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Topic Significance & Study Purpose/Background/Rationale High dose chemotherapy followed by hematopoietic cell transplantation (HCT) is an intensive cancer treatment associated with devastating complications. Persistent physical inactivity after HCT is sufficient to cause muscle mass loss, decreased strength, physical deconditioning, and potential progression to disability. Sustainable physical activity incorporated into activities of daily living may break this negative cycle. This pilot, randomized controlled trial tested the feasibility and preliminary effects of a free-living physical activity intervention (STEPS) compared to usual care on fatigue (primary outcome), functional ability, muscle strength, physical activity, and quality of life (secondary outcomes) in people with multiple myeloma treated with autologous HCT. Methods, Intervention, & Analysis This study used a two-group, randomized block, repeated measures design (n = 32). The six-week STEPS intervention aimed to increase physical activity by 10% weekly through education, goal-setting, daily step tracking using wearable technology, and guided integration of physical activity into daily routines. Data were collected using self-report questionnaires, physical performance tests, and wrist actigraphy prior to HCT and seven weeks following hospital discharge. Split-plot 2 × 2 ANOVAs were used to analyze the preliminary group (STEPS versus usual care), time (prior to HCT versus seven weeks after hospital discharge), and group x time interactions effects. Findings & Interpretation The STEPS group achieved their daily physical activity goal 53% of the time. Compared to usual care, the STEPS group experienced greater appetite loss (p = .05), more diarrhea (p = .05), and slept more (p = .03). Both groups reported improvements in mental fatigue (p = .02), emotional functioning (p = .01), pain (p = .009), sleep disturbance (p = .001), anger (p = .003), anxiety (p = .001), and depression (p = .02) seven weeks after HCT discharge compared to baseline. Conversely, both groups climbed the stairs slower (p = .003) and had weaker hand-grips (p Discussion & Implications The STEPS intervention is feasible for people with multiple myeloma treated with HCT. Although preliminary, differential improvement in the STEPS group's patient outcomes did not occur (no significant group x time interactions). Both groups reported improved symptoms and experienced some declines in physical function seven weeks after HCT hospital discharge.

Purpose: Family may play an important role in Hematopoietic stem cell transplantation (HSCT) recovery; however, little is known about the effect of family functioning on an individual’s health. The purpose of this study was to examine the effect of family cohesion (family functioning) on the trajectory of HSCT recipients’ symptom distress (symptom frequency and symptom bother) before, during, and after HSCT. Methods: Secondary analysis was conducted using data collected from178 individuals who underwent HSCT. Longitudinal parallel-process (LPP) modeling was used to examine how family cohesion and HSCT associated symptoms (symptom frequency and symptom bother) change over time; and how these longitudinal changes relate to each other. Results: The trajectory of family cohesion predicted the trajectories of HSCT associated symptom frequency and bother. HSCT recipients who experienced higher family cohesion at baseline (T1) showed lower symptom frequency (pConclusion: Findings indicate that higher family cohesion predicts decrease in symptom distress over the HSCT trajectory. Interventions aimed at enhancing family cohesion have the potential to lower HSCT recipients’ symptom distress. Further research is needed to understand the critical role of family cohesion and family functioning and their relationship with HSCT symptom distress prevention, early detection, and risk stratification.

Autologous stem cell transplantation (ASCT) is a potentially curative therapy but requires collection of sufficient blood stem cells (PBSC). Up to 40 % of patients with multiple myeloma (MM) fail to collect an optimum number of PBSC using filgrastim only and often require costly plerixafor rescue. The nonsteroidal anti-inflammatory drug meloxicam mobilizes PBSC in mice, nonhuman primates and normal volunteers, and has the potential to attenuate mobilization-induced oxidative stress on stem cells. In a single-center study, we evaluated whether a meloxicam regimen prior to filgrastim increases collection and/or homeostasis of CD34+ cells in MM patients undergoing ASCT. Mobilization was not significantly different with meloxicam in this study; a median of 2.4 × 106 CD34+ cells/kg were collected in the first apheresis and 9.2 × 106 CD34+ cells/kg were collected overall for patients mobilized with meloxicam-filgrastim, versus 4.1 × 106 in first apheresis and 7.2 × 106/kg overall for patients mobilized with filgrastim alone. CXCR4 expression was reduced on CD34+ cells and a higher CD4+/CD8+ T-cell ratio was observed after mobilization with meloxicam-filgrastim. All patients treated with meloxicam-filgrastim underwent ASCT, with neutrophil and platelet engraftment similar to filgrastim alone. RNA sequencing of purified CD34+ cells from 22 MM patients mobilized with meloxicam-filgrastim and 10 patients mobilized with filgrastim only identified > 4,800 differentially expressed genes (FDR

We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders.

Acute Myeloid Leukemia (AML) has a median age at diagnosis of 67 years. The most common curative therapy remains an allogeneic hematopoietic stem cell transplantation (HCT), yet it is complicated by treatment-related mortality (TRM) and ongoing morbidity including graft versus host disease (GVHD) that may impact survival, particularly in older patients. We examined the outcomes and predictors of success in 1321 patients aged 60 years and older receiving a HCT for AML in first complete remission (CR1) from 2007-2017 and reported to the CIBMTR. Outcomes were compared in three age cohorts (60-64; 65-69; 70+). With median follow-up of nearly 3 years, patients aged 60-64 had modestly, though significantly better OS, DFS and lower TRM than those either 65-69 or 70+; cohorts with similar outcomes. Three-year OS for the 3 cohorts was 49.4%, 42.3%, and 44.7% respectively (p = 0.026). TRM was higher with increasing age, cord blood as graft source and HCT-CI score of ≥3. Conditioning intensity was not a significant predictor of OS in the 60-69 cohort with 3-year OS of 46% for RIC and 49% for MAC (p = 0.38); MAC was rarely used over age 70. There was no difference in the relapse rate, incidence of Grade III/IV acute GVHD, or moderate-severe chronic GVHD across the age cohorts. After adjusting for other predictors, age had a small effect on OS and TRM. High-risk features including poor cytogenetics and measurable residual disease (MRD) prior to HCT were each significantly associated with relapse and accounted for most of the adverse impact on OS and DFS. Age did not influence the incidence of either acute or chronic GVHD; while graft type and associated GVHD prophylaxis were most important. These data suggest that age alone is not a barrier to successful HCT for AML in CR1 and should not exclude patients from HCT. Efforts should focus on minimizing residual disease and better donor selection.

