Search

SY-2101 is a novel oral formulation of arsenic trioxide (ATO). While intravenous (IV) ATO in combination with all trans retinoic acid is highly efficacious in the treatment of acute promyelocytic leukemia (APL) there remains a significant unmet need for patients due to the treatment burden associated with receiving daily ATO infusions over nearly a year of treatment and the risk of complications associated with indwelling central catheters. The pharmacokinetics (PK), safety, and tolerability of SY-‑2101 and ATO IV following single- and multiple-dose administration, and the impact of food on PK for SY-2101, were evaluated in this Phase 1 study in 15 participants with APL. SY-2101 in the fasted state demonstrated comparable systemic exposure to ATO IV based on the active metabolite arsenious acid [As(III)], with geometric mean ratios (GMRs) of SY-2101 to ATO IV of 1.00 for AUC0-last and AUC0-inf. The GMR of SY-2101 to ATO IV Cmax was 0.76. This difference in Cmax was expected due to the different route of administration. Comparisons of SY-2101 in fed to fasted states also showed similar exposure and no clinically relevant differences with GMRs of AUC0-last, AUC0-inf, and Cmax of 1.08, 1.12, and 0.85, respectively, allowing for administration of SY-2101 with or without food. SY-2101 was well tolerated. The majority of adverse events were low grade. This study provides the first intrapatient PK crossover results directly comparing SY-2101 to ATO IV and supports the likelihood of clinical equivalence between the two formulations if used to treat patients with APL. NCT04996030., (Copyright © 2025 American Society of Hematology.) more...

The use of opioids and/or benzodiazepines in older adults (65 y+) who received an allogeneic hematopoietic cell transplant (HCT) is not known. In March 2016, the CDC released its strongest guidelines against prescription of opioids and co-prescription of opioids + benzodiazepines. We evaluated the use of opioids and/or benzodiazepines in older (65 y + , n = 114) vs. younger (40-64 y, n = 240) allogeneic-HCT recipients before and after the CDC guidelines. The proportion of patients with >10-days of use of opioids and/or benzodiazepines peri-HCT (day-14 to +28) was compared. Opioids: the older (65 + y) group had similar odds of receiving opioids as the younger group (40-64 y) [O.R. 0.7 (95%CI:0.4-1.2)]. Those transplanted after the CDC guideline had 0.4 (95%CI:0.2-0.7) times the odds of receiving opioids. Benzodiazepines: The older (65 + y) group was 0.6 times (95%CI:0.3-0.9) as likely to receive benzodiazepines. There was no significant change in benzodiazepines use after the CDC guideline. Opioids + Benzodiazepines: The older group (65 + y) was 0.5 (95%CI:0.3-0.9) times as likely to receive both opioids+benzodiazepines. There was no significant change in opioids+benzodiazepines use after the CDC guideline. Though we observed a significant decrease in use of opioids after the CDC guideline, the use of benzodiazepines and combined opioids+benzodiazepines remained constant. Older recipients (65 + y) received less opioids, benzodiazepines, and combined opioids+benzodiazepines., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.) more...

Purpose: Chronic myeloid leukemia (CP-CML) patients can achieve undetectable minimal residual disease (UMRD) and discontinue tyrosine kinase inhibitors (TKIs). Cellular immunity plays an important role in CML disease control. We conducted a randomized, non-blinded phase II trial of adjuvant immunotherapy with TKIs to facilitate TKI discontinuation., Methods: TKI-treated patients with CP-CML were randomized to receive the K562/GM-CSF vaccine (vaccine) OR Interferon-α + Sargramostim (IFN). If UMRD was achieved, then all treatment was stopped. Patients who did not achieve UMRD within one year, had a molecular relapse, or discontinued therapy for toxicity could crossover., Results: Thirty-four patients were randomized to IFN (n = 18) or vaccine (n = 16), and 21 patients crossed over (IFN⟶vaccine: n = 9, vaccine⟶IFN, n = 12). TKIs at enrollment included imatinib (n = 31), nilotinib (n = 2), and dasatinib (n = 1). No patients discontinued vaccine due to side effects, while 33 % of IFN-treated patients discontinued treatment. More patients randomized to IFN (47.4 %, 95 % CI: 16.7-66.7 %) versus vaccine (25.0 %, 95 % CI: 0.5-43.5 %) achieved UMRD within one year. Seven patients randomized to IFN discontinued treatment with 28.6 % (95 % CI: 8.9-92.2 %) sustaining treatment-free remission (TFR) at 1 year, while three patients randomized to vaccine discontinued treatment with none sustaining TFR. Including crossover, there was a cumulative discontinuation success rate of 36.4 % (95 % CI: 16.6 %-79.5 %) after adjuvant IFN. Patients who sustained TFR received a median of 29 months of imatinib prior to discontinuation., Conclusion: Adjuvant IFN led to durable TFRs with limited prior TKI exposure with comparable success to prior discontinuation trials, but many patients stopped IFN early., (Copyright © 2021 Elsevier Ltd. All rights reserved.) more...

