ALBERT

Description: Background: Only a small subset of Lower risk (LR) MDS patients benefit from treatment with rhu-Erythropoietin (Epo). We previously reported that lenalidomide (LEN) restores sensitivity to Epo in MDS progenitors by inducing the formation of lipid rafts that are enriched for signaling competent, JAK2/Epo-receptor complexes (McGraw K, et. al. PLoS One 2014; Basiorka A, et. al. Cancer Res 2016). In the MDS-002 and MDS-005 trials, treatment with LEN monotherapy gave rise to RBC transfusion-independence (TI) in 26% of azanucleoside-naïve, transfusion-dependent (TD) LR, non-del(5q) MDS patients for a median of 10.2 and 7.75 months, respectively. In a pilot study of Epo-refractory LR-MDS patients, the addition of epoetin alfa (EA) to LEN treatment yielded erythroid responses in 28% of patients who were unresponsive to LEN alone, suggesting that LEN may overcome clinical resistance to augment response to rhEpo (Komrokji R, et. al. Blood 2012). To test this hypothesis, we performed a randomized phase III trial comparing treatment with LEN to LEN+EA in LR non-del(5q) MDS patients who were refractory to, or not candidates for treatment with rhEpo. Methods: Patients with Low or Intermediate-1 IPSS risk MDS with hemoglobin 2 units/month) with serum Epo 〉500mU/mL were eligible. Patients were stratified by serum Epo level and prior rhEpo (EA vs. darbepoetin vs. none) then randomized to treatment with LEN 10 mg/d x21d q4wk (Arm A) or LEN + EA 60,000U SC/wk (Arm B). The primary endpoint was major erythroid response (MER) at week 16 which was defined according to transfusion status at baseline: (1) achievement of RBC-TI for ≥ 8 consecutive weeks AND a sustained ≥1 g/dL hemoglobin rise compared to mean pre-transfusion baseline value in TD patients; and (2) a 〉2 g/dL rise in hemoglobin without transfusion for ≥ 8 consecutive weeks in non-TD patients (Grade 3, non-hematologic adverse events between treatment arms. Two patients progressed to AML while on study (Arm A), and no thromboembolic events were reported. Conclusions: LEN restores sensitivity to rhEpo in otherwise refractory, LR-non-del(5q) MDS patients to yield a significantly higher frequency of durable major erythroid responses compared to LEN alone. The addition of LEN to EA treatment is an effective strategy for the management of Epo-refractory patients with a potential duration of benefit extending to years. Disclosures List: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verma:Janssen: Research Funding; BMS: Research Funding; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Komrokji:JAZZ: Speakers Bureau; Novartis: Speakers Bureau; JAZZ: Consultancy; Agios: Consultancy; Incyte: Consultancy; DSI: Consultancy; celgene: Consultancy; pfizer: Consultancy. Luger:Onconova: Research Funding; Pfizer: Honoraria; Seattle Genetics: Research Funding; Cyslacel: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria; Genetech: Research Funding; Jazz: Honoraria; Daichi Sankyo: Honoraria; Kura: Research Funding; Celgene: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Altman:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; France Foundation: Speakers Bureau; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Cancer Expert Now: Consultancy; Novartis: Consultancy; Biosight: Other: US Lead. Claxton:Astellas Pharma: Other: Pharma support of clinical studies; Merck Sharp & Dohme Corp.: Other: Pharma support of clinical studies; Cyclacel Pharmaceuticals, Inc.: Other: Pharma support of clinical studies; Medimmune Inc.: Other: Pharma support of clinical studies; Novartis Pharmaceuticals: Other: Pharma support of clinical studies; Celgene Corporation: Other: Pharma support of clinical studies; Incyte Corporation: Other: Cyclacel Pharmaceuticals, Inc; Daiichi Sankyo Co. and Ambit Biosciences Corp: Other: Pharma support of clinical studies. Artz:Miltenyi: Research Funding. Tallman:Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; Biosight: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Lenalidomide used for treatment non-del 5q myelodysplastic syndromes.