Acute myeloid leukemia (AML) is an aggressive, clonally heterogeneous, myeloid malignancy, with a 5-year overall survival of approximately 27%. It constitutes the most common acute leukemia in adults, with an incidence of 3-5 cases per 100,000 in the United States. Despite great advances in understanding the molecular mechanisms underpinning leukemogenesis, the past several decades had seen little change to the backbone of therapy, comprised of an anthracycline-based induction regimen for those who are fit enough to receive it, followed by risk-stratified post-remission therapy with consolidation cytarabine or allogeneic stem cell transplantation (allo-SCT). Allo-SCT is the most fundamental form of immunotherapy in which donor cytotoxic T and NK cells recognize and eradicate residual AML in the graft-versus-leukemia (GvL) effect. Building on that, several alternative or synergistic approaches to exploit both self and foreign immunity against AML have been developed. Checkpoint inhibitors, for example, CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors block proteins found on T cells or cancer cells that stop the immune system from attacking the cancer cells. They have been used with limited success in both the AML relapsed/refractory (R/R) and post SCT settings. AML tumor mutational burden is low compared to solid tumors and thus, it is less likely to generate neoantigens and respond to antibody-mediated checkpoint blockade that has shown unprecedented results in solid tumors. Therefore, alternative therapeutic strategies that work independently of the T cell receptor (TCR) specificity have been developed. They include bispecific antibodies, which recruit T cells through CD3 engagement, and in AML have shown an overall response rate ranging between 14 and 30% in early phase trials. Chimeric Antigen Receptor (CAR) T cell therapy is a type of treatment in which T cells are genetically engineered to produce a recombinant receptor that redirects the specificity and function of T lymphocytes. However, lack of cell surface targets exclusively expressed on AML cells including Leukemic Stem Cells (LSCs) combined with clonal heterogeneity represents the biggest challenge in developing CAR therapy for AML. Antibody-Drug Conjugates (ADC) constitute the only FDA-approved immunotherapy to treat AML with Gemtuzumab Ozogamicin, a CD33-specific ADC used in CEBPα-mutated AML. The identification of additional cell surface targets is critical for the development of other ADC's potentially useful in the induction and maintenance regimens, given the ease at which these reagents can be generated and managed. Here, we will review those immune-based therapeutic interventions and highlight active areas of research investigations toward fulfillment of the great promise of immunotherapy to AML.

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12–58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21–30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57–8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.

Assessment of prognostic biomarkers of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group is lacking. To address this need, we conducted a prospective cohort study with 415 patients at 6 centers: 170 were children age 10 years or younger and 245 were patients older than age 10 years (both children and adults were accrued from 2013 to 2018). The following 4 plasma biomarkers were assessed pre-HCT and at days +7, +14, and +21 post-HCT: stimulation-2 (ST2), tumor necrosis factor receptor 1 (TNFR1), regenerating islet–derived protein 3α (REG3α), and interleukin-6 (IL-6). We performed landmark analyses for NRM, dichotomizing the cohort at age 10 years or younger and using each biomarker median as a cutoff for high- and low-risk groups. Post-HCT biomarker analysis showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in children age 10 years or younger (ST2: hazard ratio [HR], 9.13; 95% confidence interval [CI], 2.74-30.38; P = .0003; TNFR1: HR, 4.29; 95% CI, 1.48-12.48; P = .0073; REG3α: HR, 7.28; 95% CI, 2.05-25.93; P = .0022); and in children and adults older than age 10 years (ST2: HR, 2.60; 95% CI, 1.15-5.86; P = .021; TNFR1: HR, 2.09; 95% CI, 0.96-4.58; P = .06; and REG3α: HR, 2.57; 95% CI, 1.19-5.55; P = .016). When pre-HCT biomarkers were included, only ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, and graft-versus-host-disease prophylaxis), ST2 remained associated with NRM only in recipients age 10 years or younger (HR, 4.82; 95% CI, 1.89-14.66; P = .0056). Assays of ST2, TNFR1, and REG3α in the first 3 weeks after HCT have prognostic value for NRM in both children and adults. The presence of ST2 before HCT is a prognostic biomarker for NRM in children age 10 years or younger allowing for additional stratification. This trial was registered at www.clinicaltrials.gov as #NCT02194439.

We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders.

Introduction Chromosomal abnormalities are frequent events in hematological malignancies. The degree of HLA compatibility between donor and recipient in hematopoietic stem cell transplantation is critical. Purpose of the study In this report, we describe an acute myeloid leukemia case with loss of heterozygosity (LOH) encompassing the entire HLA. Materials and methods HLA molecular typing was performed on peripheral blood (PB) and buccal swabs (BS). Chromosomal microarray analysis (CMA) was performed using a whole genome platform. Results Typing results on PB sample collected during blast crisis demonstrated homozygosity at the -A, -B, -C, -DR, and -DQ loci. A BS sample demonstrated heterozygosity at all loci. A subsequent PB sample drawn after count recovery confirmed heterozygosity. The CMA performed on PB samples collected during and after blast crisis revealed a large terminal region of copy-neutral LOH involving chromosome region 6p25.3p21.31, spanning approximately 35.9 Mb. The results of the CMA assay on sample collected after count recovery did not demonstrate LOH. Conclusions LOH at the HLA gene locus may significantly influence the donor search resulting in mistakenly choosing homozygous donors. We recommend confirming the HLA typing of recipients with hematological malignancies when homozygosity is detected at any locus by using BS samples, or alternatively from PB when remission is achieved.

BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known. METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation. RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation. CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT02683525.)

Sinusoidal obstruction syndrome (SOS) is a serious complication of hematopoietic stem cell transplantation (HSCT). Sirolimus plus tacrolimus is an accepted regimen for graft-versus-host disease (GVHD) prophylaxis, with both agents implicated as risk factors for SOS. We analyzed 260 consecutive patients who underwent allogeneic HSCT following myeloablative conditioning using total body irradiation (TBI)-based (n = 151) or chemotherapy only (n = 109) regimens, with sirolimus plus tacrolimus for GVHD prophylaxis. SOS occurred in 28 patients at a median of 22 (range, 12-58) days. Mean sirolimus trough levels were higher between days 11 and 20 following transplant in patients who developed SOS (10.3 vs. 8.5 ng/ml, P = 0.008), with no significant difference in mean trough levels between days 0 and 10 (P = 0.67) and days 21-30 (P = 0.37). No differences in mean tacrolimus trough levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, a mean sirolimus trough level ≥ 9 ng/ml between days 11 and 20 increased the risk of SOS (hazard ratio 3.68, 95% CI: 1.57-8.67, P = 0.003), together with a longer time from diagnosis to transplant (P = 0.004) and use of TBI (P = 0.006). Our results suggest that mean trough sirolimus levels ≥ 9 ng/mL between days 11 and 20 post transplant may increase the risk of SOS and should be avoided.

