Comparative Analysis of Calcineurin Inhibitor–Based Methotrexate and Mycophenolate Mofetil–Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.     

The Impact of Donor Type on Outcomes and Cost of Allogeneic Hematopoietic Cell Transplantation for Pediatric Leukemia: A Merged Center for International Blood and Marrow Transplant Research and Pediatric Health Information System Analysis

Allogeneic hematopoietic stem cell transplantation (alloHCT) may be associated with significant morbidity and mortality, resulting in increased healthcare utilization (HCU). To date, no multicenter comparative cost analyses have specifically evaluated alloHCT in children with acute leukemia. In this retrospective cohort study, we examined the relationship between survival and HCU while investigating the hypothesis that matched sibling donor (MSD) alloHCT has significantly lower inpatient HCU with unrelated donor (URD) alloHCT, and that among URDs, umbilical cord blood (UCB) alloHCT will have higher initial utilization but lower long-term utilization. Clinical and transplantation outcomes data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were merged with inpatient cost data from the Pediatric Health Information System (PHIS) database using a probabilistic merge methodology. The merged dataset comprised US patients age 1 to 21 years who underwent alloHCT for acute leukemia between 2004 and 2011 with comprehensive CIBMTR data at a PHIS hospital. AlloHCT was analyzed by donor type, with specific analysis of utilization and costs using PHIS claims data. The primary outcomes of overall survival (OS), leukemia-free survival (LFS), and inpatient costs were evaluated using Kaplan-Meier curves and Cox and Poisson models. A total of 632 patients were identified in both the CIBMTR and PHIS data. The 5-year LFS was 60% for MSD alloHCT, 47% for well-matched matched unrelated donor bone marrow (MUD) alloHCT, 48% for mismatched unrelated donor alloHCT, and 45% for UCB alloHCT (P = .09). Total adjusted costs were significantly lower for MSD alloHCT versus MUD alloHCT by day 100 (adjusted cost ratio [ACR], .73; 95% confidence interval [CI], .62 to .86; P < .001), and higher for UCB alloHCT versus MUD alloHCT (ACR, 1.27; 95% CI, 1.11 to 1.45; P < .001). By 2 years, total adjusted costs remained significantly lower for MSD alloHCT compared with MUD alloHCT (ACR, .67; 95% CI, .56 to .81; P < .001) and higher for UCB alloHCT compared with MUD alloHCT (ACR, 1.25; 95% CI, 1.02 to 1.52; P = .0280). Our data show that UCB and MUD alloHCT provide similar survival outcomes; however, MUD alloHCT has a significant advantage in cost by day 100 and 2 years. More research is needed to determine whether the cost difference among URD alloHCT approaches remains significant with a larger sample size and/or beyond 2 years post-alloHCT.     

Recent Decrease in Acute Graft-versus-Host Disease in Children with Leukemia Receiving Unrelated Donor Bone Marrow Transplants

Unrelated donor (URD) bone marrow transplantation (BMT) is an effective treatment for leukemia in children, but its success is threatened by graft-versus-host disease (GVHD) and relapse. In this report, we describe the incidence of and risk factors for GVHD over time in children receiving URD BMT. We analyzed outcomes of 638 myeloablative URD BMTs performed between 1990 and 2003 to treat acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia, or myelodysplastic syndrome MDS, using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. All recipients were under age 18 years and had available high-resolution HLA typing for HLA-A, -B, -C, and -DRB1. Overall, 27% of the recipients developed acute GVHD (aGVHD) grade III-IV; the risk was significantly higher in children receiving T cell–replete grafts compared with those receiving T cell–depleted grafts (odds ratio [OR] = 3.12; 95% confidence interval [CI] = 2.02 to 4.83; P < .0001). Acute GVHD significantly reduced the risk of relapse in children with ALL (OR = 0.34; 95% CI = 0.13 to 0.86; P = .0052), but not in those with AML (OR = 0.58; 95% CI = 0.22 to 2.98; P = .26). The risk of aGVHD was higher in children undergoing transplantation in 1990-1998 (n = 365) compared with those doing so in 1999-2003 (OR = 1.93; 95% CI = 1.27 to 2.91; P = .002). We conclude that outcomes have changed significantly over time, with a reduced risk of aGVHD associated with the more recent transplantations.     

