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Numerous clinical studies link cytomegalovirus (CMV) infection with incomplete posttransplantation T-cell recovery. We hypothesized that the inability of transplant recipients to handle CMV reactivation might correlate with a defective graft-versus-leukemia response and increased posttransplantation morbidity. Between May 1995 and August 2001, 82 patients who were CMV seropositive and survived the first 100 days after transplantation were identified for a day 100 landmark analysis of the effect of CMV reactivation patterns on eventual transplantation outcome. All patients underwent a myeloablative HLA-identical sibling donor T cell-depleted stem cell transplantation with scheduled donor T-cell add-back on day 45. Median follow-up was 1032 days. Forty-two patients who had either no reactivation or only 1 positive test with quick clearance were designated as a CMV immune competent group. Forty patients designated as CMV immune deficient (ID) had at least 2 positive tests. Apart from younger age (33 versus 38 years; P = .05) in the ID group, the 2 groups were balanced for clinical characteristics. In multivariate analysis, ID patients had a significantly higher incidence of leukemia relapse (58% versus 21%; P = .03) and worse disease-free survival (31% versus 66%; P = .04). There was no significant difference in week 1 to 14 posttransplantation lymphocyte counts between the 2 groups. In 67 patients tested 3 to 6 months after transplantation, a proliferative response to CMV antigen (stimulation index ≥2) occurred in 27 of 36 immune competent patients compared with 15 of 31 ID patients (P = .006). These results show that recurrent CMV reactivation in the first 100 days after transplantation predicts for reduced disease-free survival and increased leukemic relapse beyond 100 days and correlates with inferior proliferative responses to CMV. The higher relapse rate may reflect poor immune reconstitution in ID patients or an adverse effect of prolonged antiviral treatment. [Copyright &y& Elsevier]

We sought to optimize and standardize stem cell and lymphocyte doses of T cell-depleted peripheral blood stem cell transplants (T-PBSCT), using delayed add-back of donor T cells (DLI) to prevent relapse and enhance donor immune recovery. Fifty-one patients with haematological malignancies received a T-PBSCT from an HLA-identical sibling, followed by DLI of 1 × 107 and 5 × 107 CD3+ cells/kg on d +45 and +100 respectively. Twenty-four patients were designated as standard risk and twenty-seven patients with more advanced leukaemia were designated as high risk. Median recipient age was 38 years (range 10–56). Median (range) of CD34+ and CD3+ cell transplant doses were 4·6 (2·3–10·9) × 106/kg and 0·83 (0·38–2) × 105/kg respectively. The cumulative probability of acute GVHD was 39%. No patient died from GVHD or its consequences. The probability of developing chronic GVHD was 54% (18% extensive). The probability of relapse was 12% for the standard-risk patients and 66% for high-risk patients. In multivariate analysis, the risk factors for lower disease-free survival and overall survival were high-risk disease, CD34+ dose < 4·6 × 106/kg and CD3+ dose < 0·83 × 105/kg. Predictive factors for chronic GVHD were a T-cell dose at transplant > 0·83 × 105 CD3+ cells/kg. These results further define the impact of CD34 and CD3 cell dose on transplant outcome and show that careful dosing of stem cells and lymphocytes may permit the control and optimization of transplant outcome. [ABSTRACT FROM AUTHOR]

Abbreviations CIBMTR Center for International Blood in Marrow Transplant Research CMWP Chronic Malignancies Working Party EBMT European Society for Blood and Marrow Transplantation Chronic neutrophilic leukaemia (CNL) is a rare, frequently aggressive Philadelphia (Ph)-negative myeloproliferative neoplasm (MPN). The disease status at allo-HCT was reported to be no response/stable disease in 11 (38%) patients and complete remission (CR) in four (14%) patients. In the case series from Japan, two patients received cord blood grafts and one patient received a related haploidentical donor marrow graft. [Extracted from the article]