Histoplasma capsulatum infection is a rare complication in the allogeneic stem cell transplant patients. Minimal guidance exists on how to appropriately manage histoplasmosis in these patients. We report a patient who developed Histoplasma pneumonia while receiving voriconazole prophylaxis at a therapeutic trough level. The patient experienced significant clinical improvement after initiation of itraconazole pharmacotherapy. We recommend a lower threshold for evaluation for histoplasmosis in allogeneic hematopoietic stem cell transplant recipients who live in endemic regions, regardless of their antifungal prophylactic regimen.

Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34+ cell doses > 5.0 × 106/kg/single transplant led to decreased resource utilization. Because most GCT patients have received prior cisplatin-based treatment, collecting >10 × 106 CD34+ cells/kg is challenging. We analyzed the effect of CD34+ cell dose on resource utilization and outcome in 131 GCT patients, median age 29.5 years (range, 16 to 58), undergoing tandem ASCT. Of 262 individual transplants performed, 120 were performed as inpatient and 142 as planned outpatient. Overall, median CD34+ dose per transplant was 3.1 × 106/kg (range, 0.8 to 16.0), with no significant difference between inpatient and outpatient transplants. Patients were divided into quartiles based on the CD34 cell dose infused: Q1, 0.8 to 1.9 × 106/kg; Q2, 2.0 to 2.9 × 106/kg; Q3, 3.0 to 4.1 × 106/kg; and Q4, 4.2 to 16.0 × 106/kg. For all patients higher CD34+ cell doses were associated with significantly shorter times to neutrophil (P

Background: Umbilical cord blood hematopoietic stem cell transplant (UCBT) has been practiced as an alternative source of hematopoietic stem cells for patients in need of transplantation. Double-units UCBT has been established as a means of achieving a cell dose of at least 2.5x10 7 nucleated cells per kilogram of body weight in adult recipients. The advantages of UCBT include its rapid availability, reduced stringency in terms of human leukocyte antigen (HLA) match requirements, and subsequent increase in access to transplants for racial minorities. Both related and unrelated UCBTs with single or double units have been performed with high rates of success in both pediatric and adult settings to treat a variety of medical conditions. Prior to undergoing UCBT, recipients must undergo a conditioning regimen to create space in the bone marrow, suppress the immune system to allow for donor stem cell engraftment, and reduce the tumor burden in cases of neoplastic disease. Total body irradiation (TBI) is commonly incorporated into conditioning regimens to enforce these efforts. Although intense myeloablation in general is associated with a lower risk of relapse and graft rejection, greater regimen intensity also leads to a higher rate of transplant related morbidity and mortality (TRM). Inclusion of TBI specifically in conditioning regimens has been shown to result in organ toxicity and subsequent malignant neoplasm. To help mitigate the risks of myeloablative conditioning (MAC) regimens, non-TBI and reduced-intensity conditioning (RIC) regimens have been investigated as a means of reducing TRM and increasing access of transplantation to patients with age disadvantages or significant comorbidities. Despite ongoing investigation, studies comparing conditioning regimens of UCBT, with and without TBI, remain limited. This study, using real-world data collected from 4 institutions, retrospectively analyzed the impact of TBI as part of MAC or RIC conditioning regimens in patients undergoing UCBT. Methods: This is a retrospective study that analyzed the outcomes of 136 patients receiving umbilical cord blood transplants at four institutions. Seventy-nine patients received myeloablative condition (MAC), in which 36 underwent TBI and 33 did not; 67 patients received reduced-intensity condition (RIC), in which 24 underwent TBI and 43 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in MAC subgroup and RIC subgroup, respectively. Results: Characteristics of UCBT recipients who did and did not undergo TBI, stratified by conditioning regimen were compared with both multivariate and univariate analyses and didn't see significant difference. We didn't observe significant difference in GVHD and transplant-related infection incidence rates between patient subgroup that did and did not undergo TBI as part of their pre-UCBT conditioning regimen via both multivariate and univariate analyses. In RIC subgroup, the patients who underwent TBI appeared to have superior overall survival (adjusted hazard ratio [aHR]=0.25, 95% confidence interval [CI]: 0.09-0.66, p=0.005) (Figure 1), progression-free survival (aHR=0.26, 95% CI: 0.10-0.66, p=0.005) (Figure 2), and shorter time to neutrophil engraftment (aHR=6.26, 95% CI: 2.27 - 17.31, p=0.0004) (Figure 3). However, in MAC subgroup, there were no statistically significant difference between using and not using TBI. There were also no differences between the patients who either underwent or not underwent TBI in terms of acute or chronic GVHD rates or rates of transplant-related infections in both subgroups. Conclusion: Combining with RIC, TBI may improve OS, PFS, and neutrophil engraftment time. However, the incidences of other post-transplant complication were comparable between patients who underwent and did not undergo TBI as part of conditioning regimens during umbilical cord blood transplant. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Delayed engraftment remains a limitation of umbilical cord blood (UCB) transplantation. We previously showed that inhibition of dipeptidylpeptidase (DPP)-4 using sitagliptin 600 mg daily was safe with encouraging results on engraftment, but inhibition was not sustained. We evaluated the efficacy and feasibility of higher doses of sitagliptin to enhance engraftment of UCB in patients with hematological cancers. Fifteen patients, median age 41 (range, 18-59) years, received single UCB grafts matched at 4 (n=11) or 5 (n=4) of 6 HLA loci with median nucleated cell dose of 3.5 (range, 2.57-4.57) x107/kg. Sitagliptin 600 mg every 12 hours was administered days -1 to +2. All patients engrafted by day 30, with 12 (80%) engrafting by day 21. The median time to neutrophil engraftment was 19 (range, 12-30) days. Plasma DPP-4 activity was better inhibited with a mean residual trough DPP-4 activity of 70%±19%. Compared to patients previously treated with 600 mg/day, sitagliptin 600 mg every 12 hours appeared to improve engraftment, supporting the hypothesis that more sustained DPP-4 inhibition is required. In-vivo inhibition of DPP-4 using high-dose sitagliptin compares favorably with other approaches to enhance UCB engraftment with greater simplicity, and may show synergy in combination with other strategies.