Unrelated Donor Allogeneic Hematopoietic Cell Transplantation Is Underused as a Curative Therapy in Eligible Patients from the United States

Allogeneic hematopoietic cell transplantation (alloHCT) is a curative therapy for hematologic disorders including acute lymphoblastic and myeloid leukemia, chronic lymphocytic and myeloid leukemia, Hodgkin's and non-Hodgkin lymphoma, multiple myeloma, and myelodysplastic syndrome. To determine the utilization of alloHCT from unrelated donors (URDs) in the United States, we calculated the number of patients diagnosed with hematologic disorders age 20 to 74 years based on 2004 to 2008 Surveillance, Epidemiology and End Results and 2007 US Census data, estimated the percentage of patients who would be eligible for URD alloHCT after discounting the mortality rate during induction therapy and the rate of severe comorbidities, and compared these with the actual 2007 alloHCTs facilitated by the National Marrow Donor Program. We found that the number of URD alloHCT as a percentage of the estimated potential transplantations ranged from 11% for multiple myeloma to 54% for chronic myeloid leukemia, with an average percentage of 26% for all the disorders considered. In an analysis stratified by age groups (20 to 44, 45 to 64, and 65 to 74 years), the utilization of URD alloHCT was higher in younger patients than in older patients for all disorders. Of acute lymphoblastic and myeloid leukemia patients, approximately 66% underwent URD alloHCT later in the course of their disease (in second or greater complete remission). URD alloHCT is likely underused for potentially curable hematologic disorders, particularly in older patients. Understanding the reasons for low use of alloHCT may lead to strategies to expand the use of this curative therapy for more patients with hematologic disorders.     

Donor Killer Cell Immunoglobulin-Like Receptor Genotype Does Not Improve Graft-versus-Leukemia Responses in Chronic Lymphocytic Leukemia after Unrelated Donor Transplant: A Center for International Blood and Marrow Transplant Research Analysis

Allogeneic hematopoietic cell transplantation (alloHCT) remains the sole curative therapy for patients with chronic lymphocytic leukemia (CLL), leading to 40% to 45% long-term survival. The impact of donor killer immunoglobulin-like receptor (KIR) genotype on outcomes of unrelated donor (URD) alloHCT for CLL is unknown. We examined 573 adult URD CLL recipient pairs. KIR genotype (presence/absence) was determined for each donor, and comprehensive modeling of interactions with recipient HLA class I loci (KIR ligands) was used to evaluate their effect on relapse and survival. Recipients had a median age of 56 years, and most were not in remission (65%). Both 8/8 HLA-matched (81%) or 7/8 HLA matched grafts (19%) were studied. Factors associated with improved overall survival (OS) were reduced-intensity conditioning (hazard ratio [HR] of death, .76) and good performance status (HR, .46), whereas alloHCT in nonremission (HR, 1.96) and mismatched donors (HR, 2.01) increased mortality. No models demonstrated a relationship between donor KIR genotype and transplant outcomes. Cox regression models comparing donors with A/A versus B/x KIR haplotypes and those with KIR gene content scores of 0 versus 1 versus ≥2 yielded similar rates of nonrelapse mortality, relapse, acute graft-versus-host disease (GVHD), and chronic GVHD and the same progression-free survival and OS. Relapse risk was not different for grafts from donors with KIR3DL1 transplanted into HLA C1/1 versus C2 recipients. This large analysis failed to demonstrate an association between URD KIR genotype and transplant outcome for patients with CLL, and thus KIR genotyping should not be used as a donor selection criterion in this setting.     