Prognostic factors associated with clinical outcomes of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients with central nervous system (CNS) involvement are unknown. We retrospectively studied the characteristics and outcomes of 66 (18 pediatric and 48 adult) patients with CNS leukemia with ALL (n = 41) or AML (n = 25). The median age of patients at diagnosis of CNS leukemia was 30 (range, 1-69) years. Nearly two-third patients had CNS involvement at the initial diagnosis of leukemia. Complete remission of CNS leukemia was attained in 58 (88%) patients, and probability of overall survival at 36 months after the diagnosis of CNS leukemia was 43% for the entire cohort. We identified that achieving remission of systemic leukemia and having CNS leukemia diagnosed and treated before allogeneic transplantation were the factors associated with CNS leukemia remission. Prognostic factors associated with better overall survival in patients with CNS leukemia included pediatric age, diagnosis of CNS leukemia before receiving allogenic transplantation, achieving clearance of systemic or CNS leukemia, receiving no cranial radiation in conjunction with intrathecal chemotherapy (IT), and receiving IT consolidation after achieving remission of CNS leukemia. Our findings show that patients with CNS leukemia are at considerable risk of mortality. Awareness of modifiable prognostic factors such as avoidance of cranial radiation whenever possible and use of IT consolidation can result in improved outcomes in subset of patients with CNS leukemia., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2020 King Faisal Specialist Hospital & Research Centre. Published by Elsevier Ltd. All rights reserved.) more...

Following the 2017 European LeukemiaNet (ELN) guidelines, we changed our practice from using high-dose cytarabine (HIDAC-3 g/m 2 q12h-D1,3,5) to intermediate-dose cytarabine (IDAC-1·5 g/m 2 q12h-D1,3,5/D1-3) for consolidation in young(<60 years) favourable-risk acute myeloid leukaemia (AML) patients. We assessed the clinical impact of this practice change. Of 80 patients, 51 received HIDAC prior to the protocol change, and subsequently, 29 received IDAC. The three-year risk of relapse was significantly higher with IDAC [61%; 95% confidence interval (CI) 40-82] compared with HIDAC (22%; 10-34), P < 0·01. Our findings suggest HIDAC, rather than IDAC, is the preferred dose for single-agent cytarabine consolidation in young, favourable-risk AML following 7+3 induction., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.) more...

Myelodysplastic syndromes (MDS) are a heterogeneous group of blood disorders. Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with a chemopreventive effect in some cancers. We evaluated associations between NSAID use and MDS in a population-based case-control study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Secondary analyses stratified by sex and MDS subtype were also conducted.The analysis included 399 MDS cases and 698 controls. No significant associations between MDS and use of aspirin (OR = 0.87, 95% CI 0.67-1.14), ibuprofen (OR = 0.91, 95% CI 0.64-1.30), acetaminophen (OR = 1.29, 95% CI 0.90-1.84) or NSAIDs overall (OR = 0.92, 95% CI 0.68-1.23) were observed. No significant associations were observed in models stratified by sex or MDS subtype; however, the direction of the effect between NSAID use and MDS varied by MDS subtype. Our results do not support an association between NSAID use and MDS overall. more...