Introduction Allogeneic HCT is the only established curative therapy for high risk hematologic malignancies. The major challenges are leukemia relapse and high grade GVHD. We have developed the CD24Fc fusion protein to selectively inhibit danger-associated molecular pattern (DAMP)-induced inflammation and discovered that it effectively prevents GVHD without affecting the desirable GVL effect in preclinical models. With the support of SBIR awards from the NCI, we have completed a phase II randomized, double blind, multi-center, dose escalation trial comprised of 3 dosing cohorts of 8 patients (3:1 CD24Fc vs. placebo), with a total enrollment of 24 subjects. Notably, clinical data from this trial demonstrate that CD24Fc reduces the incidence of severe GVHD, resulting in statistically significant increases of acute 180-day GVHD-free survival (aGFS). A Phase II expansion cohort to enroll an additional 20 subject is ongoing (NCT02663622). Here we propose a phase III clinical trial with 180 patients (1:1 CD24Fc vs placebo) to test the hypothesis that CD24Fc prophylaxis can significantly improve 180 day acute GVHD-free survival (aGFS) over placebo control. Study Design A Randomized, Double-blind, Placebo-controlled, Multi-Center, Phase III Study of CD24Fc for the Prevention of Acute GVHD Following Myeloablative Allogeneic HCT (CATHY) (NCT04095858). This study will compare CD24Fc or Placebo with standard GVHD prophylaxis of tacrolimus and methotrexate in the setting of myeloablative conditioning (MAC), matched unrelated donor (MUD) allogeneic HCT in patients with AML/ALL or MDS. Patients will be randomized 1:1 to receive CD24Fc or placebo at the dose levels of 480mg, 240mg and 240mg on Days -1, +14 and +28, respectively. The primary endpoint is the rate of 180 days grade III-IV acute GVHD-free survival (aGFS). Secondary endpoints are 1 yr DFS, 1 yr OS, and D180 Gr II-IV aGFS. Other exploratory evaluations will be 1 yr chronic GVHD, 1 yr relapse, NRM at 1 year, incidence and rate of infection at 100 days, and rate of Gr III and above mucositis at 28 days. The study will enroll 180 patients, or 90 per arm, with an estimated accrual period of 24 months. Statistical Consideration The study will include one interim analysis for efficacy. Z test statistics for comparing the two arms will be compared to the critical values and results be reviewed by the independent DSMB.

Introduction DPP-IV is a homodimeric type II transmembrane receptor identical to the leucocyte surface antigen CD26. The interaction of CD26/DPP-IV on T cells with its ligand caveolin-1 on antigen-presenting cells (APC) enhances T cell activation, proliferation, and cytokine production. It also upregulates CD86 on APC resulting in co-stimulation. In a xenograft mouse model, reducing CD26 expression by a monoclonal antibody prevented aGVHD and preserved graft-versus-tumor effects (Hatano et al. BJH 2013). In a pilot trial testing sitagliptin for enhancement of cord blood engraftment, we observed a lower than expected rate of aGVHD (Farag et al. Stem Cell Dev 2013) and hypothesized that CD26/DPP-IV inhibition with sitagliptin may prevent aGVHD following allogeneic PBSC transplants. Objective Conduct a prospective phase II trial to test if sitagliptin can reduce the rate of grade II-IV aGVHD by day +100 following myeloablative allogeneic PBSC transplants (ClinicalTrials.gov, NCT02683525). The primary endpoint was grade II-IV aGVHD by day +100. Methods Patients received thiotepa (15 mg/kg) and cyclophosphamide (120 mg/kg), followed by G-CSF mobilized PBSC from matched related (6/6 HLA match) or unrelated (10/10 HLA match) donors. Sitagliptin (600 mg q12 hours) was given on days -1 to day +14, together with tacrolimus and sirolimus through day +100, then tapering until day +180. In a Simon two-stage design, Results Thirty-six (17 M; 19 F) patients of median age 46 (20-59) years were enrolled. Patients had AML (n=19), ALL (n=9), MDS (n=4), and CML (n=4). Transplants were from matched related (13 patients) or unrelated (23 patients) donors. Acute GVHD occurred in 2 of 36 patients by day +100 (1 grade II; 1 grade IV), for cumulative incidences of 5.6% (95% confidence interval [CI], 0% - 13.2%) and 2.8% (95% CI, 0% - 8.2%) for grade II-IV aGVHD and grade III-IV aGVHD at day +100, respectively (Fig 1). An additional patient developed late-onset grade II aGVHD at day +140 following abrupt stopping of immunosuppression on day +100 for low donor chimerism in absence of relapse. Significant toxicities though day +30 included grades III-IV mucositis (n=15), acute kidney injury (4 with high tacrolimus levels, 1 sepsis), viral reactivation/infection (4 CMV, 2 BK, 1 EBV, 1 HHV6), and passenger lymphocyte syndrome (n=2). Non-relapse mortality was 0% at 12 months. With median follow-up of 699 (118-1312) days, the relapse-free survival was 77.2% (95% CI, 63.2% - 91.1%) and overall survival was 94.3% (95% CI, 86.7% - 100%) at 12 months (Fig 2a-b). Conclusion CD26/DPP-IV inhibition with sitagliptin is well-tolerated and significantly reduced the rate of aGVHD by day +100 in patients undergoing myeloablative allogeneic PBSCT transplantation.

