplication positive acute myeloid leukemia who relapsed after allogeneic hematopoietic stem cell transplantation and were treated with the combination of re-induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Three cases are described and all patients achieved prolonged complete remission with the combined therapy. The combination of induction chemotherapy followed by donor lymphocyte infusion, and the maintenance with azacitidine and sorafenib can be effective approaches in the treatment of post-hematopoietic stem cell transplant and relapsed FLT3 internal tandem duplication positive acute myeloid leukemia patients. This strategy should be further explored in the context of clinical trials.

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“…Although direct comparisons are limited, outcomes after alloHCT generally compare favorably to chemotherapy-based approaches with overall survival (OS) at two or more years as high as 60%, although results are variable. [2][3][4][5] Unfortunately, many patients lack a suitable HLA-matched donor, precluding alloHCT consolidation. Umbilical cord blood (UCB) transplantation provides an alternative donor source for alloHCT and has given promising results in many hematologic malignancies.…”

mentioning

confidence: 99%

“…1 FLT3-ITD + AML is associated with an increased risk of relapse and shorter overall survival. 1,2 Because of this, allogeneic hematopoietic cell transplantation (alloHCT) has been commonly used for consolidation of FLT3-ITD + AML patients. Although direct comparisons are limited, outcomes after alloHCT generally compare favorably to chemotherapy-based approaches with overall survival (OS) at two or more years as high as 60%, although results are variable.…”

mentioning

confidence: 99%

Umbilical cord blood transplantation is a suitable option for consolidation of acute myeloid leukemia with FLT3-ITD

et al. 2016

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Impact of FLT3 Internal Tandem Duplication on the Outcome of Related and Unrelated Hematopoietic Transplantation for Adult Acute Myeloid Leukemia in First Remission: A Retrospective Analysis

Cited by 258 publications

References 33 publications

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML

Reduced-intensity conditioning with fludarabine and thiotepa for second allogeneic transplantation of relapsed patients with AML

Successful treatment of post-transplant relapsed acute myeloid leukemia with FLT3 internal tandem duplication using the combination of induction chemotherapy, donor lymphocyte infusion, sorafenib and azacitidine. Report of three cases

Umbilical cord blood transplantation is a suitable option for consolidation of acute myeloid leukemia with FLT3-ITD

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