Several prospective randomized trials comparing conditioning intensity before allogeneic hematopoietic cell transplantation (HCT) have been performed, with conflicting results. Although reduced-intensity conditioning (RIC) leads to lower treatment-related mortality (TRM), this is offset by higher rates of relapse. Long-term follow-up of randomized comparative trials are limited. Here we present long-term follow-up of a randomized comparison of myeloablative conditioning (MAC) compared with RIC before HCT for acute myelogenous leukemia (AML) or myelodysplasia (MDS). Long-term comparative analyses of overall survival, relapse, and relapse-free survival were performed. Patients age 18 to 65 years with <5% marrow myeloblasts were randomized to receive MAC (n = 135) or RIC (n = 137), followed by HCT from an HLA-matched donor. The primary endpoint of the trial was an 18-month pointwise comparison of overall survival. The analyses were performed using a proportional hazards model. The median follow-up of the entire cohort was 51 months. At 4 years, the transplant-related mortality (TRM) was 25.1% for MAC, compared with 9.9% for RIC (P < .001). Patients who received RIC had a significantly higher risk of relapse compared to those who received MAC (hazard ratio [HR], 4.06; 95% CI, 2.59 to 6.35; P < 0.001). Among the patients who relapsed after HCT, postrelapse survival was similar at 3 years (24% for MAC and 26% for RIC). Overall survival was superior for patients who received MAC compared to those who received RIC (HR, 1.54; 95% CI, 1.07 to 2.2; P = .03). Our data show that patients who received MAC were at higher risk of late TRM compared with those who received RIC; however, because of the exceedingly high rates of relapse in the RIC arm, overall survival remained significantly better for patients who received MAC. Among patients with MDS or AML eligible for either MAC or RIC regimens, long-term follow up demonstrates a survival advantage for patients who received MAC., (Copyright © 2021. Published by Elsevier Inc.) more...

Purpose: Myelodysplastic syndromes (MDS) are classified as de novo and therapy-related (tMDS). We evaluated associations between MDS risk factors separately for de novo and tMDS., Methods: The study population included 346 de novo MDS cases, 37 tMDS cases and 682 population controls frequency matched by age and sex. Polytomous logistic regression was performed to calculate odds ratios (OR) and 95% confidence intervals (CI)., Results: After adjustment, former smoking status (OR = 1.45, 95% CI: 1.10-1.93), personal history of autoimmune disease (OR = 1.34, 95% CI: 0.99-1.82) and exposure to benzene (OR = 1.48, 95% CI: 1.00-2.19) were associated with de novo MDS. Risk estimates for the associations between smoking, autoimmune disease, and benzene exposure were similar in magnitude but non-significant in tMDS cases. Among individuals with a previous diagnosis of cancer, de novo MDS cases and controls were more likely to have had a previous solid tumor, while tMDS cases more commonly had a previous hematologic malignancy., Conclusions: We observed similar associations between smoking, history of autoimmune disease and benzene exposure in de novo and tMDS although estimates for tMDS were imprecise due to small sample sizes. Future analyses with larger sample sizes will be required to confirm whether environmental factors influence risk of tMDS. more...

Regimen-related toxicities with high-dose therapy followed by hematopoietic cell rescue leads to considerable patient distress, morbidity, and high readmission rates. Palifermin is a recombinant keratinocyte growth factor that is Food and Drug Administration-approved to decrease severe oral mucositis (OM) associated with autologous hematopoietic cell transplantation (ASCT) for hematologic malignancies. We added palifermin as a supportive care measure for patients with lymphoma undergoing ASCT with BEAM conditioning. We compared patients receiving palifermin (n = 35) with historical controls (n = 38) for toxicity and readmission outcomes. The cumulative incidence of OM of any grade was 23% in the palifermin-treated patients and 42% in the control group. Patients receiving palifermin were less likely to be readmitted (57% versus 82%; P = .04), had fewer hospital readmission days (median, 4 days versus 7 days; P < .01), and had fewer total days in the hospital through day +30 after ASCT (median, 12 days versus 15 days; P = .05). Fewer patients in the palifermin group had >20 days in the hospital through day +30 (9% in the palifermin group versus 23% of controls). Adverse events associated with palifermin were mild and transient. The addition of palifermin limits severe regimen-related toxicities and decreases readmissions and duration of hospital stay. This and other measures are needed to identify comprehensive and cost-effective approaches, possibly including palifermin, to prevent severe regimen-related toxicities and decrease health care resource utilization., (Copyright © 2020 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.) more...