• The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (VEN-HMA) as a bridge to allogeneic hematopoietic cell transplantation (alloHCT) is associated with favorable HCT outcomes. • VEN-HMA could allow more patients of older age to proceed to potentially curative alloHCT. • AlloHCT outcomes are particularly good in patients who undergo HCT in complete remission after VEN-HMA therapy. The combination of hypomethylating agents with the selective Bcl-2 inhibitor venetoclax (HMA-VEN) has emerged as a highly active regimen in patients with acute myelogenous leukemia (AML) in both the upfront and relapsed/refractory (r/r) settings. We report our early experience with a cohort of patients who were able to proceed to allogeneic hematopoietic cell transplantation (alloHCT) after HMA-VEN therapy. Thirty-two patients with AML (19 r/r and 13 de novo) with a median age of 62 years underwent alloHCT after HMA-VEN therapy. Twenty-two (68.8%) were in complete remission (CR)/CR with incomplete count recovery at time of HCT. With a median follow up of 14.4 months, the 1-year overall survival (OS) was 62.5%, and disease-free survival was 43.8%. The 1-year nonrelapse mortality rate was 18.8%, and the cumulative incidence of relapse was 37.5%. Among patients who underwent alloHCT in CR, the 1-year OS was 77.3%, and the cumulative incidence of nonrelapse mortality was 9.1%. The cumulative incidence of grade II-IV acute graft-versus-host disease was 43.8%. We conclude that alloHCT after HMA-VEN is therapy associated with favorable allogeneic HCT outcomes in newly diagnosed older patients with AML, as well as those with r/r AML. [ABSTRACT FROM AUTHOR]

Background: Long-term mortality after hematopoietic cell transplantation (HCT) is conventionally calculated from the time of HCT, ignoring temporal changes in survivors' mortality risks. Conditional survival rates, accounting for time already survived, are relevant for optimal delivery of survivorship care but have not been widely quantified. We estimated conditional survival by elapsed survival time in allogeneic HCT patients and examined cause-specific mortality.Methods: We calculated conditional survival rates and standardized mortality ratio for overall and cause-specific mortality in 4485 patients who underwent HCT for malignant hematologic diseases at a large transplant center during 1976-2014. Statistical tests were two-sided.Results: The 5-year survival rate from HCT was 48.6%. After surviving 1, 2, 5, 10, and 15 years, the subsequent 5-year survival rates were 71.2%, 78.7%, 87.4%, 93.5%, and 86.2%, respectively. The standardized mortality ratio was 30.3 (95% confidence interval [CI] = 29.2 to 35.5). Although the standardized mortality ratio declined in longer surviving patients, it was still elevated by 3.6-fold in survivors of 15 years or more (95% CI = 3.0 to 4.1). Primary disease accounted for 50% of deaths in the overall cohort and only 10% in 15-year survivors; the leading causes of nondisease-related mortality were subsequent malignancy (26.1%) and cardiopulmonary diseases (20.2%). We also identified the risk factors for nondisease-related mortality in 1- and 5-year survivors.Conclusion: Survival probability improves the longer patients survive after HCT. However, HCT recipients surviving 15 years or more remain at elevated mortality risk, largely because of health conditions other than their primary disease. Our study findings help inform preventive and interventional strategies to improve long-term outcomes after allogeneic HCT. [ABSTRACT FROM AUTHOR]

• Impact of iron overload (serum ferritin [SF] >2000 ng/mL) on umbilical cord blood hematopoietic cell transplantation (HCT) outcomes was examined. • Overall survival rate at 2 years was significantly lower in patients with higher pre-HCT SF levels (P =.005). • Nonrelapse mortality was significantly higher in patients with higher SF (P =.02). • Significantly faster engraftment was seen in patients with lower SF levels. • Iron overload is a strong adverse prognostic factor for cord blood transplant. The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P =.005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P =.025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P =.034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P =.044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor. [ABSTRACT FROM AUTHOR]

