Betty K. Hamilton

Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI

Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

Secondary solid cancer screening following hematopoietic cell transplantation.

Hematopoietic stem cell transplant (HCT) recipients have a substantial risk of developing secondary solid cancers, particularly beyond 5 years after HCT and without reaching a plateau overtime. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to facilitate implementation of cancer screening appropriate to HCT recipients. The working group reviewed guidelines and methods for cancer screening applicable to the general population and reviewed the incidence and risk factors for secondary cancers after HCT. A consensus approach was used to establish recommendations for individual secondary cancers. The most common sites include oral cavity, skin, breast and thyroid. Risks of cancers are increased after HCT compared with the general population in skin, thyroid, oral cavity, esophagus, liver, nervous system, bone and connective tissues. Myeloablative TBI, young age at HCT, chronic GVHD and prolonged immunosuppressive treatment beyond 24 months were well-documented risk factors for many types of secondary cancers. All HCT recipients should be advised of the risks of secondary cancers annually and encouraged to undergo recommended screening based on their predisposition. Here we propose guidelines to help clinicians in providing screening and preventive care for secondary cancers among HCT recipients.

Concise Review: The Role of Hematopoietic Stem Cell Transplantation in the Treatment of Acute Myeloid Leukemia

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative option for patients with acute myeloid leukemia (AML). Our understanding of the biology of leukemic stem cells has continued to improve over the last decade and risk stratification using cytogenetics and molecular markers have improved our ability to select patients who would benefit from allogeneic transplantation. Results of HSCT have also improved substantitally, extending the potential application of allogeneic transplant to more patients. This review discusses the theoretical aspects of transplant, analyzes clinical results, and provides recommendations for the use of HSCT in AML. Further study of the biology of leukemic stem cells and the role for HSCT is necessary to optimize outcomes in AML patients. STEM CELLS2012;30:1581–1586

Scoring System Prognostic of Outcome in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome

PURPOSE To develop a system prognostic of outcome in those undergoing allogeneic hematopoietic cell transplantation (allo HCT) for myelodysplastic syndrome (MDS). PATIENTS AND METHODS We examined 2,133 patients with MDS undergoing HLA-matched (n = 1,728) or -mismatched (n = 405) allo HCT from 2000 to 2012. We used a Cox multivariable model to identify factors prognostic of mortality in a training subset (n = 1,151) of the HLA-matched cohort. A weighted score using these factors was assigned to the remaining patients undergoing HLA-matched allo HCT (validation cohort; n = 577) as well as to patients undergoing HLA-mismatched allo HCT. RESULTS Blood blasts greater than 3% (hazard ratio [HR], 1.41; 95% CI, 1.08 to 1.85), platelets 50 × 10(9)/L or less at transplantation (HR, 1.37; 95% CI, 1.18 to 1.61), Karnofsky performance status less than 90% (HR, 1.25; 95% CI, 1.06 to 1.28), comprehensive cytogenetic risk score of poor or very poor (HR, 1.43; 95% CI, 1.14 to 1.80), and age 30 to 49 years (HR, 1.60; 95% CI, 1.09 to 2.35) were associated with increased hazard of death and assigned 1 point in the scoring system. Monosomal karyotype (HR, 2.01; 95% CI, 1.65 to 2.45) and age 50 years or older (HR, 1.93; 95% CI, 1.36 to 2.83) were assigned 2 points. The 3-year overall survival after transplantation in patients with low (0 to 1 points), intermediate (2 to 3), high (4 to 5) and very high (≥ 6) scores was 71% (95% CI, 58% to 85%), 49% (95% CI, 42% to 56%), 41% (95% CI, 31% to 51%), and 25% (95% CI, 4% to 46%), respectively (P < .001). Increasing score was predictive of increased relapse (P < .001) and treatment-related mortality (P < .001) in the HLA-matched set and relapse (P < .001) in the HLA-mismatched cohort. CONCLUSION The proposed system is prognostic of outcome in patients undergoing HLA-matched and -mismatched allo HCT for MDS.