Danger-associated molecular patterns (DAMPs) released during conditioning have been shown to amplify experimental GVHD. CD24 fusion protein (CD24Fc; OncoImmune), a glycoprotein linked to human IgG1 Fc, binds to Siglec-10 to negatively regulate host response to DAMPs. We have reported that infusion of CD24Fc prior to HCT significantly decreased GVHD-related mortality in murine models of HCT (Toubai, Blood 2015 & Toubai, JCI Insight 2017). We hypothesized that enhancing Siglec10-CD24 interactions by administration of CD24Fc would prevent acute GVHD. A randomized, prospective, multi-site, placebo controlled phase 2a clinical trial was initiated to investigate safety of three dose levels of CD24Fc (or blinded placebo) plus standard GVHD prophylaxis with tacrolimus and methotrexate (MTX) in matched unrelated donors. T cell replete PBSC or BMT was infused. Randomization (3:1 ratio of CD24Fc:Placebo) was in 3 cohorts of 8 pts: 240mg single dose on D -1, 480mg single dose on D -1, and a 480mg, 240mg, and 240mg multiple dose regimen on D -1, 14 and 28, respectively. The primary endpoint was safety and determination of a recommended dose. Pts were followed for secondary endpoints of aGVHD, relapse and survival at D180. The trial enrolled 24 pts (CD24Fc, n=18; Placebo, n=6) with minimum follow up on one year (Table1). All planned dosages were administered without reaching an MTD. There were no infusion-related toxicities or DLTs. In placebo treated pts, there was one DLT resulting in death from pneumonia. Between groups there were no overall differences in AEs, although CD24Fc was associated with fewer days of severe (≥ Grade III) mucositis. There was no infection-related mortality related to CD24Fc treatment. The CD24Fc pts achieved neutrophil and platelet engraftment at a median of D 13 (12-23) and D 13 (9-23), respectively. PK studies demonstrated sustained drug levels through D 100 in the multi-dosing cohort. The incidence of grade II-IV GVHD was 39% (18-62%) and III-IV GVHD was 6% (95% CI 0-20%) at D 180 among CD24Fc treated pts. Grade 3 involvement of the lower-GI tract was observed in 1/18 pts, while the remainder of acute GVHD involved the upper GI tract or skin. All pts receiving treatment for GVHD experienced response. At D 180, relapse occurred in 2/18 pts, and OS was 100%. The endpoint of grade 3-4 GVHD-free survival (AGFS) was 94% at D 180 in pts receiving treatment with CD24Fc versus 50% in pts receiving placebo (HR 0.1; 90% CI 0.0-0.7). AGFS in contemporaneous case matched controls (n=68; CIBMTR) receiving myeloablative 8/8 HLA matched unrelated donor HCT with tacrolimus + MTX was 68% (95% CI: 56-78). In this translational phase 2a trial administration of CD24Fc was safe and tolerable. Additional investigations are required determine efficacy for improving AGFS after HCT. This trial represents the first attempt to prevent GVHD by inhibiting host response to DAMPs.

Natural killer (NK) cell recognition and killing of target cells are enhanced when inhibitory killer immunoglobulin-like receptors (KIR) are unable to engage their cognate HLA class I ligands. The genes of the KIR locus are organized into either KIR B haplotypes, containing 1 or more activating KIR genes or KIR A haplotypes, which lack those genes. Analysis of unrelated donor (URD) hematopoietic cell transplants (HCT), given to acute myeloid leukemia (AML) patients between 1988 and 2009, showed that KIR B haplotype donors were associated with better outcomes, primarily from relapse protection. Most of these transplants involved marrow grafts, fully myeloablative (MAC) preparative regimens, and significant HLA mismatch. Because the practice of HCT continues to evolve, with increasing use of reduced intensity conditioning (RIC), peripheral blood stem cell grafts, and better HLA match, we evaluated the impact of URD KIR genotype on HCT outcome for AML in the modern era (2010-2016). This analysis combined data from a prospective trial testing URD selection based on KIR genotypes (n = 243) with that from a larger contemporaneous cohort of transplants (n = 2419). We found that KIR B haplotype donors conferred a significantly reduced risk of leukemia relapse and improved disease-free survival after RIC, but not MAC HCT. All genes defining KIR B haplotypes were associated with relapse protection, which was significant only in transplant recipients expressing the C1 epitope of HLA-C. In the context of current HCT practice using RIC, selection of KIR B donors could reduce relapse and improve overall outcome for AML patients receiving an allogeneic HCT.

Over the past decade, our increased understanding of the interactions between the immune system and cancer cells has led to paradigm shifts in the clinical management of solid and hematologic malignancies. The incorporation of immune-targeted strategies into the treatment landscape of acute myeloid leukemia (AML), however, has been challenging. While this is in part due to the inability of the immune system to mount an effective tumor-specific immunogenic response against the heterogeneous nature of AML, the decreased immunogenicity of AML cells also represents a major obstacle in the effort to design effective immunotherapeutic strategies. In fact, AML cells have been shown to employ sophisticated escape mechanisms to evade elimination, such as direct immunosuppression of natural killer cells and decreased surface receptor expression leading to impaired recognition by the immune system. Yet, cellular and humoral immune reactions against tumor-associated antigens (TAA) of acute leukemia cells have been reported and the success of allogeneic stem cell transplantation and monoclonal antibodies in the treatment of AML clearly provides proof that an immunotherapeutic approach is feasible in the management of this disease. This review discusses the recent progress and persisting challenges in cellular immunotherapy for patients with AML.

Background: To address the need for establishing prognostic markers of Non-Relapse Mortality (NRM) and acute graft-versus-hostdisease (aGVHD) after allogeneic hematopoietic cell transplantation (HCT) in the pediatric age group, we conducted a prospective study (NCT02194439). Methods: 415 patients at six U.S. centers including 170 children ≤10 years were accrued from 2013 to 2018. Four biomarkers [stimulation-2 (ST2), interleukin-6, regenerating-islet-derived-3-alpha (REG3α) and tumornecrosis-factor-receptor-1 (TNFR1)] were assessed in the plasma pre-HCT (day -7), and at days +7, +14, +21 post-HCT. We performed landmark analyses for NRM and grade II-IV aGVHD, dichotomizing the cohort at ≤10 years and using each biomarker median as a cutoff for high and low risk groups. The multivariable analyses included the significant covariates. Findings: The NRM was not different among children ≤10 years compared to subjects >10 years. Landmark analyses using post-HCT assays showed that ST2 (>26 ng/mL), TNFR1 (>3441 pg/mL), and REG3α (>25 ng/mL) are associated with NRM in both children 10 years [HR (CI): ST2: 2.60 (1.15-5.86), p=0.021; TNFR1: 2.09 (0.96-4.58), p=0.06; REG3α: 2.57 (1.19-5.55), p=0.016]. When pre-HCT biomarkers were included, ST2 remained significant in both cohorts. After adjustment for significant covariates (race/ethnicity, malignant disease, graft, GVHD prophylaxis), ST2 remained associated with NRM only in recipients ≤10 years [HR(CI): 4.82 (1.89-14.66), p=0.0056]. ST2 was also associated with grade II-IV aGVHD in both ≤10 years and >10 years groups (p=0.0059, and p

The primary purpose of this research was to develop and evaluate the efficacy and feasibility of a brief, cost-effective family-focused intervention to promote adaptive coping and quality of life throughout a parent's bone marrow transplantation (BMT). Targeted outcomes were cohesion, decreased use of avoidance coping, open communication and effective management of emotional distress. Participants included an intervention group of 31 families and 29 families in a control group who received usual care. Each family included the BMT recipient, a partner/caregiver and children 10-18 years old. The intervention included two dyadic sessions for the BMT recipient and the partner/caregiver, one individual session for the caregiver and two digital video discs (DVDs) for children. Statistical analyses indicated that the intervention had a positive impact on at least one aspect of the adaptation of each family member. Caregivers reported the most distress but benefitted least from the intervention, whereas recipients and children reported improvement in distress. Ratings of satisfaction/acceptability were high, with 97% responding that they would recommend the intervention to others. Plans for future research include increased intervention intensity for the caregiver, a larger more diverse sample and implementation over an extended period post BMT.