Background: Hematopoietic cell transplantation (HCT) is a curative option for a growing number of patients with hematologic diseases and malignancies. However, HCT-related factors, such as total body irradiation used for conditioning, graft-versus-host disease, and prolonged exposure to immunosuppressive therapy, result in very high risk for melanoma and non-melanoma skin cancer (NMSC). In fact, skin cancer is the most common subsequent neoplasm in HCT survivors, tending to develop at a time when survivors' follow-up care has largely transitioned to the primary care setting. The goal of this study is to increase skin cancer screening rates among HCT survivors through patient-directed activation alone or in combination with physician-directed activation. The proposed intervention will identify facilitators of and barriers to risk-based screening in this population and help reduce the burden of cancer-related morbidity after HCT.Methods/design: 720 HCT survivors will be enrolled in this 12-month randomized controlled trial. This study uses a comparative effectiveness design comparing (1) patient activation and education (PAE, N = 360) including text messaging and print materials to encourage and motivate skin examinations; (2) PAE plus primary care physician activation (PAE + Phys, N = 360) adding print materials for the physician on the HCT survivors' increased risk of skin cancer and importance of conducting a full-body skin exam. Patients on the PAE + Phys arm will be further randomized 1:1 to the teledermoscopy (PAE + Phys+TD) adding physician receipt of a portable dermatoscope to upload images of suspect lesions for review by the study dermatologist and an online course with descriptions of dermoscopic images for skin cancers.Discussion: When completed, this study will provide much-needed information regarding strategies to improve skin cancer detection in other high-risk (e.g. radiation-exposed) cancer survivor populations, and to facilitate screening and management of other late effects (e.g. cardiovascular, endocrine) in HCT survivors.Trial Registration: ClinicalTrials.gov, NCT04358276 . Registered 24 April 2020. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in hematopoietic cell transplantation (HCT) survivors. In these patients, such risk factors as hypertension, diabetes, obesity, and physical inactivity are important modifiers of CVD risk. However, the period when HCT survivors are at greatest risk of developing these risk factors, and in turn CVD, coincides with a drop in engagement in survivorship care. We examined the feasibility and acceptability of a 4-week remote risk-based monitoring (blood pressure monitor, weight scale, pulse oximeter, glucometer) and management program in 18 (11 allogeneic and 7 autologous) HCT survivors at intermediate-high risk of CVD. The median patient age was 66 years (range, 53 to 74 years), 67% had hypertension, 22% had diabetes, 11% were obese (body mass index ≥30 kg/m2), 56% were at intermediate risk of CVD, and 44% were at high risk of CVD. Weekly compliance with the remote monitoring schedule (≥3 readings/week using all devices) ranged from 72% in week 1 to 83% in weeks 2 to 4. Fifteen participants (83%) generated 86 alerts that were outside the predetermined range of normal; 63 of these readings (73%) normalized without intervention, and 23 (27%) necessitated triage by the study research nurse. Nearly all participants reported that the study kept them motivated and involved in their healthcare, and >85% agreed that the study supported their healthcare goals, helped them learn and manage their health conditions, and increased their access to healthcare. These findings may set the foundation for innovative risk-based and remote interventions to reduce the burden of CVD in this growing population of patients. [ABSTRACT FROM AUTHOR]

• HCT outcomes were analyzed in r/r ALL patients, after salvage with blinatumomab. • Pre-HCT blinatumomab was given for morphologic (n = 24) or MRD-positive disease (n = 11). • No unusual toxicities or delayed engraftment was observed post-HCT. • Subgroup analysis (MRD/cytogenetics) showed no significant difference in survival. • Blinatumomab may be considered as a safe and effective salvage therapy pre-HCT. Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT. [ABSTRACT FROM AUTHOR]

Background: Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti‐CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction. Methods: Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post‐transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs. Results: Total duration of therapy was longer in the GCV group (37 days vs 28 days, P =.21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P <.05). Conclusion: Preemptive anti‐CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV. [ABSTRACT FROM AUTHOR]

Background: High intensity treatments such as hematopoietic cell transplantation (HCT) can be curative for patients with hematologic malignancies, but this needs to be balanced by the high risk of nonrelapse mortality (NRM) during the first 2 years after HCT. Sarcopenia (low muscle mass) is associated with physical disability and premature mortality in individuals with nonmalignant diseases and may be a predictor of NRM and poor overall survival in patients undergoing HCT.Methods: This was a retrospective cohort study of 859 patients with acute leukemia or myelodysplastic syndrome who underwent a first HCT as adults (≥18 years) between 2007 and 2014. Sarcopenia was assessed from pre-HCT abdominal computed tomography scans. Two-year cumulative incidence of NRM was calculated, with relapse/progression considered as a competing risk event. Fine-Gray subdistribution hazard ratio estimates and 95% confidence intervals (CI) were obtained and adjusted for relevant covariates. Kaplan-Meier method was used to examine overall survival. All statistical tests were two-sided.Results: Median age at HCT was 51 years (range = 18-74 years); 52.5% had a high [≥3] HCT-comorbidity index; 33.7% had sarcopenia pre-HCT. Sarcopenia was an independent predictor of higher NRM risk (hazard ratio = 1.58, 95% CI = 1.16 to 2.16) compared with patients who were not. The 2-year incidence of NRM approached 30% in patients with sarcopenia and high (≥3) HCT-comorbidity index. Patients with sarcopenia had on average a longer hospitalization (37.2 days vs 31.5 days, P < .001) and inferior overall survival at 2 years (55.2%, 95% CI = 49.5% to 61.0% vs 66.9%, 95% CI = 63.0% to 70.8%, P < .001).Conclusions: Sarcopenia is an important and independent predictor of survival after HCT, with potential additional downstream impacts on health-economic outcomes. This information can be used to facilitate treatment decisions prior to HCT and guide interventions to decrease the risk of treatment-related complications after HCT. [ABSTRACT FROM AUTHOR]