The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.) more...

The use of potentially inappropriate medications (PIMs) using Beers criteria and its impact on older allogeneic hematopoietic cell transplantation (HCT) recipients is not known. Here the use of any PIMs and their therapeutic classes in reduced-intensity conditioning allogeneic HCT recipients were compared between older (≥65 years; n = 114) and younger (40 to 64 years; n = 240) patients during their initial HCT admission, defined as the number of days that a patient received 1 or more PIMs between day -14 and day +28. Poisson regression was used to determine rate ratios (RRs) in the 2 groups. In the ≥65 years group, we evaluated the impact of PIMs on Common Terminology Criteria for Adverse Events (CTCAE) grade 3-4 toxicities within 100 days and on overall mortality within 1 year post-HCT. The rate of any PIM use was similar in the older and younger groups (RR, .98; 95% confidence interval [CI], .90 to 1.06; P = .65). In terms of PIM classes, the older group had a 48% higher rate of gastrointestinal (GI) medication use (RR, 1.48; 95% CI, 1.32 to 1.65; P < .01) and a 25% higher rate of genitourinary (GU) medication use (RR, 1.25; 95% CI, 1.02 to 1.53; P = .03). Compared with males, females had a 19% higher rate of central nervous system (CNS) medication use (RR, 1.19; 95% CI, 1.03 to 1.37; P = .02) and a 30% higher rate of benzodiazepine use (RR, 1.30; 95% CI. 1.09 to 1.54; P < .01). A high-risk HCT-CI was associated with a higher rate of use of any PIMs (RR, 1.13; 95% CI, 1.01 to 1.26; P = .02), CNS medications (RR, 1.26; 95% CI, 1.04 to 1.53; P = .02) and GU medications (RR, 1.46; 95% CI, 1.09 to 1.94; P = .01). Compared with matched sibling donor HCT recipients, umbilical cord blood transplantation recipients had higher rates of GI medication use (RR, 1.32; 95% CI, 1.14 to 1.53; P < .01) and anticholinergic medication use (RR, 1.30; 95% CI, 1.06 to 1.61; P = .01). In the ≥65 years group, increasing duration of narcotic use was associated with a 1.3-fold (95% CI, 1.0 to 1.7; P = .05) higher risk of overall mortality and a 1.6-fold (95% CI, 1.02 to 2.69) greater odds of CTCAE grade 3-4 toxicities (P = .04). Our data show that older recipients (≥65 years) were as likely as their younger counterparts to receive PIMs. Among older recipients, the use of PIMs, particularly narcotics, was associated with higher mortality and higher incidence of grade 3-4 toxicities. Identifying and reducing the use of PIMs in older HCT recipients may help decrease the burden of adverse events and associated health care costs., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.) more...

Allogeneic hematopoietic stem cell transplantation (HCT) remains the only potentially curative option for myelodysplastic syndromes (MDS). Mortality after HCT is high, with deaths related to relapse or transplant-related complications. Thus, identifying patients who may or may not benefit from HCT is clinically important. We identified 1514 patients with MDS enrolled in the Center for International Blood and Marrow Transplant Research Registry and had their peripheral blood samples sequenced for the presence of 129 commonly mutated genes in myeloid malignancies. A random survival forest algorithm was used to build the model, and the accuracy of the proposed model was assessed by concordance index. The median age of the entire cohort was 59 years. The most commonly mutated genes were ASXL1(20%), TP53 (19%), DNMT3A (15%), and TET2 (12%). The algorithm identified the following variables prior to HCT that impacted overall survival: age, TP53 mutations, absolute neutrophils count, cytogenetics per International Prognostic Scoring System-Revised, Karnofsky performance status, conditioning regimen, donor age, WBC count, hemoglobin, diagnosis of therapy-related MDS, peripheral blast percentage, mutations in RAS pathway, JAK2 mutation, number of mutations/sample, ZRSR2, and CUX1 mutations. Different variables impacted the risk of relapse post-transplant. The new model can provide survival probability at different time points that are specific (personalized) for a given patient based on the clinical and mutational variables that are listed above. The outcomes' probability at different time points may aid physicians and patients in their decision regarding HCT., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. All rights reserved.) more...

