scholarly journals Myeloablative, Intravenous Busulfan-Based Regimen Prior to Allogeneic Hematopoietic Cell Transplantation for Myeloid Malignancies is Safe and Effective in Patients Age 60 and Older

2018 ◽  
Vol 24 (3) ◽  
pp. S332-S333
Author(s):  
Catherine J. Lee ◽  
Kristen Vinik ◽  
Claudia Langebrake ◽  
Michael Boyer ◽  
Daniel R. Couriel ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Myeloid Malignancies

FLAMSA Conditioning Regimen for Allogeneic Hematopoietic Cell Transplantation in High Risk Myeloid Malignancies Is Also Feasible with Partially Mismatched Donors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3068-3068
Author(s):  
Michael Stadler ◽  
Elke Dammann ◽  
Stefanie Buchholz ◽  
Bernd Hertenstein ◽  
Juergen Krauter ◽  
...  
Keyword(s):  
High Risk ◽  
Complete Remission ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Myeloid Malignancies

Abstract BACKGROUND: A conditioning regimen for HLA-identical allogeneic hematopoietic cell transplantation in relapsed, refractory, or otherwise high risk myeloid malignancies has been developed, called FLAMSA (Schmid et al.; J Clin Oncol2005; 23: 5675–5687). This protocol combines a four-day salvage chemotherapy consisting of daily fludarabine 30 mg/m2, amsacrine 100 mg/m2, and cytarabine 2000 mg/m2, followed by three days of pause, with a reduced-intensity conditioning in the subsequent week, comprising total body irradiation 4 Gy (or busulfan 8 mg/kg), cyclophosphamide 80 or 120 mg/kg and antithymocyte globulin 30 or 60 mg/kg (for related / unrelated donors, respectively). Tapering of immunosuppression until day 90 and prophylactic donor lymphocyte infusions for patients without GvHD are integral parts of FLAMSA. This protocol has since enjoyed widespread use due to its tolerability even in patients of older age or reduced performance, as well as its salvage effect and curative potential even in patients without remission before transplantation. However, the lack of a fully HLA-matched donor might render this last chance unsuitable. Our purpose was to compare outcome after FLAMSA with HLA-identical versus partially HLA-mismatched donors. PATIENTS AND METHODS: We have employed the FLAMSA protocol in 90 patients between March 2004 and June 2007, of whom 69 (the ident group) had a fully HLA-matched related (8/8 loci) or unrelated (10/10 loci) donor and 21 (the nonident group) a partially HLA-mismatched donor (1 locus in sixteen patients, 2 loci in four and haplo-identical in one). Half were females and half males, with a median age of 54 years (range: 19 to 71 years). 39 had been diagnosed with de novo acute myeloid leukemia (AML), 39 with secondary AML, 11 with myelodysplasia and one with acute lymphoblastic leukemia. 12 were in first and 4 in subsequent complete remission, whereas 74 were untreated, refractory or in relapse. Both the ident and the nonident groups were comparable regarding gender, age, diagnoses, cytogenetic risk group, remission status at transplant, as well as cytomegalovirus and sex match with their respective donor. RESULTS: With 9.2 months (range: 0.3 to 38.2 months) median follow-up of all patients, 11/21 (52%) nonident patients are alive and 10/21 (48%) in complete remission, as compared to 39/69 (57%) ident patients (not significant). Probabilities of overall and disease-free survival at 2.5 years after allogeneic hematopoietic cell transplantation (Figure) are 43% and 35% for nonident and 45% and 41% for ident patients, respectively (p = 0.54 and p = 0.56; not significant). Treatment related mortality among nonident patients was 6/21 (29%) versus 12/69 (17%) in ident patients, whereas relapse related death occurred in 18/69 (26%) in the ident group with compared to 4/21 (19%) in the nonident group. CONCLUSION: In our single-center, retrospective comparison with limited median follow-up, both fully HLA-identical and partially HLA-mismatched donors were suitable for the FLAMSA protocol. Confirmation of this finding in a prospective study is warranted. Figure Figure

Impact of Mutations in the Spliceosome Machinery and Ring Sideroblasts in Patients with Myeloid Malignancies Who Received Conventional Chemotherapy or Allogeneic Hematopoietic Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1973-1973
Author(s):  
Betty K. Hamilton ◽  
Ali Tabarroki ◽  
Valeria Visconte ◽  
Edy Hasrouni ◽  
Hideki Makishima ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Statistical Significance ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Conventional Chemotherapy ◽  
Myeloid Malignancies ◽  
Ring Sideroblasts ◽  
The Impact