Highlights • PepVax is an investigational cytomegalovirus (CMV) vaccine that has shown tolerability and clinical benefits in a Phase Ib trial. • Longitudinal immune monitoring of memory phenotypes was performed in enrolled patients to study the functionality and antiviral role of CMV-specific T cells. • In vaccinated hematopoietic cell transplantation recipients, PepVax elicited marked levels of differentiated effector memory pp65-specific CD8+ T cells in the absence of viremia. • The functional memory phenotype of the expanded CMV-specific T cell subsets may have been key to the favorable outcomes of the PepVax clinical trial. ABSTRACT Early cytomegalovirus (CMV) reactivation remains a significant cause of morbidity and mortality in allogeneic hematopoietic cell transplant (HCT) recipients. CMVPepVax is an investigational peptide vaccine designed to control CMV infection in HCT recipients seropositive for CMV by stimulating the expansion of T cell subsets that target the CMV tegument protein pp65. In a randomized Phase Ib pilot trial (ClinicalTrials.gov NCT01588015), two injections of CMVPepVax (at days 28 and 56 post-HCT) demonstrated safety, immunogenicity, increased relapse-free survival, and reduced CMV reactivation and use of antivirals. In the present study, we assessed the phenotypes and time courses of the pp65-specific CD8 T cell subsets that expanded in response to CMVPepVax vaccination. The functionality and antiviral role of CMV-specific T cells have been linked to immune reconstitution profiles characterized predominantly by differentiated effector memory T (TEM) subsets that have lost membrane expression of the costimulatory molecule CD28 and often reexpress the RA isoform of CD45 (TEMRA). Major histocompatibility complex class I pp65 495 - 503 multimers, as well as CD28 and CD45 memory markers, were used to detect immune reconstitution in blood specimens from HCT recipients enrolled in the Phase Ib clinical trial. Specimens from the 10 (out of 18) vaccinated patients who had adequate (≥.2%) multimer binding to allow for memory analysis showed highly differentiated TEM and TEMRA phenotypes for pp65 495-503 -specific CD8 T cells during the first 100days post-transplantation. In particular, by day 70, during the period of highest risk for CMV reactivation, combined TEM and TEMRA phenotypes constituted a median of 90% of pp65 495-503 -specific CD8 T cells in these vaccinated patients. CMV viremia was not detectable in the patients who received CMVPepVax, although their pp65 495-503 -specific CD8 T cell profiles were strikingly similar to those observed in viremic patients who did not receive the vaccine. Collectively, our findings indicate that in the absence of clinically relevant viremia, CMVPepVax reconstituted significant levels of differentiated pp65 495-503 -specific CD8 TEMs early post-HCT. Our data indicate that the rapid reconstitution of CMV-specific T cells with marked levels of effector phenotypes may have been key to the favorable outcomes of the CMVPepVax clinical trial. Graphical abstract Image, graphical abstract [ABSTRACT FROM AUTHOR]

ABSTRACT The current standard of care for patients with Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) is high-dose conditioning followed by autologous stem cell transplantation (ASCT). For some patients (ie, those with highest-risk disease, insufficient stem cell numbers after mobilization, or bone marrow involvement) allogeneic hematopoietic cell transplantation (alloHCT) offers the potential for cure. However, the majority of patients undergoing alloHCT receive reduced-intensity conditioning as a preparative regimen, and studies assessing outcomes of patients after alloHCT with myeloablative conditioning are limited. In this retrospective study, we reviewed outcomes of 22 patients with recurrent and refractory NHL who underwent alloHCT with myeloablative BEAM conditioning and received tacrolimus/sirolimus as graft-versus-host disease (GVHD) prophylaxis at City of Hope between 2005 and 2018. With a median follow-up of 2.6 years (range, 1.0 to 11.2 years), the probabilities of 2-year overall survival and event-free survival were 58.3% (95% confidence interval [CI], 35.0% to 75.8%) and 45.5% (95% CI, 24.4% to 64.3%), respectively. The cumulative incidence of grade II to IV acute GVHD was 45.5% (95% CI, 23.8% to 64.9%), with only 1 patient developing grade IV acute GVHD. However, chronic GVHD was seen in 55% of the patients (n = 12). Of the 22 eligible patients, 2 had undergone previous ASCT and 2 had undergone previous alloHCT. Both patients with previous ASCT developed severe regimen-related toxicity. Patients who underwent alloHCT with chemorefractory disease had lower survival rates, with 1-year OS and EFS of 44.4% and 33.0%, respectively. In conclusion, alloHCT with a BEAM preparative regimen and tacrolimus/sirolimus-based GVHD should be considered as an alternative option for patients with highest-risk lymphoma whose outcomes are expectedly poor after ASCT. [ABSTRACT FROM AUTHOR]