Purpose: Myelodysplastic syndromes (MDS) are a class of clonal neoplastic disorders of largely unknown etiology, and published data remain inconclusive regarding the association between lifetime alcohol consumption and MDS risk. In these analyses, data from a population-based case-control study were used to investigate this association., Methods: Eligible cases of MDS were identified through the Minnesota Cancer Reporting System; controls were matched by sex and age-decile. A central review process was used to confirm MDS diagnosis and classify subtypes. Unconditional and polytomous logistic regression were used to calculate odds ratios (OR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to compare survival by category of lifetime alcohol consumption., Results: In total, 398 cases of MDS and 698 controls were included. Alcohol consumption at 23-30, 31-49, and 50-65 years of age, recent consumption 1 year before diagnosis/interview, and lifetime consumption were not found to be significantly associated with MDS in males (OR range 0.63-0.99) or females (OR range 0.58-1.70). Analysis by MDS subtype further suggested there was not a significant association between recent alcohol consumption and odds of disease by subtype (OR range 0.39-1.13). Lifetime alcohol consumption was not significantly associated with survival after diagnosis of MDS CONCLUSIONS: Previously reported associations between alcohol consumption and MDS risk were inconsistent. Results from our analyses by sex and disease subtype do not support alcohol as a significant contributor to risk of MDS. more...

Importance: In 2010, the US Centers for Medicare & Medicaid Services (CMS) indicated that data regarding efficacy of allogeneic hematopoietic stem cell transplantation (HCT) in the CMS beneficiary population with myelodysplastic syndrome (MDS) were currently insufficient, but that coverage would be provided for patients enrolled in a clinical study that met its criteria for Coverage with Evidence Development (CED)., Objective: The Center for International Bone Marrow Transplant Research (CIBMTR) submitted a study concept comparing the outcomes of patients aged 55 to 64 years vs aged 65 years or older who met those criteria, effectively providing coverage by CMS for HCT for MDS., Design, Setting, and Participants: Data on patients aged 65 years or older were prospectively collected and their outcomes compared with patients aged 55 to 64 years. Patients were enrolled in the study from December 15, 2010, to May 14, 2014. The results reported herein were analyzed as of September 4, 2017, with a median follow-up of 47 months. The study was conducted by the CIBMTR. It comprises a voluntary working group of more than 420 centers worldwide that contribute detailed data on allogeneic and autologous HCT and cellular therapies., Interventions: Patients with MDS received HCT according to institutional guidelines and preferences., Main Outcomes and Measures: The primary outcome was overall survival (OS); secondary outcomes included nonrelapse mortality (NRM), relapse-free survival, and acute and chronic graft vs host disease., Results: During the study period, 688 patients aged 65 years or older underwent HCT for MDS and were compared with 592 patients aged 55 to 64 years. Other than age, there were no differences in patient and disease characteristics between the groups. On univariate analysis, the 3-year NRM rate was 28% vs 25% for the 65 years or older group vs those aged 55 to 64 years, respectively. The 3-year OS was 37% vs 42% for the 65 years or older group vs the 55 to 64 years age group, respectively. On multivariable analysis after adjusting for excess risk of mortality in the older group, age group had no significant association with OS (HR, 1.09; 95% CI, 0.94-1.27; P = .23) or NRM (HR, 1.19; 95% CI, 0.93-1.52; P = .16)., Conclusions and Relevance: Older patients with MDS undergoing HCT have similar OS compared with younger patients. Based on current data, we would recommend coverage of HCT for MDS by the CMS., Trial Registration: ClinicalTrials.gov identifier: NCT01166009. more...