Alternative Donor Transplantation for Older Patients with Acute Myeloid Leukemia in First Complete Remission: A Center for International Blood and Marrow Transplant Research-Eurocord Analysis

We studied patients with acute myeloid leukemia (AML) over age 50 and in first complete remission (CR1) after adult unrelated donor (URD) (n = 441, 8/8 HLA matched; n = 94, 7/8 HLA matched) or umbilical cord blood (UCB; n = 205) transplantations. UCB recipients achieved CR1 within 8 weeks less often, and received reduced-intensity conditioning and cyclosporine-based graft-versus-host disease (GVHD) prophylaxis more often. Neutrophil recovery was slower in UCB (69% by day 28) compared with 8/8 HLA-matched URD (97%) and 7/8 HLA-matched (91%) (P < .001) recipients. Three-year transplantation-related mortality (TRM) was higher and leukemia-free survival (LFS) lower with UCB (35% and 28%, respectively) versus 8/8 HLA-matched URD (27% and 39%, respectively). TRM was higher in 7/8 HLA-matched URD (41%, P = .01), but LFS was similar at 34% (P = .39). Three-year chronic GVHD was the lowest in UCB (28%) versus 53% and 59% in 8/8 and 7/8 HLA-matched URD recipients, respectively. Three-year survival was 43% in 8/8 HLA-matched URD (95% confidence interval [CI], 38% to 48%), 30% in UCB (95% CI, 23% to 37%) (P = .002) and 37% in 7/8 URD (95% CI, 27 to 46). Allotransplantation for AML in CR1 with any of these grafts extends LFS for over one third of older patients. In the absence of an 8/8 HLA-matched URD or when transplantation is needed urgently, UCB can provide extended survival. Less frequent chronic GVHD with UCB transplantation may be of particular value for older patients.     

Favorable Effect of Cytomegalovirus Reactivation on Outcomes in Cord Blood Transplant and Its Differences Among Disease Risk or Type

The effects of cytomegalovirus (CMV) reactivation on cord blood transplant (CBT) are unclear. We assessed the effect of CMV reactivation in adult single-unit CBT without in vivo T cell depletion. Of 3147 eligible cases, 2052 were acute myeloid leukemia (AML), 643 acute lymphoblastic leukemia (ALL), and 452 myelodysplastic syndrome (MDS). CMV reactivation up to 100 days after CBT was associated with better overall survival (OS) compared with no reactivation cases (57.3% versus 52.6% at 3 years after CBT), whereas nonrelapse mortality (NRM) was increased in ALL (16.2% versus 8.9%) and standard disease risk (17.1% versus 10.6%, P = .014) by CMV reactivation. On multivariate analysis, CMV reactivation had favorable effects on relapse in MDS (hazard ratio [HR], .55; P = .044) and high disease risk (HR, .77; P = .047). In NRM, only standard-risk cases showed adverse effects of CMV reactivation (HR, 1.56; P = .026). OS was significantly improved with CMV reactivation in a subgroup of patients with AML (HR, .84; P = .044), MDS (HR, .68; P = .048), and high disease risk (HR, .81; P = .013). This favorable effect of CMV reactivation on OS in AML and high disease risk cases was maintained even after considering the effect of grades II to IV acute graft-versus-host disease. Thus, CMV reactivation might have beneficial or adverse effects on relapse, NRM, and OS, depending on the disease type or disease risk.     

Allocation to Matched Related or Unrelated Donor Results in Similar Clinical Outcomes without Increased Risk of Failure to Proceed to Transplant among Patients with Acute Myeloid Leukemia: A Retrospective Analysis from the Time of Transplant Approval

Clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-SCT) from unrelated donors (URDs) approach those of matched related donor (MRD) transplants in patients with acute myeloid leukemia (AML). Yet, available data fail to account for differences in pretransplantation outcomes between these donor selection strategies. In this regard, URD allo-HSCT is associated with longer waiting times to transplantation, potentially resulting in higher probabilities of failure to reach transplant. We retrospectively analyzed 108 AML patients accepted for first allo-HSCT from the time of approval to proceed to transplant. Fifty-eight (54%) patients were initially allocated to MRD, while URD search was initiated in 50 (46%) patients. Time to transplant was longer in patients allocated to a URD when compared with patients assigned to an MRD (median 142 days versus 100 days; p < .001). Forty-three of 58 (74%) patients in the MRD group and 35 of 50 (70%) patients in the URD group underwent transplantation (odds ratio [OR], 1.22; p?=?.63). Advanced disease status at the time of allo-HSCT approval was the only predictor of failure to reach transplantation in the multivariate analysis (OR, 4.78; p?=?.001). Disease progression was the most common cause of failure to reach allo-HSCT (66.7%) in both the MRD and URD groups. With a median follow-up from transplantation of 14.5 (interquartile range, 5 to 29) months, the 2-year estimate of overall survival (OS) from allo-HSCT was 46% in the MRD group and 57% in the URD group (p?=?.54). There were no differences in OS according to donor type allocation in the multivariate analysis (hazard ratio, 1.01; p?=?.83). When including patients from the time of transplant approval, 2-year OS was 39% in the MRD group versus 42% in the URD group. Our study suggests that allocation of AML patients to URDs may result in comparable clinical outcomes to MRD assignment without a significant increase in the risk of failure to reach transplant.     