Highlights • Ruxolitinib use was associated with a reduction in prednisone dose. • The rate of infectious/bacterial infections was high and contributed to the overall mortality. • Ruxolitinib as salvage therapy is promising for chronic graft-versus-host disease refractory to steroids. Abstract Chronic graft-versus-host disease (cGVHD) continues to be a major complication after allogeneic hematopoietic cell transplantation, significantly affecting patients' quality of life. A regimen of systemic corticosteroids is considered first-line therapy but is often associated with inadequate responses and multiple side effects. In patients with refractory disease, an evidenced-based consensus is lacking as to the single best approach to managing symptoms. Ruxolitinib, a selective JAK1/2 inhibitor, has recently gained favor as a second-line approach in patients with steroid-refractory cGVHD. In this retrospective study, we evaluated the outcomes of 46 patients who received ruxolitinib for cGVHD between March 2016 and December 2017 at our institution, and evaluated ruxolitinib's impact at 6 and 12 months, based on the National Institutes of Health Severity Scale, including organ-specific responses, and mean prednisone dose. Furthermore, we present the first reported probability of ruxolitinib's treatment failure-free survival (FFS) in patients with cGVHD. After 12 months of ruxolitinib therapy, complete response, partial response, and stable disease was observed in 13% (n = 6), 30.4% (n = 14), and 10.9% (n = 5) of patients, respectively. The 1-year probability of FFS was 54.2% (95% confidence interval,.388 to.673), and ruxolitinib use was associated with a reduction in prednisone dose. In conclusion, our data, which represent the largest cohort of patients with cGVHD reported to date, support the use of ruxolitinib for cGVHD refractory to steroids and currently available salvage therapies, discontinued due to lack of response and high cost. [ABSTRACT FROM AUTHOR]

Allelic variants of genes implicated in drug absorption, distribution, metabolism, and excretion (ADME) determine the pharmacokinetic variability of many medications and are increasingly recognized as important factors determining the success or failure of medical treatments. Both tacrolimus and sirolimus have narrow therapeutic ranges maintained by therapeutic drug monitoring (TDM). Using an ADME panel that covers >99% of the PharmaADME working group core list (188 single nucleotide polymorphism [SNP] and 12 copy number variant [CNV] assays in 36 pharmacogenetically relevant genes), we studied 177 patients who underwent allogeneic hematopoietic cell transplantation (HCT) using tacrolimus/sirolimus–based graft-versus-host disease (GVHD) prophylaxis. We tested for possible associations between ADME variants and tacrolimus/sirolimus drug levels, concentration/dose (C/D) ratio, and clinical endpoints, including acute GVHD. A total of 62 SNP and 6 CNV assays were evaluable after removing the variants, which were homozygous in (nearly) all samples. For sirolimus, rs2032582 (ABCB1) T-carriers versus non–T-carriers were associated with higher blood levels ( P = .01), with similar results for C/D ratio. Generalized estimating equation analysis supported these findings. For tacrolimus, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were associated with higher blood levels than CYP3A5*1/*1 ( P = .002). By multivariable analysis, rs776746 CYP3A5*3/*3 and CYP3A5*3/*1 were independently associated with decreased acute GVHD compared with CYP3A5*1/*1 , after adjustment for conditioning, donor type, race/ethnicity, and age. We demonstrated association of specific ADME genetic polymorphisms with blood levels of tacrolimus/sirolimus, and incidence of acute GVHD after HCT, in spite of TDM and dose adjustment. A larger ongoing study will determine whether these associations have clinical utility beyond TDM. [ABSTRACT FROM AUTHOR]