Background TT/Cy has been reported as a well-tolerated conditioning regimen in patients with a variety of advanced leukemias undergoing allogeneic HCT (Blood 1996, 88:353-7). While other TT-containing regimens have been investigated, outcomes with TT/Cy, specifically, in a more uniform population have not been reported. Here, we report the outcome of TT/Cy in patients with myeloid malignancies undergoing allogeneic HCT, and compare the results with TBI/Cy. Methods We retrospectively analyzed 149 consecutive patients with AML (n=101), advanced CML (n=29), and high-grade MDS with >5% blasts (n=19) who received either TBI/Cy (TBI >13.5 Gy; Cy 120 mg/kg) or TT/Cy (TT 15 mg/kg; Cy 120 mg/kg) and allogeneic HCT from HLA-matched sibling or 10/10 or 9/10 HLA-matched volunteer unrelated donors (VUD) between 2007-2016 at Indiana University. Results Sixty-seven patients received TBI/Cy and 82 received TT/Cy. Baseline characteristics were not significantly different. TBI/Cy resulted in significantly higher grades 3-4 toxicity, including mucositis (64% vs. 48%, P=0.048), acute respiratory failure (22% vs. 10%, P=0.04), transaminase elevation (24% vs. 9%, P=0.01), acute renal failure (16% vs. 5%, P=0.02), and sinusoidal obstruction syndrome (16% vs. 0%, P=0.0001). Cumulative incidence of 100-day grades 2-4 acute GVHD (TBI/Cy 15.0% ± 4.4%, TT/Cy 20.7% ± 4.5%; P=0.15) and extensive stage chronic GVHD at 1-year (TBI/Cy 35.3% ± 6%, TT/Cy 43.6% ± 5.6%; P=0.27) were not significantly different. The cumulative incidence (CI) of non-relapse mortality (NRM) was higher following TBI/Cy (Fig 1A, P 5 were both associated with a higher hazard of death (P=0.02 and P=0.004). Conclusion TT/Cy is an effective conditioning regimen in patients with myeloid malignancies undergoing allogeneic HCT and is associated with lower NRM compared with TBI/Cy. Future studies should assess whether addition of other agents to TT and Cy improve outcomes or simply increase toxicity.

Corticosteroids are considered the standard first-line treatment for moderate/severe acute graft versus host disease (aGVHD), yet there is no consensus on the optimal management of patients that are steroid-refractory (SR). Infliximab is a chimeric monoclonal antibody with anti-TNF-α activity that has previously demonstrated efficacy in SR-aGVHD. We performed a retrospective review of 59 patients at Indiana University who underwent allogeneic stem cell transplantation and developed SR grade III-IV aGVHD from January 2007 to August 2018. Infliximab was administered 10 mg/kg weekly intravenously. Response criteria was in accordance with Martin et al (BBMT 2009; 12:777-784). Median age of treated patients was 49.5 years (range, 34.5-60) and median time from transplant to diagnosis of aGVHD was 106 days (range, 42-185) Patients received a median of 12 days (range, 8-20) of systemic steroids prior to infliximab. At the start of infliximab, 52 (88%) patients were on non-steroidal immunosupressants and 39 (66%) on non-absorbable steroids concurrently with systemic steroids. Patients received a median of 3 doses of infliximab with 37 (62.7%) patients receiving There was no significant difference between responders (n=16) and non-responders (n=43) in baseline demographic, transplant-related characteristics, initial GVHD prophylaxis regimen, number of non-steroidal systemic immunosuppressants at time of aGVHD diagnosis, or use of non-absorbable steroids. There was no difference in time from diagnosis of aGVHD to start of infliximab (median 16 vs. 11 days, P=0.06). Responders were less likely to have liver aGVHD involvement vs. non-responders (18% vs. 53%, P=0.016) and had slower tapering of systemic steroids, both at median time to 50% steroid dose (18 vs. 12 days, P=0.02) and 25% steroid dose (36 vs. 24 days, P=0.01). Responders had lower incidence of bacterial infection (44% vs. 74%, P=0.04), but not viral infections (56% vs. 47%, P=0.57). Responders had a longer overall survival (median 20.3 vs. 2.8 months, P=0.01). Our single center report of 59 patients with SR-aGVHD treated with infliximab is among the largest reported. The outcomes of response to SR-aGVHD are poor and there is an unmet need for better agents. Additional studies with greater patient numbers are needed to identify factors associated with improved response to infliximab.

Umbilical cord blood (CB) is a clinically useful source of hematopoietic stem (HSC) and progenitor (HPC) cells for treatment of a wide variety of malignant and non-malignant disorders. Amongst the benefits of CB, compared to bone marrow (BM) and mobilized peripheral blood (MPB), as a source of engrafting HSC and HPC are its ready availability through CB banks, and a relatively low level of graft vs. host disease (GVHD) elicited after transplantation. Disadvantages of CB, compared to BM and MPB, include the low, and sometimes limiting, number of cells collected in single donor units which can be less than optimal for engraftment of many adults and higher weight children, and the relatively slower speed to engraftment of neutrophils and platelets. While limiting numbers of nucleated cells found in single units of CB can be compensated for by transplantation of more than 1 unit of CB, this use of multiple cord blood units may be associated with increased GVHD, and has not meaningfully reduced the time to neutrophil and platelet engraftment. Thus, means to enhance numbers and/or potency of collected cells and their engrafting capability through ex-vivo and/or in-vivo maneuvers would likely enhance the efficacy and applicability of CB transplantation. Such efforts require a deeper understanding of the cell biology of HSC and HPC, the microenvironment that nurtures these cells, and greater mechanistic insight into cell surface receptors and intracellular signaling pathways regulating HSC/HPC function. This information could provide the means to modulate these cells for greater clinical advantage. There is also the potential, as yet far from proven in a clinical sense for use of mature cells generated from HSC/HPC, and for non-HSC/HPC uses of CB. Non-HSC/HPC include mesenchymal stem/stromal cells (MSC), endothelial progenitor cells (EPC), and induced pluripotent stem cells (iPSC). Caution is clearly required for non HSC/HPC stem/progenitor cell uses of CB, based on insufficient biological and preclinical information for MSC, EPC, and iPSC. This review addresses current knowledge and potential future means to enhance the quantity, quality and/or engrafting activity of CB HSC/HPC, and where the field stands in context of MSC, EPC, and iPSC from CB.