Country-Level Macroeconomic Indicators Predict Early Post-Allogeneic Hematopoietic Cell Transplantation Survival in Acute Lymphoblastic Leukemia: A CIBMTR Analysis

For patients with acute lymphoblastic leukemia (ALL), allogeneic hematopoietic cell transplantation (alloHCT) offers a potential cure. Life-threatening complications can arise from alloHCT that require the application of sophisticated health care delivery. The impact of country-level economic conditions on post-transplantation outcomes is not known. Our objective was to assess whether these variables were associated with outcomes for patients transplanted for ALL. Using data from the Center for Blood and Marrow Transplant Research, we included 11,261 patients who received a first alloHCT for ALL from 303 centers across 38 countries between the years of 2005 and 2013. Cox regression models were constructed using the following macroeconomic indicators as main effects: Gross national income per capita, health expenditure per capita, and Human Development Index (HDI). The outcome was overall survival at 100 days following transplantation. In each model, transplants performed within lower resourced environments were associated with inferior overall survival. In the model with the HDI as the main effect, transplants performed in the lowest HDI quartile (n?=?697) were associated with increased hazard for mortality (hazard ratio, 2.42; 95% confidence interval, 1.64 to 3.57; P?<?.001) in comparison with transplants performed in the countries with the highest HDI quartile. This translated into an 11% survival difference at 100 days (77% for lowest HDI quartile versus 88% for all other quartiles). Country-level macroeconomic indices were associated with lower survival at 100 days after alloHCT for ALL. The reasons for this disparity require further investigation.     

Combination assay of IAP and ADA in hematologic malignancies

We measured the levels of adenosine deaminase (ADA) and immunosuppressive acid protein (IAP) in 10 patients with acute myeloid leukemia (AML), 5 with acute lymphoblastic leukemia (ALL), 8 with chronic myeloid leukemia (CML), 7 with myelodysplastic syndrome (MDS), 5 with malignant lymphoma (ML), 3 with multiple myeloma (MM) and one with adult T cell leukemia. On admission, the level of IAP was abnormally high in all cases of AML and ALL 50% of CML cases, 71.4% of MDS cases, 60% of ML cases and none of MM cases. ADA was elevated in all cases of ALL, 77.8% of AML and CML cases, 57.1% of MDS cases, 60% of ML cases and 33.3% of MM cases. In 7 patients with AML, the level of IAP returned to normal when they achieved complete remission. On the other hand, the level of ADA had already returned to normal even during induction therapy. ADA showed a positive correlation with the absolute number of peripheral blasts and lactic dehydrogenase both in AML and ALL. These results suggest that ADA indicates the activity of leukemia and IAP indicates the immunocompetence of the host.     

