scholarly journals A Phase II Multicenter Study of the Addition of Azacitidine to Reduced-Intensity Conditioning Allogeneic Transplant for High-Risk Myelodysplasia (and Older Patients with Acute Myeloid Leukemia): Results of CALGB 100801 (Alliance)

2019 ◽  
Vol 25 (10) ◽  
pp. 1984-1992 ◽  
Author(s):  
Ravi Vij ◽  
Jennifer Le-Rademacher ◽  
Kristina Laumann ◽  
Vera Hars ◽  
Kouros Owzar ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Phase Ii ◽  
Multicenter Study ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Allogeneic Transplant ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity ◽  
Acute Myeloid

Sequential Chemotherapy Followed By Reduced Intensity Conditioning and Allogeneic Hematopoietic Transplantation For High Risk Acute Myeloid Leukemia Patients In First Complete Remission: A Prospective Pilot Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2162-2162
Author(s):  
Mauricette Michallet ◽  
Mohamad Sobh ◽  
Marie Y. Detrait ◽  
Helene Labussiere ◽  
Sandrine Hayette ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myeloid Leukemia ◽  
Reduced Intensity Conditioning ◽  
Secondary Aml ◽  
Prospective Pilot Study ◽  
First Complete Remission ◽  
Reduced Intensity ◽  
Acute Myeloid

Abstract Advances in chemotherapy have improved the prognosis of patients with acute myeloid leukemia (AML), however, high-risk patients still have a poor outcome. In this category of patients, the only therapeutic strategy with curative potential remains allogeneic hematopoietic stem cell transplantation (allo-HSCT). With the aim to improve the effect of allo-HSCT by sequential use of chemotherapy followed by reduced intensity conditioning (RIC), we conducted a prospective pilot study in high-risk AML patients in first complete remission (CR1). The high-risk population included intermediate II [t(9;11)(p22;q23); MLLT3-MLL, cytogenetic abnormalities not classified as favorable or adverse] and unfavourable patients [inv(3)(q21q26.2) or t(3;3)(q21;q26.2); t(6;9)(p23;q34); t(v;11)(v;q23); MLL rearranged, -5 or del(5q); -7; abnl(17p); complex karyotype] (Dohner et al. Blood 2010), secondary AML, and patients requiring 2 induction courses to obtain CR. The chemotherapy sequential regimen consisted in fludarabine 30 mg/m2, high-dose cytarabine 2 g/m2, and amsacrine 100 mg/m2 from days -12 to -9 (FLAMSA). After 3 days of rest, RIC consisted of 4 Gy total-body irradiation (TBI) on day -5, cyclophosphamide (40 mg/kg with HLA-identical sibling, 60 mg/kg for unrelated or mismatched donors) on days -4 and -3, and rabbit antithymocyte globulin (ATG, Genzyme) (5 mg/kg total dose) from day -3 to day -1. As a new experimental approach, we replaced TBI by iv. busulfan (BU) (Busilvex, Pierre Fabre) 3.2 mg/kg/d during either 4 or 2 days according to patient age (>55 years) (from day -7 to -4 or from day -5 to -4). Peripheral-blood stem cells (PBSC) were preferred; bone marrow (BM) and cord blood (CB) were also accepted. Graft-versus-host disease (GvHD) prophylaxis consisted in ciclosporine from day -1, and mycophenolate mofetil (15 mg/kg bid), starting from day 0. In the absence of GvHD, MMF was discontinued by day+50 and ciclosporine was tapered from day +60 to +90. Except for cord blood transplantation, patients received 3 prophylactic increased doses of donor lymphocyte infusions (DLI) if they were in CR and GvHD-free at day +120 or 30 days after discontinuation of immunosuppressive agents starting at 1x106 CD3+ cells/kg. Between August 2010 and March 2013, 26 consecutive AML patients in CR1 were included; 11 males and 15 females with a median age at allo-HSCT of 55 years (range: 24-67), 19 (73%) were de novo AML and 7 (27%) secondary AML. According to cytogenetics and molecular markers, 22 (85%) were unfavourable and 4 (15%) were in intermediate II category. Before allo-HSCT, to reach CR1, 20 (77%) patients received one induction chemotherapy and 6 (23%) needed 2 inductions. Cell source was PBSC for 23 (88%) patients, CB for 2 and BM for 1 patient. Donors were 10/10 HLA matched siblings in 9 (35%) patients, 10/10 HLA matched unrelated in 8 (31%) patients and HLA mismatched for the rest of patients [unrelated 9/10 (n=7), CB 4/6 (n=2)]. For ABO compatibility, 13 (50%) were compatible, 5 (19%) had minor incompatibility and 8 (31%) had major incompatibility. For conditioning, 6 (23%) patients received TBI, 13 (50%) received 4 days BU and 7 (27%) received 2 days BU. After transplantation, 23 (88%) patients engrafted, 3 patients died early (1 at day 1 and 1 at day 2 both from septic shock; 1 at day 8 from pneumonia and pericardial effusion). At day 90 post-allo-HSCT, 18 (78%) showed total donor chimerism and 5 (22%) had mixed chimerism and all patients were in CR. There were 6/23 (26%) patients with acute GvHD [2 gr I, 2 gr II and 2 gr III] and 5/23 (22%) chronic GvHD [4 limited and 1 extensive], all before DLI. After a median follow-up of 9 months (range: 0.03-35), the 2-years probability of overall survival (OS) for the whole population was 58% (confidence interval: 47-69) (Figure 1a) and the 2 years cumulative incidence of relapse was 18% (confidence interval: 17-19). At the latest follow-up, 16/23 (70%) engrafted patients were alive, 4/23 (17%) patients relapsed and died later and 3/23 (13%) patients died from transplant related infectious complications. No statistical difference in terms of OS and relapse incidence was found between the 3 types of conditioning, (Figure 1b). FLAMSA-RIC regimen followed by allo-HSCT showed promising results in high-risk CR1 AML patients. Because of some early severe infections, an efficient prophylactic anti-infectious strategy is recommended. The use of BU instead of TBI does not impact on transplant outcomes. Disclosures: No relevant conflicts of interest to declare.