Metabolic Syndrome and Cardiovascular Disease after Hematopoietic Cell Transplantation: Screening and Preventive Practice Recommendations from the CIBMTR and EBMT

Metabolic syndrome (MetS) is a constellation of cardiovascular risk factors that increases the risk of cardiovascular disease, diabetes mellitus, and all cause mortality. Long-term survivors of hematopoietic cell transplantation (HCT) have a substantial risk of developing MetS and cardiovascular disease, with the estimated prevalence of MetS being 31–49% amongst HCT recipients. While MetS has not yet been proven to impact cardiovascular risk after HCT, an understanding of the incidence and risk factors for MetS in HCT recipients can provide the foundation to evaluate screening guidelines and develop interventions that may mitigate cardiovascular-related mortality. A working group was established through the Center for International Blood and Marrow Transplant Research and the European Group for Blood and Marrow Transplantation with the goal to review literature and recommend practices appropriate to HCT recipients. Here we deliver consensus recommendations to help clinicians provide screening and preventive care for MetS and cardiovascular disease among HCT recipients. All HCT survivors should be advised of the risks of MetS and encouraged to undergo recommended screening based on their predisposition and ongoing risk factors.

Cyclosporine in combination with mycophenolate mofetil versus methotrexate for graft versus host disease prevention in myeloablative HLA‐identical sibling donor allogeneic hematopoietic cell transplantation

Graft‐versus‐host disease (GVHD) remains a major cause of morbidity and mortality in allogeneic hematopoietic cell transplantation (HCT) despite current prophylaxis. Methotrexate (MTX) with a calcineurin inhibitor (CNI) is the current standard, however, has several toxicities. Mycophenolate mofetil (MMF) is frequently used in reduced‐intensity HCT, but data in myeloablative transplants is limited. We thus retrospectively identified 241 patients who underwent myeloablative HCT from an HLA‐identical sibling donor; 174 patients received cyclosporine (CSA) + MMF and 67 received CSA+MTX. Patients receiving MMF + CSA had rapid neutrophil (median 11 vs. 19 days with MTX+CSA), and platelet recovery (median 19 vs. 25 days), lower incidence of severe mucositis by OMAS (19% vs. 53%), and shorter length of hospital stay (median 25 vs. 36 days) (P < 0.001 for all comparisons). There were no significant differences in incidence of grade 2–4 (MMF+CSA 37% vs. MTX+CSA 39%) or 3–4 acute GVHD (17% vs. 12%), chronic GVHD (46% vs. 56%), relapse (28% vs. 27%), non‐relapse mortality (20% vs. 27%), or overall survival (47% vs. 44%) (P = NS for all). However, in multivariable analysis, the use of MMF+CSA was associated with an increased risk of severe grade 3–4 acute GVHD (HR 2.92, 95% CI 1.2–7.15, P = 0.019). There were no differences between the two regimens in multivariable analyses for other survival outcomes. This analysis demonstrates that the use of MMF in myeloablative sibling donor transplantation is well tolerated. However, there may be an increased risk of severe GVHD with MMF+CSA compared to MTX+CSA. Further studies evaluating optimal dosing strategies are needed. Am. J. Hematol. 90:144–148, 2015.

SF3B1 mutations are infrequently found in non-myelodysplastic bone marrow failure syndromes and mast cell diseases but, if present, are associated with the ring sideroblast phenotype

The bone marrow failure syndromes (BMFS) are hematologic disorders characterized by impaired production and sometimes function of peripheral blood (PB) cells. While they can be either acquired or inherited, the majority are acquired and include myelodysplastic syndromes (MDS), aplastic anemia (AA),

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia

Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia.

Impact of allogeneic hematopoietic cell transplant in patients with myeloid neoplasms carrying spliceosomal mutations.

Molecular predictors of outcome are increasingly important in determining optimal therapy for myeloid neoplasms. Mutations in the spliceosomal genes (U2AF1 and SRSF2) predict for poor outcomes in myelodysplastic syndromes (MDS) and related diseases. We investigated the effect of hematopoietic cell transplant (HCT) on the negative prognostic impact of U2AF1 and SRSF2 mutations. In total, 122 patients with MDS (30%), acute myeloid leukemia (51%), myeloproliferative neoplasms (MPN) (11%), and MDS/MPN (8%) receiving a HCT from 2003 to 2012 were evaluated for mutations in U2AF1 and SRSF2 by direct sequencing. Median time of follow up was 24 months (range 0.46–110). SRSF2 mutations were detected in 11 (10%) patients and U2AF1 in 3 (3%) patients. There were no significant differences in baseline characteristics between mutated and wild‐type (WT) patients. Patients carrying SRSF2 and U2AF1 mutations had similar overall survival (P = 0.84), relapse mortality (P = 0.50), and non‐relapse mortality (P = 0.72) compared to WT patients. However, taking into account disease status and cytogenetics in a subset of AML patients, SRSF2 and U2AF1 mutations were associated with worse survival (HR 3.71, P = 0.035). Am. J. Hematol. 91:406–409, 2016.