Extramedullary Relapse of Acute Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Different Characteristics between Acute Myelogenous Leukemia and Acute Lymphoblastic Leukemia

Extramedullary relapse (EMR) of acute leukemia (AL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a contributor to post-transplantation mortality and remains poorly understood, especially the different characteristics of EMR in patients with acute myelogenous leukemia (AML) and those with acute lymphoblastic leukemia (ALL). To investigate the incidence, risk factors, and clinical outcomes of EMR for AML and ALL, we performed a retrospective analysis of 362 patients with AL who underwent allo-HSCT at the First affiliated Hospital of Soochow University between January 2001 and March 2012. Compared with patients with AML, those with ALL had a higher incidence of EMR (12.9% versus 4.6%; P = .009). The most common site of EMR was the central nervous system, especially in the ALL group. Multivariate analyses identified the leading risk factors for EMR in the patients with AML as advanced disease status at HSCT, hyperleukocytosis at diagnosis, history of extramedullary leukemia before HSCT, and a total body irradiation–based conditioning regimen, and the top risk factors for EMR in the patients with ALL as hyperleukocytosis at diagnosis, adverse cytogenetics, and transfusion of peripheral blood stem cells. The prognosis for EMR of AL is poor, and treatment options are very limited; however, the estimated 3-year overall survival (OS) was significantly lower in patients with AML compared with those with ALL (0 versus 18.5%; P = .000). The characteristics of post–allo-HSCT EMR differed between the patients with AML and those with ALL, possibly suggesting different pathogenetic mechanisms for EMR of AML and EMR of ALL after allo-HSCT; further investigation is needed.     

Myelodysplastic syndrome associated with monosomy 7 in childhood: a retrospective study

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis, peripheral cytopenia, and dysplastic changes in the bone marrow. Monosomy 7 or partial loss of 7q is a common cytogenetic abnormality in MDS patients and is associated with poor prognosis. This study examined eight patients with monosomy 7 and MDS. Five MDS patients with monosomy 7 progressed to acute leukemia: three cases transformed into acute myelogenous leukemia (AML) in a mean time of only 4.6 months and two cases into acute lymphoblastic leukemia (ALL) in a mean time of 9 months. To our knowledge, this is the first report showing progression of monosomy 7 associated with MDS to ALL in the childhood period.     

Geographic heterogeneity of neoplasia-associated chromosome aberrations

Using a database comprising 13,266 cytogenetically abnormal neoplasms, the geographic heterogeneity of neoplasia-associated chromosomal abnormalities was investigated by comparing the frequencies of characteristic aberrations in consecutive series of patients with the same diagnosis. Significant frequency differences between geographic areas were found for the aberrations +8, i(17q), +19, and an additional Ph1 chromosome in chronic myeloid leukemia (CML); -5, 5q-, and +8 in acute nonlymphocytic leukemia (ANLL); t(8;21) in ANLL-M2; t(15;17) in ANLL-M3; 5q- and -7 in myelodysplastic syndromes (MDS); t(9;22) and +21 in acute lymphocytic leukemia (ALL); t(14;18) in follicular lymphoma; -8 and -22/22q- in meningioma; and structural abnormalities of 12q in pleomorphic adenoma of the salivary glands (PAS). No geographic incidence variation was detected for -7 and +21 in ANLL; +8 in MDS; 6q- and +8 in ALL; +12 in chronic lymphocytic leukemia; 6q- in non-Hodgkin's lymphoma (NHL); t(8;14) in Burkitt's lymphoma; t(11;22) in Ewing's sarcoma; i(12p) in germ cell tumors; 1p- in neuroblastoma; structural abnormalities of 3q, 8q, and 9p in PAS; or 3p- in renal cell carcinoma. Intraregional frequency similarities between cytogenetically identical abnormalities in related tumor types were also analyzed. No significant correlations were found regarding the incidence of 5q- in ANLL and MDS, 6q- in ALL and NHL, -7 in ANLL and MDS, +8 in ANLL and CML, +8 in ANLL and MDS, +8 in ALL and ANLL, or +21 in ALL and ANLL. The findings indicate that some geographic heterogeneity of tumor-associated aberrations exists both in hematologic neoplasms and in solid tumors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Different characteristics identified by single nucleotide polymorphism array analysis in leukemia suggest the need for different application strategies depending on disease category