Abstract Abstract 1973 Mutations in the spliceosome machinery have recently been identified in myeloid neoplasms including acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN), and MDS/MPN overlap syndromes. Somatic alterations in SF3B1, U2AF1 and SRSF2 are the most frequently affected spliceosome genes in myeloid malignancies with the frequencies of any of the 3 genes being 39% in low risk MDS, 11% in high risk MDS/AML (primarily U2AF1), and 24% in MDS/MPN, (primarily SRSF2). While SF3B1 mutations as well as ring sideroblasts (RS) appear to be associated with improved survival and lower risk of leukemic evolution, mutations of U2AF1 and SRSF2 appear to be associated with poorer outcomes. Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for many myeloid malignancies, however, the prognostic role of SF3B1, U2AF1 or SRSF2 mutations in patients (pts) undergoing high intensity chemotherapy (HIC) and HCT has yet to be investigated. We evaluated 404 pts with the diagnosis of AML (n=96), MDS and MDS/MPN (n=294), MPN (n=13), and congenital sideroblastic anemia (n=1). 35 pts received HIC defined as treatment with 7+3, high dose cytarabine, clofarabine, or other comparable chemotherapy in the context of a clinical trial. 97 pts underwent a myeloablative (n=69) or reduced intensity (n=28) allogeneic HCT from an HLA matched related (n=39), unrelated (n=50) or cord blood (n=8) donor from April 2003 until August 2011. Median age of the whole cohort was 69 and those who underwent BMT at time of transplant was 52 (range 19–70). We performed direct sequencing for the three most commonly mutated spliceosome genes, SF3B1 (exon 13–16), SRSF2 (exon 1 and 2) and U2AF1 (exon 2–6). Given the close association between SF3B1 mutations and RS, we analyzed the impact of the presence or absence of RS on the outcomes associated with the type of therapy received. We found a total of 24 SF3B1 mutations in MDS and MDS/MPN (primarily in pts with RS), 37 SRSF2 mutations in MDS and MDS/MPN (primarily CMML), and 13 U2AF1 mutations in MDS, MDS/MPN and secondary AML. Among pts with MDS and MDS/MPN, significant overall survival (OS) differences were found between SF3B1 mutant and wild type (WT), (83 vs. 31 months, p=0.001) and U2AF1 or SRSF2 mutant (18 vs. 37 months, p=0.007). The U2AF1 mutation by itself was more strongly associated with poor outcome (8 vs. 37 months, p<0.0001), compared to an SRSF2 mutation (26 vs. 36 months, p=0.16). Analysis of survival according to treatment type revealed that no pts who underwent HIC or HCT carried an SF3B1 mutation. The presence of RS was also associated with improved survival (38 vs. 25 months, p=0.04), and this benefit remained if pts received HIC (18 vs. 9 months, p=0.04). However, this benefit became non-significant if pts underwent HCT. There were 19 pts who had either an U2AF1 or SRSF2 mutation that underwent HIC. Although it appeared that having either mutation was associated with worse survival, (9 vs. 21 months), it did not reach statistical significance (p=0.46). Among pts who underwent HCT, there were 10 pts who carried either an U2AF1 or SRSF2 mutation. Those pts with mutations appeared to have superior survival with HCT compared to WT, (53 vs. 34 months), but this did not reach statistical significance (p=0.54). Among pts with either an U2AF1 or SRSF2 mutation, those who underwent HCT had a superior survival (53 vs. 17 months, p=0.05) compared to those who received conventional chemotherapy, defined as HIC or low intensity chemotherapy (LIC), such as hypomethylating agents. There was no difference in survival between receiving HCT or conventional chemotherapy in pts who were WT for U2AF1 or SRSF2 (34 vs. 31 months, p=0.08). Consistent with previous findings of improved survival and loss of SF3B1 with leukemic progression in MDS and MDS/MPN pts, we found no SF3B1 mutations in our cohort of pts receiving HIC or HCT. In contrast, we found poorer outcomes with SRSF2 or U2AF1 mutations. Although the incidence of these mutations was rare in our cohort of pts, we found statistically significant survival benefit for pts with these mutations if they underwent HCT compared to conventional chemotherapy. This is the first study evaluating the impact of spliceosomal mutations on the survival outcomes of pts undergoing HCT. Our preliminary findings of improved survival with HCT in poorer-risk spliceosome mutations is provoking and further molecular analysis is ongoing. Disclosures: Maciejewski: NIH: Research Funding; Aplastic Anemia&MDS International Foundation: Research Funding.

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