Allogeneic hematopoietic cell transplantation for adults with acute myeloid leukemia: myths, controversies, and unknowns

Blood ◽  
2011 ◽  
Vol 117 (8) ◽  
pp. 2307-2318 ◽  
Author(s):  
Vikas Gupta ◽  
Martin S. Tallman ◽  
Daniel J. Weisdorf
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity ◽  
Acute Myeloid

AbstractProgress in the last decade has improved the understanding of leukemia biology. Molecular markers in combinations with cytogenetics have improved the risk stratification of acute myeloid leukemia (AML) and informed decision-making. In parallel, several important advances in the transplant field, such as better supportive care, improved transplant technology, increased availability of alternative donors, and reduced-intensity conditioning have improved the safety as well as access of allogeneic hematopoietic cell transplantation (HCT) for a larger number of patients. In this review, the positioning of HCT in the management of patients with AML is evaluated in view of changing risk/benefit ratios associated with both conventional treatments and transplantation, and some of the controversies are addressed in light of emerging data. Increasing data demonstrate outcomes of alternative donor transplantation approaching HLA-identical sibling donors in high-risk AML supporting the inclusion of alternative donors in trials of prospective studies evaluating post remission strategies for high-risk AML. The use of reduced-intensity conditioning has expanded the eligibility of HCT to older patients with AML, and outcome data are encouraging. Continued study of HCT versus alternative therapies is required to optimize patients' outcomes in AML.

Sustained Remissions of High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome After Reduced-Intensity Conditioning Allogeneic Hematopoietic Transplantation: Chronic Graft-Versus-Host Disease Is the Strongest Factor Improving Survival

2008 ◽  
Vol 26 (4) ◽  
pp. 577-584 ◽  
Author(s):  
David Valcárcel ◽  
Rodrigo Martino ◽  
Dolores Caballero ◽  
Jesus Martin ◽  
Christelle Ferra ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Graft Versus Host Disease ◽  
Myeloid Leukemia ◽  
Chronic Gvhd ◽  
Reduced Intensity Conditioning ◽  
Graft Versus Host ◽  
Reduced Intensity ◽  
Acute Myeloid

Purpose Reduced-intensity conditioning (RIC) for allogeneic stem-cell transplantation (allo-SCT) reduces nonrelapse mortality (NRM). This reduction makes it possible for patients who are ineligible for high-dose myeloablative conditioning allo-SCT to benefit from graft-versus-leukemia reaction. In this multicenter, prospective study of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of RIC allo-SCT from a human leukocyte antigen–identical sibling by using a regimen that uses fludarabine and busulfan. Patients and Methods Ninety-three patients with AML (n = 59) and MDS (n = 34) were included, and the median age was of 53 years. Follow-up for survivors was 43 months (range, 3 to 89 months). The conditioning regimen consisted of fludarabine (150 mg/m2) and oral busulfan (8 to 10 mg/kg). All except one patient received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine and methotrexate or mycophenolate mofetil. Results The 100-day, 1-year, and 4-year incidences of NRM were 8, 16%, and 21%, respectively. The 1- and 4-year relapse cumulative incidences were 23% and 37%, respectively, and leukemia recurrence was the main cause of death. The 4-year disease-free survival (DFS) and overall survival (OS) rates were 43% and 45%, respectively. The 4-year cumulative incidence of chronic GVHD was 53% (45% extensive), and its development was the major factor associated with lower relapse incidence and improved DFS and OS. Conclusion Our results confirm the capacity of this RIC regimen to obtain long-term remissions in patients ineligible for a conventional allo-SCT. The results suggest an important role of the development of chronic GVHD in reducing relapse and improving DFS and OS.

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