The purpose of this study was to evaluate the detection rate of chromosomal rearrangements in leukemia using single nucleotide polymorphism array (SNP‐A) in combination with metaphase cytogenetics (MC), with the aim of proposing a practical approach for clinical karyotyping applications of SNP‐A. The Genome‐Wide Human SNP Array 6.0 (Affymetrix, Santa Clara, CA) was applied in 469 patients with a variety of hematologic malignancies. Combined use of SNP‐A with MC improved the detection rate in comparison with MC alone: acute myeloid leukemia (AML) with normal karyotype (NK), 32% versus 0%; core binding factor (CBF)‐AML 40% versus 29%; myelodysplastic syndrome (MDS), 54% versus 39%; chronic myeloid leukemia (CML), 24% versus 3%; and acute lymphoblastic leukemia (ALL), 88% versus 63%. Different patterns of abnormalities (especially the type, size, and location) were noted in the leukemia subtypes. Copy neutral loss of heterozygosity lesions was detected in 23% of AML‐NK, 3% of CBF‐AML, 25% of MDS, 2% of CML, and 20% of ALL. SNP‐A also provided information on cryptic deletions and a variety of aneuploidies in ALL, while the benefit was minimal in CML. In conclusion, different patterns of abnormal lesions were presented according to the disease category, thus requiring a different approach of adopting SNP‐A‐based karyotyping among different leukemia subtypes. © 2012 Wiley Periodicals, Inc.     

Prior Gemtuzumab Ozogamicin Exposure in Adults with Acute Myeloid Leukemia Does Not Increase Hepatic Veno-Occlusive Disease Risk after Allogeneic Hematopoietic Cell Transplantation: A Center for International Blood and Marrow Transplant Research Analysis

Gemtuzumab ozogamicin (GO) therapy before allogeneic hematopoietic cell transplantation (alloHCT) has been historically associated with an increased risk of hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) in patients with acute myeloid leukemia (AML). The current analysis examined VOD/SOS risk and outcomes in a cohort of patients who in recent years were reported to the Center for International Blood and Marrow Transplant Research. Adults with AML who had GO exposure before myeloablative alloHCT were matched 1:4 by age and disease status at transplant to recipients without GO exposure (control subjects). One hundred thirty-seven patients with GO exposure and 548 matched control subjects who underwent alloHCT between 2008 and 2011 were included in this analysis. With a median ∼8-year follow-up of survivors, the 5-year overall survival probability was similar in the 2 cohorts: 38% and 38% in the GO-exposed versus control groups (P = .97). Incidence of VOD/SOS and severe VOD/SOS, respectively, at 100 days was 4% (95% confidence interval [CI], 1% to 7%) and 3% (95% CI, 1% to 6%) in GO-exposed patients and 3% (95% CI, 2% to 5%) and 1% (95% CI, 0% to 2%) in control subjects. Correspondingly, among patients who developed VOD/SOS, 1-year survival probability after VOD/SOS diagnosis was 33% (95% CI, 5% to 72%) and 27% (95% CI, 11% to 47%; P = .78). In multivariate analyses, GO exposure before alloHCT was not associated with an increased risk of VOD/SOS (odds ratio, 1.10; P = .85) or death (hazard ratio, 1.08; P = .57). Three deaths (3%) in the GO group and 3 deaths (<1%) in the control group were attributed to VOD/SOS. Our results suggest that GO treatment before myeloablative alloHCT in the recent era is not associated with an increased risk of post-transplant VOD/SOS or death.     

Transplant Conditioning with Treosulfan/Fludarabine with or without Total Body Irradiation: A Randomized Phase II Trial in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia

In this prospective, randomized, phase II “pick the winner” trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine?±?2?Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n?=?51) or acute myeloid leukemia (AML; n?=?49). Patients received i.v. treosulfan, 14?g/m²/day on days –6 to –4 and i.v. fludarabine, 30?mg/m²/day on days –6 to –2, alone or combined with 2?Gy TBI (day 0). Donors were related (n?=?43) or unrelated (n?=?57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P?=?.04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P?=?.06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P?=?.20) and for patients with high-risk disease, 26% and 36% (P?=?.18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P?=?.49) and among AML patients 16% versus 35% (P?=?.05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P?=?.18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.     