The important role of activating killer immunoglobulin-like receptors (KIRs) in protecting against cytomegalovirus (CMV) reactivation has been described previously in patients undergoing hematopoietic cell transplantation (HCT). More specifically, the presence of multiple activating KIRs and the presence of at least KIR2DS2 and KIR2DS4 in the donor genotype identified a group of HCT patients at low risk for CMV reactivation. However, CMV infection still occurs in patients with the KIR protective genotype, and the question has been raised as to whether this is related to the lack of KIR expression. In this report, expression of the KIR2DS2 and KIR2DS4 genes, as measured by mRNA-based quantitative polymerase chain reaction in both the donor cells and the HCT recipient cells, was studied relative to CMV reactivation. In the control samples from healthy donors, the median range for KIR2DS2 and KIR2DS4 expression was low, with 35% of donors considered null-expressers. Interestingly, KIR2DS2 and KIR2DS4 expression was elevated after HCT compared with donor expression before HCT, and was significantly elevated in CMV viremic compared with CMV nonviremic HCT recipients. The CMV seropositivity of donors was not associated with activating KIR expression, and donor null expression in those with the KIR2DS2 or KIR2DS4 genotype was not predictive for CMV reactivation in the recipient. After controlling for other transplant factors, including donor type (sibling or unrelated), transplant source (bone marrow or peripheral blood stem cells), and acute GVHD grade, regression analysis of elevated KIR gene expression found an association for both KIR2DS2 and KIR2DS4, with a 7-fold increase in risk for CMV reactivation. We speculate that the elevated activating KIR expression in CMV-viremic HCT recipients is either coincidental with factors that activate CMV or is initiated by CMV or cellular processes responsive to such CMV infection reactivation. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus ± methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)±MTX, and the current series of 14 patients who received tacrolimus/sirolimus±MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P =.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P =.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus±MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF±MTX. [Copyright &y& Elsevier]

Abstract: In the era of cytomegalovirus (CMV)-preemptive therapy, it is unclear whether CMV serostatus of donor or recipient affects outcome of allogeneic hematopoietic stem cell transplantation (HSCT) among children with leukemia. To investigate, consecutive patients aged 0-18 who underwent primary HSCT for acute leukemia in 1997-2007 (HLA-matched sibling or unrelated donor, myeloablative conditioning, unmanipulated bone marrow or peripheral blood, preemptive therapy, no CMV prophylaxis) were followed retrospectively through January 2008. Treatment failure (relapse or death) was analyzed using survival-based proportional hazards regression. Competing risks (relapse and nonrelapse mortality, NRM) were analyzed using generalized linear models of cumulative incidence-based proportional hazards. Excluding 4 (2.8%) patients lacking serostatus of donor or recipient, there were 140 subjects, of whom 50 relapsed and 24 died in remission. Pretransplant CMV seroprevalence was 55.7% in recipients, 57.1% in donors. Thirty-five (25.0%) grafts were from seronegative donor to seronegative recipient (D−/R−). On univariate analysis, D−/R− grafts were associated with shorter relapse-free survival (RFS) than other grafts (median 1.06 versus 3.15 years, P < .05). Adjusted for donor type, diagnosis, disease stage, recipient and donor age, female-to-male graft, graft source, and year, D−/R− graft was associated with relapse (hazards ratio 3.15, 95% confidence interval 1.46-6.76) and treatment failure (2.45, 1.46-4.12) but not significantly with NRM (2.00, 0.44-9.09). In the current era, children who undergo allogeneic HSCT for acute leukemia have reduced risk of relapse and superior RFS when recipient and/or donor is CMV-seropositive before transplantation. However, no net improvement in RFS would be gained from substituting seropositive unrelated for seronegative sibling donors. [Copyright &y& Elsevier]