Altered BM hematopoiesis and immune suppression are hallmarks of myelodysplastic syndrome (MDS). While the BM microenvironment influences malignant hematopoiesis, the mechanism leading to MDS-associated immune suppression is unknown. We tested whether mesenchymal stromal cells (MSCs) contribute to this process. Here, we developed a model to study cultured MSCs from patients with MDS (MDS-MSCs) compared with those from aged-matched normal controls for regulation of immune function. MDS-MSCs and healthy donor MSCs (HD-MSCs) exhibited a similar in vitro phenotype, and neither had a direct effect on NK cell function. However, when MDS- and HD-MSCs were cultured with monocytes, only the MDS-MSCs acquired phenotypic and metabolic properties of myeloid-derived suppressor cells (MDSCs), with resulting suppression of NK cell function, along with T cell proliferation. A MSC transcriptome was observed in MDS-MSCs compared with HD-MSCs, including increased expression of the ROS regulator, ENC1. High ENC1 expression in MDS-MSCs induced suppressive monocytes with increased INHBA, a gene that encodes for a member of the TGF-β superfamily of proteins. These monocytes also had reduced expression of the TGF-β transcriptional repressor MAB21L2, further adding to their immune-suppressive function. Silencing ENC1 or inhibiting ROS production in MDS-MSCs abrogated the suppressive function of MDS-MSC-conditioned monocytes. In addition, silencing MAB21L2 in healthy MSC-conditioned monocytes mimicked the MDS-MSC-suppressive transformation of monocytes. Our data demonstrate that MDS-MSCs are responsible for inducing an immune-suppressive microenvironment in MDS through an indirect mechanism involving monocytes. more...

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events. One patient had a decrease in transfusion requirements and another demonstrated hematologic improvement suggesting a signal for clinical activity. In vitro correlative studies indicated biological effects on immune cells following vaccination. Although only a pilot study, results are encouraging that an immunotherapeutic approach with a whole-cell vaccine may be feasible in MDS patients. more...

Clofarabine and cytarabine (Clo + Ara-C) combinations have efficacy in treatment of acute myeloid leukemia (AML). We retrospectively analyzed clinical outcomes of 71 AML patients receiving Clo + Ara-C regimens at the University of Minnesota from 2011 to 2016: 44 patients (62%) had newly diagnosed AML and 27 patients (38%) had relapsed/refractory AML. The median age of patients was 69 years (interquartile range [IQR], 63-75 years). Nearly 60% of the patients had secondary AML, and about half of patients had adverse risk cytogenetics. Objective response rate (ORR) was 42% in all patients with complete remission (CR) rate of 20%. Progression-free survival (PFS) at 2 years was 16% (95% CI 8-27%) and overall survival (OS) at 2 years was 21% (95% CI 11-33%) for all patients. The 30-day mortality rate was 18%. Clo + Ara-C- containing regimens are an acceptable upfront therapy option for patients who are not candidates for "7 + 3" induction, but do not induce durable remissions. more...

Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells. To mediate a productive immune response against MDS, negative regulatory checkpoints, like TIGIT, expressed on MDS NK cells must be overcome. NK cells can be directed to lyse MDS cells by bispecific killer engagers (BiKEs) that ligate CD16 on NK cells and CD33 on MDS cells. However, such CD16 × CD33 (1633) BiKEs do not induce the proliferative response in MDS NK cells needed to sustain their function. Here, we show that the addition of an NK stimulatory cytokine, interleukin-15 (IL-15), into the BiKE platform leads to productive IL-15 signaling without TIGIT upregulation on NK cells from MDS patients. Lower TIGIT expression allowed NK cells to resist MDSC inhibition. When compared with 1633 BiKE, 161533 trispecific killer engager (TriKE)-treated NK cells demonstrated superior killing kinetics associated with increased STAT5 phosphorylation. Furthermore, 161533 TriKE-treated MDS NK cells had higher proliferation and enhanced NK-cell function than 1633 BiKE-treated cells without the IL-15 linker. Collectively, our data demonstrate novel characteristics of the 161533 TriKE that support its application as an immunotherapeutic agent for MDS patients., (© 2018 by The American Society of Hematology.) more...