Multiple myeloma (MM) remains an incurable malignancy indicating a need for continued investigation of novel therapies. Recent studies have highlighted the role of cyclin-dependent kinases (CDK) in the pathogenesis of MM. PD0332991 (Palbociclib) is an orally bioavailable, highly selective inhibitor of the CDK4/6-cyclin complex and downstream retinoblastoma protein (Rb) activation pathway that induces cell cycle arrest in the G1 phase.In this review, the authors summarize the role of the CDK4/6 signaling pathway in MM. They also summarize the development of PD0332991 as a specific inhibitor of CDK4/6, and the reported preclinical and clinical data supporting the potential role of PD0332991 in MM.While PD0332991 is essentially cytostatic, inducing prolonged G1 arrest, it enhances the cytotoxic effect of other agents effective in MM, including bortezomib and lenalidomide, as confirmed in early phase clinical trials. However, with a plethora of other drugs of different classes being tested in MM, further development of PD0332991 will depend on defining the most efficacious combination with least toxicity. An unexplored opportunity remains the potential protective effect of PD0332991 against lytic bone lesions of MM. The next few years are likely to better define the place of PD0332991 in the treatment of MM.

Tandem autologous stem cell transplantation (ASCT) improves long-term survival of platinum-refractory germ cell tumors (GCT) patients. Studies, predominantly in lymphoma, showed that CD34

Intensive chemotherapeutic protocols and allogeneic stem cell transplantation continue to represent the mainstay of acute myeloid leukemia (AML) treatment. Although this approach leads to remissions in the majority of patients, long-term disease control remains unsatisfactory as mirrored by overall survival rates of approximately 30%. The reason for this poor outcome is, in part, due to various toxicities associated with traditional AML therapy and the limited ability of most patients to tolerate such treatment. More effective and less toxic therapies therefore represent an unmet need in the management of AML, a disease for which therapeutic progress has been traditionally slow when compared to other cancers. Several studies have shown that leukemic blasts elicit immune responses that could be exploited for the development of novel treatment concepts. To this end, early phase studies of immune-based therapies in AML have delivered encouraging results and demonstrated safety and feasibility. In this review, we discuss opportunities for immunotherapeutic interventions to enhance the potential to achieve a cure in AML, thereby focusing on the role of monoclonal antibodies, hypomethylating agents and the leukemic microenvironment.

Background and Objectives Dipeptidyl peptidase-4 (DPP4) inhibition is a potential strategy to increase the engraftment rate of haematopoietic stem/progenitor cells. A recent clinical trial using sitagliptin, a DPP4 inhibitor approved for type 2 diabetes mellitus, has been shown to be a promising approach in adults with haematological malignancies after umbilical cord blood (UCB) haematopoietic cell transplantation (HCT). On the basis of data from this clinical trial, a semi-mechanistic model was developed to simultaneously describe DPP4 activity after multiple doses of sitagliptin in subjects with haematological malignancies after a single-unit UCB HCT.

Hepatic SOS is a potentially life-threatening complication occurring in up to 14% following HCT. Sirolimus (Siro) plus tacrolimus (FK) is an accepted regimen for graft-versus-host disease (GvHD) prophylaxis, with target Siro trough levels 10-20 ng/mL suggested to prevent acute GvHD (Blood 2016 128:3429). We previously reported that higher trough Siro levels might increase the risk of SOS, although a small sample size precluded detailed analysis. (Pharmacotherapy 2012; 32:441-5). In this study, we investigated if Siro and FK levels at specified times post-transplant are associated with an increased risk of SOS following non-busulfan, myeloablative conditioning. We analyzed 260 consecutive patients with hematological malignancies treated at Indiana University from 2007 to 2016 who underwent allogeneic HCT following myeloablative conditioning using TBI-based (n=151) or non-busulfan chemotherapy only (n=109) regimens. Patients received Siro plus FK for GvHD prophylaxis. No prophylaxis for SOS was used. Trough levels of Siro (target 5-15 ng/mL) and FK (target 5-10 ng/mL) were obtained at least twice weekly through day 30. SOS occurred in 28 patients at a median of 22 (range, 12-58) days for a cumulative incidence of 10.8%. Nine patients died of other causes before day 40 and were excluded from further analysis. Siro and FK troughs were compared in patients who developed SOS (n=28) with those who did not (n=223). Baseline characteristics were similar between the two groups. Mean Siro trough levels were higher between days 11-20 following transplant in patients who developed SOS (10.3 vs 8.5 ng/mL, P=0.008), while there was no significant difference in mean trough levels between days 0-10 (P=0.67) and days 21-30 (P=0.37) (Fig. 1). Patients with mean Siro trough level >9 ng/mL had higher incidence of SOS compared with those with Siro ≤ 9 ng/ml (71.4% vs. 41.7%; P=0.003). No differences in mean FK levels during the same time intervals were observed between those developing SOS and others. On multivariable analysis, mean Siro trough level >9 ng/ml between days 11-20 post-transplant was associated with an increased risk of SOS (odds ratio [OR] 3.9, 95% CI: 1.6-9.8, P=0.003), together with a longer time from diagnosis to transplant (P=0.004) and use of a TBI-based regimen (P=0.006). Among patients who did not develop SOS, mean Siro trough levels ≤9 ng/ml between days 11-20 were not associated with an increased risk of grade II-IV acute GvHD at day 100 compared with levels >9 ng/mL (13.8% vs. 17.3%, P=0.99). We conclude that mean trough Siro levels >9 ng/mL between days 11-20 post-transplant significantly increase the risk of SOS. Targeting lower Siro trough levels (e.g., 5-10 ng/mL) may reduce the risk of SOS without increasing acute GvHD. By interfering with endothelial cell function and potential healing following damage caused by TBI and/or high-dose chemotherapy, higher Siro levels could lead to SOS.