Pretransplant Consolidation Is Not Beneficial for Adults with ALL Undergoing Myeloablative Allogeneic Transplantation

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR1) with chemotherapy. However, the benefit of consolidation chemotherapy remains uncertain in patients undergoing alloHCT. We compared clinical outcomes of 524 adult patients with ALL in CR1 who received ≥2 (n?=?109), 1 (n?=?93), or 0 cycles (n?=?322) of consolidation before myeloablative alloHCT from 2008 to 2012. As expected, time to alloHCT was longer with increasing cycles of consolidation. Patients receiving ≥2, 1, or 0 cycles of consolidation had an adjusted 3-year cumulative incidence of relapse of 20%, 27%, and 22%; 1-year transplant-related mortality (TRM) of 16%, 18%, and 23%; adjusted 3-year leukemia-free survival (LFS) of 54%, 48%, and 47%; and 3-year overall survival (OS) of 63%, 59%, and 54% (all P values >.40). Multivariable analysis confirmed that consolidation was not prognostic for LFS (relative risk,?1.20, 95% confidence interval, .86 to 1.67; P?=?.28 for no consolidation; RR,?1.18, 95% confidence interval, .79 to 1.76; P?=?.41 for 1 cycle versus ≥2 cycles = reference). Similarly, consolidation was not associated with OS, relapse, TRM, or graft-versus-host disease. We conclude that consolidation chemotherapy does not appear to provide added benefit in adult ALL patients with available donors who undergo myeloablative alloHCT in CR1.     

Multicenter Biologic Assignment Trial Comparing Reduced-Intensity Allogeneic Hematopoietic Cell Transplant to Hypomethylating Therapy or Best Supportive Care in Patients Aged 50 to 75 with Intermediate-2 and High-Risk Myelodysplastic Syndrome: Blood and Marrow Transplant Clinical Trials Network #1102 Study Rationale,Design, and Methods

The introduction of reduced-intensity conditioning (RIC) regimens made it possible to offer allogeneic hematopoietic cell transplantation (alloHCT) to older patients with myelodysplastic syndromes (MDS). However, the relative risks and benefits of alloHCT compared with novel nontransplant therapies continue to be the source of considerable uncertainty. We will perform a prospective biologic assignment trial to compare RIC alloHCT with nontransplant therapies based on donor availability. Primary outcome is 3-year overall survival. Secondary outcomes include leukemia-free survival, quality of life, and cost-effectiveness. Four hundred patients will be enrolled over roughly 3 years. Planned subgroup analyses will evaluate key biologic questions, such as the impact of age and response to hypomethylating agents on treatment effects. Findings from this study potentially may set a new standard of care for older MDS patients who are considered candidates for alloHCT.     

Distinct Clinical Features of Infectious Complications in Adult T Cell Leukemia/Lymphoma Patients after Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis in the Nagasaki Transplant Group

Although allogeneic hematopoietic stem cell transplantation (allo-SCT) is performed as a curative option in adult T cell leukemia-lymphoma (ATL) patients, its high transplantation-related mortality raises a serious issue. The clinical features of infectious complications after transplantation are not well known. To analyze the impact of infections after allo-SCT for ATL, we retrospectively compared infectious complications in 210 patients at 3 institutions in Nagasaki prefecture between 1997 and 2009. There were 91 patients with acute myeloid leukemia (AML), 51 with acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL), and 68 with ATL. No patient received ganciclovir or foscarvir as prophylaxis, and most patients received antifungal prophylaxis with fluconazole or itraconazole. The cumulative incidence of cytomegalovirus (CMV) infection at 3 years was 69.2% in ATL patients versus 54.4% in AML patients (P = .0255). Cumulative infection-related mortality was significantly higher in ATL patients than in the 2 other groups (ATL versus AML, P = .0496; ATL versus ALL/LBL, P = .0075), and most death-causing pathogens were bacteria and fungus. The appearance of CMV infection was negatively associated with infectious mortality in ATL patients, but the P value for this association was near the borderline of significance (P = .0569). In multivariate analysis, transplantation using unrelated bone marrow and episodes of CMV infection were associated with worse overall survival in ATL patients, but were not in either AML or ALL/LBL patients. Collectively, the impact of infectious complications after transplantation in ATL patients was different from that in AML and ALL/LBL patients, suggesting that a more intensive strategy for infection control in ATL patients is required to reduce infectious mortality.