Description: Introduction: Filgrastim is widely used for mobilizing CD34+ cells into the peripheral blood that are easily collected by apheresis for allogeneic transplantation. With case reports documenting splenomegaly with life-threatening complications in normal donors, we prospectively evaluated spleen size using ultrasonography and clinical examination during PBPC mobilization and collection in a single-arm trial. Methods: Subjects ≥18 yrs eligible to be PBPC donors per institutional guidelines enrolled. Splenic assessments were done before, during, and after PBPC mobilization. Filgrastim dose and schedule and leukapheresis (LK) procedures were per institutional practice. The primary endpoint was fold change from baseline in splenic volume in post-baseline measurements during mobilization (measured by ultrasound [US]). Spleen size by US was measured in 3 dimensions similarly by all centers: longitudinal (craniocaudal), transverse, and diagonal (perpendicular to transverse in transverse image) diameters. Splenic volume was estimated by taking the cross-product of 3 dimensions and multiplying by 0.52, approximating the volume of an ellipse. Physical examination was performed on US days, assessing spleen palpability. US and palpation results were blinded from each other at assessment times. Timepoints included baseline (before first filgrastim dose), first LK (done before LK, typically day 4 or 5 of filgrastim), 2 and 4 days after first LK, and 7 days after last LK. Timepoints in the post-amendment cohort (n=219) were reduced to facilitate enrollment and were baseline and day of first LK (before LK). Results: 309 donors enrolled, median age 44yrs (range 18 to 74), 56% male. Mean daily filgrastim dose was 11.4mcg/kg (SD=3.0). Median number of LK was 1.5 (range 1 to 4). In all donors, the median increase in each measured dimension on first LK day was 1.4cm, 1.4cm, and 0.6cm (12.8%, 12.6%, and 15.0%), and the median fold volume increase from baseline to first LK was 1.47, resolving to near baseline 1 week after last LK. There was no apparent relationship between volume fold change and filgrastim dose, ANC, or CD34+ yield. Of 861 splenic palpation assessments reported in all donors, 98% were reported as nonpalpable (842 assessments), and 2% were palpable (19 assessments, 2 at baseline). Reporting of palpable spleens did not correlate with increased spleen size. Tenderness or guarding upon splenic palpation was reported in 2 donors with a spleen considered palpable and in 6 donors with nonpalpable spleens. No donor experienced a splenic rupture. Adverse events related to filgrastim were generally mild to moderate. Conclusion: During PBPC mobilization with filgrastim in normal donors, the spleen increased a median of approximately 50% from baseline to day of first LK and returned to near baseline 1 week after last LK. Size change was not associated with significant clinical sequelae. Timepoint Median fold change from baseline in splenic volume (Q1, Q3) *statistically significant (p

Description: Rationale: Allogeneic hematopoietic stem cell transplantation (HSCT) remains the most effective therapy for patients with acute myeloid leukemia (AML). The graft-versus-leukemia effect (GVL), mediated by the engrafted T lymphocytes targeting leukemic cells, is thought to play an important role in affecting the overall outcome of patients with AML. Umbilical cord blood (UCB) has emerged as an alternative and effective source of hematopoietic stem cells in high risk patients. We previously reported the hematopoietic reconstitution and clinical outcomes in 45 patients undergoing haplo-cord transplant, a novel approach which combines haploidentical and cord blood grafts to avoid delayed hematopoietic recovery after cord blood transplant (Liu H,et al. Blood. 