Cord blood (CB) has been used since 1988 as a source of hematopoietic stem cells (HSCs) and progenitor cells for hematopoietic cell transplantation (HCT) to treat patients with malignant and nonmalignant disorders. CB has both advantages and disadvantages when compared with other tissue sources of HSCs such as bone marrow and mobilized peripheral blood, which are also being used in the setting of HCT. This short review focuses on some historical information, as well as current efforts that are being assessed to enhance the efficacy of CB HCT. Also of importance are the costs of CB, and the feasibility and economics of using such to be identified, and newly confirmed improvements worldwide for the greatest number of patients. In this context, simple methods that would not necessarily entail the need for selected cell-processing facilities to ex vivo expand or improve the CB graft's functional activity may be of interest, with one such possibility being the use of an orally active inhibitor of the enzyme dipeptidylpeptidase 4, alone or in combination with other new and innovative approaches for improving HSC engraftment and in vivo repopulating capability of CB.

We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse.

Delayed engraftment is a significant limitation of umbilical cord blood (UCB) transplantation due to low stem cell numbers. Inhibition of dipeptidyl peptidase (DPP)-4 enhanced engraftment in murine transplants. We evaluated the feasibility of systemic DPP-4 inhibition using sitagliptin to enhance engraftment of single-unit UCB grafts in adults with hematological malignancies. Twenty-four patients (21–58 years) received myeloablative conditioning, followed by sitagliptin 600 mg orally days −1 to +2, and single UCB grafts day 0. Seventeen receiving red cell-depleted (RCD) grafts, matched at 4 (n=10) or 5 (n=7) of 6 human leucocyte antigen (HLA) loci with median nucleated cell dose 3.6 (2.5–5.2)×107/kg, engrafted at median of 21 (range, 13–50) days with cumulative incidence of 94% (95% confidence interval, 84%–100%) at 50 days. Plasma DDP-4 activity was reduced to 23%±7% within 2 h. Area under DPP-4 activity-time curve (AUCA) correlated with engraftment; 9 of 11 with AUCA

Enhancement of hematopoietic recovery after radiation, chemotherapy, or hematopoietic stem cell (HSC) transplantation is clinically relevant. Dipeptidylpeptidase (DPP4) cleaves a wide variety of substrates, including the chemokine stromal cell-derived factor-1 (SDF-1). In the course of experiments showing that inhibition of DPP4 enhances SDF-1-mediated progenitor cell survival, ex vivo cytokine expansion and replating frequency, we unexpectedly found that DPP4 has a more general role in regulating colony-stimulating factor (CSF) activity. DPP4 cleaved within the N-termini of the CSFs granulocyte-macrophage (GM)-CSF, G-CSF, interleukin-3 (IL-3) and erythropoietin and decreased their activity. Dpp4 knockout or DPP4 inhibition enhanced CSF activities both in vitro and in vivo. The reduced activity of DPP4-truncated versus full-length human GM-CSF was mechanistically linked to effects on receptor-binding affinity, induction of GM-CSF receptor oligomerization and signaling capacity. Hematopoiesis in mice after radiation or chemotherapy was enhanced in Dpp4(-/-) mice or mice receiving an orally active DPP4 inhibitor. DPP4 inhibition enhanced engraftment in mice without compromising HSC function, suggesting the potential clinical utility of this approach.

Multiple myeloma (MM) patients who receive killer cell Ig–like receptor (KIR) ligand–mismatched, T cell–depleted, allogeneic transplantation may have a reduced risk of relapse compared with patients who receive KIR ligand–matched grafts, suggesting the importance of this signaling axis in the natural killer (NK) cell-versus-MM effect. Expanding on this concept, IPH2101 (1-7F9), an anti-inhibitory KIR mAb, enhances NK-cell function against autologous MM cells by blocking the engagement of inhibitory KIR with cognate ligands, promoting immune complex formation and NK-cell cytotoxicity specifically against MM cell targets but not normal cells. IPH2101 prevents negative regulatory signals by inhibitory KIR, whereas lenalidomide augments NK-cell function and also appears to up-regulate ligands for activating NK-cell receptors on MM cells. Lenalidomide and a murine anti-inhibitory NK-cell receptor Ab mediate in vivo rejection of a lenalidomide-resistant tumor. These mechanistic, preclinical data support the use of a combination of IPH2101 and lenalidomide in a phase 2 trial for MM.

We compared the outcomes of patients age 60-70 years with acute myelogenous leukemia receiving reduced-intensity allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1) reported to the Center for International Blood and Marrow Research (n = 94) with the outcomes in patients treated with induction and postremission chemotherapy on Cancer and Leukemia Group B protocols (n = 96). All patients included had been in CR1 for at least 4 months. The HCT recipients were slightly younger than the chemotherapy patients (median age, 63 years vs 65 years; P < .001), but there were no significant between-group differences in the proportion with therapy-related leukemia or in different cytogenetic risk groups. Time from diagnosis to CR1 was longer for the HCT recipients (median, 44 days vs 38 days; P = .031). Allogeneic HCT was associated with significantly lower risk of relapse (32% vs 81% at 3 years; P < .001), higher nonrelapse mortality (36% vs 4% at 3 years; P < .001), and longer leukemia-free survival (32% vs 15% at 3 years; P = .001). Although overall survival was longer for HCT recipients, the difference was not statistically significant (37% vs 25% at 3 years; P = .08). Our findings suggest that reduced-intensity conditioning allogeneic HCT in patients age 60-70 with acute myelogenous leukemia in CR1 reduces relapse and improves leukemia-free survival. Strategies that reduce nonrelapse mortality may yield significant improvements in overall survival.

Aurora kinases play an important role in the control of the cell cycle and have been implicated in tumourigenesis in a number of cancers. Among the haematological malignancies, overexpression of Aurora kinases has been reported in acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, multiple myeloma, aggressive non-Hodgkin lymphoma and Hodgkin lymphoma. A large number of Aurora kinase inhibitors are currently in different stages of clinical development. In addition to varying in their selectivity for the different Aurora kinases, some also have activity directed at other cellular kinases involved in important molecular pathways in cancer cells. This review summarizes the biology of Aurora kinases and discusses why they may be good therapeutic targets in different haematological cancers. We describe preclinical data that has served as the rationale for investigating Aurora kinase inhibitors in different haematological malignancies, and summarize published results from early phase clinical trials. While the anti-tumour effects of Aurora kinase inhibitors appear promising, we highlight important issues for future clinical research and suggest that the optimal use of these inhibitors is likely to be in combination with cytotoxic agents already in use for the treatment of various haematological cancers.