There is a paucity of information on late-occurring (≥1y) infectious complications in contemporary survivors of hematopoietic cell transplantation (HCT). Addressing these knowledge gaps can help tailor post-HCT infection surveillance and proactive immune reconstitution practices in this growing population. Patients were eligible if they underwent a first HCT at City of Hope between 2010 and 2013, and were alive and in remission at 1y post HCT; 696 were eligible and included in this study. Standardized (national guidelines) definitions were used to determine the occurrence of late-occurring (≥1y after HCT) severe/life-threatening/fatal bacterial, viral and fungal infections. Infections that occurred within 4 weeks of a previous one were considered polymicrobial. Follow-up was censored at relapse, subsequent malignancy, death, or December 31, 2017, whichever occurred first. Chronic GVHD (cGVHD) was categorized as none, mild, moderate/severe at 1y post HCT. We determined the cumulative incidence of: first, polymicrobial, vaccine-preventable, and subsequent infection (>4 weeks from initial infection), taking into consideration competing risk. We used multivariable regression (hazard ratio [HR], 95% confidence interval [CI]) to adjust for relevant covariates. Median age at HCT was 53.3y (range, 0.7y-78.1y); 58.5% were male; 73.1% were non-Hispanic white; 57.2% underwent allogeneic HCT; 42.8% were at high risk of relapse; 69.1% received myeloablative conditioning. Overall, 194 (27.9%) developed a late infection; 75 (10.8%) had at least one vaccine-preventable infection. Median time to first infection was 1.8y (range, 1.0-6.6y) from HCT. The 5y cumulative incidence of a late infection was 28.6%; 5y incidence of vaccine-preventable infection was 11.7%; 5y incidence of polymicrobial infection was 6.4%; and there was a steep increase in the incidence of each subsequent infection (Fig 1). Survivors of allogeneic HCT had a significantly higher 5y incidence (Fig 2), and the incidence was highest in patients with moderate/severe cGVHD at 1y post-HCT (Fig 3). Overall, there was a four-fold risk among allogeneic compared to autologous patients (HR 4.11; 95%CI 2.83-5.97; p<0.001). Mild cGVHD at 1y was associated with a 1.96-fold (95% CI 1.06-3.61) risk, while moderate/severe cGVHD was associated with a 3.61-fold (95% CI 1.98-6.58) risk of developing a late-occurring infection (reference: no cGVHD). Nearly one third of long-term HCT survivors developed a severe/life-threatening/fatal infection, and one in ten developed a vaccine-preventable infection. Allogeneic HCT survivors had a higher risk than autologous survivors, due in part to cGVHD and its management. There was a steep increase in risk of subsequent infections with each infectious episode, emphasizing the need for closer monitoring and prevention strategies in these patients. [ABSTRACT FROM AUTHOR]

Abstract: Reduced-intensity regimens (RIRs) are being used with increasing frequency in patients with non-Hodgkin’s lymphoma (NHL) undergoing allogeneic transplantation. The impact of dose reduction on relapse and survival has not been extensively studied. We performed a retrospective analysis of 88 patients conditioned with conventional myeloablative regimens (CMRs) (n = 48) and an RIR (n = 40) of fludarabine 125 mg/m2 and melphalan 140 mg/m2. Compared with the patients receiving CMR, those receiving RIR were older, had more often failed autologous transplantation, and had more frequently received peripheral blood and unrelated donor transplants. Graft-versus-host disease prophylaxis was provided with cyclosporine + methotrexate ± prednisone for the CMR and with cyclosporine + mycophenolate ± methotrexate for the RIR. The relapse rate was significantly lower in the patients receiving CMR than in those receiving RIR (13% vs 28%; P = .05). The 1-year transplantation-related mortality rate was 33% for CMR and 28% for RIR (P = .40). Kaplan-Meier 2-year overall survival and progression-free survival were 52% and 46% for CMR versus 53% and 40% for RIR (P = not significant). Using cumulative incidence functions based on competing risks, univariate analysis, and treatment-related prognostic factors, we found that higher treatment intensity (P = .03; relative risk [RR] = 35%) and absence of previous autologous transplantation (P = .0007; RR = 20%) were associated with a lower relapse rate. Using a Cox univariate proportional hazards model, we found that chemosensitive disease at transplantation (P = .05; RR = 57%) and absence of previous autologous transplantation (P = .002; RR = 37%) were associated with improved survival. Our observation of similar survival in the patients receiving CMR and those receiving RIR confirms that RIRs are feasible alternatives for high-risk patients with NHL; however, the data suggest that reduced treatment intensity and previous autologous transplantation are associated with increased relapse. [Copyright &y& Elsevier]

Despite of the continuous increase in the number of volunteer donors available through the registry, many patients who require an allogeneic hematopoietic cell transplantation (HCT) cannot find a fully-matched donor. While a mismatched unrelated donor (MMUD) is frequently available, it is associated with inferior outcomes and increased risk of graft-versus-host disease (GvHD). Post-transplant cyclophosphamide (PTCy) has been effective in haploidentical HCT, and increasingly used in matched donor HCTs. However, limited data exist in MMUD setting. We conducted a prospective single center trial (NCT 03128359) of PTCy for MMUD HCT with the primary objective of estimating 1-year GvHD-free relapse/progression-free survival (GRFS). As of October 2019, all planned 39 patients have been enrolled with a median follow up of 11 months (range: 1-23). Here we present the preliminary estimate of 1-year GRFS and other HCT outcomes in two strata; myeloablative conditioning (n=19) using Fludarabine (90 mg/m2) and FTBI (1200 cGy) or reduced intensity conditioning (n=19) using Fludarabine (100 mg/m2) and Melphalan (140 mg/m2 or 100 mg/m2 if >60 years old). Patients between 0 to 75 years of age and KPS of ≥70% with hematologic malignancies undergoing HCT from a 7/8 HLA-matched (A-, B-, C-, and DR-) donor were eligible. Patients with donor specific antibodies to the mismatched HLA-locus were excluded. All patient received PBMCs (3-5 × 106/kg) followed by GVHD prophylaxis consisting of PTCy (50 mg/kg for 2 days), Tacrolimus (1 mg), and mycophenolate mofetil (1 gr 3 × a day). Median age at the time of HCT was 53 years (range: 21-72), and 50% of patients were male. Disease risk was low in 47% (n=18), intermediate in 37% (n=14), and high in 16% of the patients (n=6). At transplant, 29 patients were in complete remission, and 9 had active disease. HCT-CI was 0 in six (16%) and 1-2 in 15 (39%) and >2 in 17 (45%) patients. Donors' median age was 32 years (range: 19-53) and donors were mismatched at HLA-A (n=14), -B (n=12), -C (n=8), or DR-loci (n=5). Median number of mismatches was 2 of 12 (range: 1-4). Female to male donor HCT was in 11% of recipients. Neutrophil engraftment occurred in all patients (median time to engraft: 16 days; range 13-35). One-year overall survival (OS) and GRFS were 92% (95% CI: 70-98) and 70% (95% CI: 51-83), respectively. Non-relapse mortality and relapse rate at 1 year were at 8% (95% CI: 2-29) and 13% (95% CI: 5-34), respectively. Cumulative incidence of day 100 acute GvHD grade 2-4 was 50% (95% CI: 35-71) and 1-year chronic GvHD was 56% (95% CI: 39-81). No severe chronic GvHD by the NIH criteria was observed. In conclusion, the data from our phase II trial of PTCy showed highly promising OS/GRFS in patients receiving 7/8 MMUD HCT, and that PTCy in MMUD setting offers an alternative and effective HCT approach for patients who do not have an available matched donor. [ABSTRACT FROM AUTHOR]

We previously demonstrated poor outcomes of patients with acute myeloid leukemia (AML) with antecedent myeloproliferative neoplasms (MPN) undergoing allogeneic hematopoietic stem cell transplantation (HCT) (Gupta et al, BBMT, 2019; abstract 140). In particular, we did not find any difference in outcomes of patients who received transplant "in remission" defined as blood and bone marrow blasts < 5% compared to those with "active leukemia" defined as blood and or bone marrow blasts ≥ 5%. We hypothesized that genetic mutations may help in predicting the efficacy of HCT in molecularly defined sub-groups of post MPN AML. In addition, we hypothesized that patients considered "in remission" at the time of HCT may have a molecular profile similar to those who have "active leukemia" at the time of HCT. Of the 177 patients with post MPN AML identified in the Center for International Blood and Marrow Transplant Research (CIBMTR) database, 95 (54%) had sufficient DNA to perform molecular analysis that consisted of targeted Next-Generation sequencing on 49 genes clinically relevant in hematologic malignancies. Of the 95 patients analyzed, 54 were "in remission", and 41 had "active leukemia". Adverse risk cytogenetics was seen in 39 patients. The most frequently mutated genes (≥10% patients) in study cohort were: JAK2 (55%); TP53 (23%); ASXL1 (22%); TET2 (19%), SRSF2 (16%); DNMT3A (14%), RUNX1 (14%); CALR (13%); SF3B1 (10%). Cumulative incidence of non-relapse mortality (NRM), relapse, progression-free survival (PFS), and survival in the study cohort at 5-years were 23% (95% CI 15-32), 66% (95% CI 56-75), 11% (95% CI 6-19) and 16% (95% CI 9-25). In a multivariate model, TP53 mutation status was the only factor associated with outcomes of HCT; patients with mutated TP53 mutations had inferior overall survival [RR 1.99 (95% CI 1.14-3.49)] and increased relapse [RR 2.59 (95% CI 1.41-4.74)], and inferior PFS (RR 2.18 (95% CI 1.25-3.82)]. Disease status at HCT was not associated with outcomes. Moreover, there were no differences in the mutational landscape, number of mutations and variant allele frequency (VAF) between patients who underwent HCT "in remission" (n=54) versus those with "active leukemia" (n=41). We conclude that there is minimal benefit of HCT in patients with post MPN AML with mutated TP53, and novel strategies are required for these patients. We did not observe any difference in clinical outcomes or mutational profile of patients undergoing transplant "in remission" compared to those with "active leukemia" questioning the clinical benefit of blast reduction strategies in post MPN AML. [ABSTRACT FROM AUTHOR]