2011;118(24):6438-45). However, very little is known about immune reconstitution of cord blood cells and whether the emerging immune repertoire correlates with clinical outcome. The great majority of T cell receptors in T lymphocytes are heterodimers of alpha (TCRA) and beta (TCRB) subunits. Somatic recombination combining the VJ (alpha) and VDJ (beta) segments results in an astronomical functional diversity and complexity of TCR receptors, and makes the characterization of their functions a tremendously complex process. To obtain insights into the T-cell repertoire, we have utilized next-generation sequencing (NGS) technology to comprehensively characterize T-cell kinetics and diversity following haplo-cord transplantation. Methods: We evaluated the emerging T-cell repertoire in 10 patients (pts) with high-risk AML enrolled on a clinical trial of haplo-cord transplantation at the University of Chicago. The median age of the pts was 57 years old (range: 26-67) and 3 pts had active disease at the time of transplant. The median UCB dose was 1.6x107 TNC/kg with HLA cord matching of 4/6 in 3 pts and 5/6 or 6/6 in 7 pts. The median overall and disease free survival were 2.4 and 2.2 years, respectively. cDNA was generated from mRNA isolated from peripheral blood mononuclear cells prior to and at sequential time points 30, 100, 180 and 365 days post haplo-cord transplant were sequenced the samples with Ion Personal Genome Machine (PGM) Sequencer and a 400-bp reading kit. We analyzed the sequences by applying a recently developed algorithm in order to determine the VJ and VDJ combinations and CDR3 sequences. Chimerism was determined by microsatellite sequences of DNA of donor and recipient cells. Diversity was calculated for each of TCRA and TCRB using the inverse Simpson’s index. Results: Several clones found in pre-treatment samples obtained from recipients before transplant persisted at low frequency on days 100 and 365 post-transplant suggesting that these clones have evaded the immuno-suppressive conditioning regimens. In order to correlate the diversity of TCRs with the percentage of cord cells in patients’ blood at different time points, we dichotomized patients into cord present (〉5%) and cord absent (≤5%) groups, based on the cord blood percentage in blood on day 30 post haplo-cord transplant and correlated it with diversity on day 100. We found that TCRs of pts with 〉5% cord cells on day 30 post haplo-cord transplant were significantly more diverse (TCRA; P=0.008) and (TCRB; P=0.01) (Fig.1) on day 100 compared to TCRs in patients with 90% cord cells on day 100 post-transplant. Therefore, we examined the correlation between diversity calculated on day 100 and percentage of persisting haplo-identical cells on the same day. We found,, the diversity of TCRB of pts with persistence of 〉10% haplo-identical cells were 15.05 compared with 72.95 for those with 10% and

Description: Background: Disease relapse remains the primary cause of mortality following allogeneic hematopoietic cell transplantation (alloHCT). One important mechanism of disease relapse in this setting is failure of the graft-versus-tumor (GvT) effect, and the PD-1/PD-L1 axis may diminish GvT after alloSCT. We hypothesized that PD-1/PD-L1 interactions prevent donor-derived T cells from eliminating malignant cells expressing minor histocompatibility antigens, and that blocking PD-1/PD-L1 interactions with the anti-PD-1 antibody, pembrolizumab (pem), might restore GvT and induce clinical responses in patients (pts) with relapsed hematologic malignancies following alloHCT. However, PD-1 blockade therapy has been associated with severe graft-versus-host disease (GVHD) in murine models, and GVHD has been reported in humans treated with anti-PD-1 therapy after alloHCT. Thus, we developed a prospective clinical study to test the tolerability and preliminary efficacy of pembrolizumab in patients with relapsed leukemia/lymphoma after alloSCT. Methods: Pts with AML, MDS, or B cell lymphomas with biopsy-proven recurrence after alloSCT were eligible, as long as no active acute GVHD 〉 grade 1 or chronic GVHD was present. Pts were treated with pem 200 mg IV q3 weeks for up to 2 years, provided that neither intolerable side-effects nor disease progression occurred. Pem could be delayed for treatment-limiting toxicities (TLT), defined as immune-related adverse events (irAEs) not meeting criteria for a dose-limiting toxicity (DLT). DLT was defined as the development of grade 3 or 4 acute GVHD/irAE, any unexpected grade 〉 2 toxicity related to pem, or development of 〉 grade 2 vital organ dysfunction secondary to an irAE within 90 days of pem initiation. A two-stage mini-max design was chosen, with an early stopping rule for DLT after the first 11 patients were enrolled. Results: 11 pts (7 male, 4 female), mean age 49.5 yrs (range, 27-62 yrs) have been enrolled. 8 pts had AML and 3 had lymphoma (DLBCL - 2, cHL - 1). 6 pts had matched-related donors (MRD) and 5 pts had haploidentical/umbilical cord blood (haplo-cord) donors. Pts with MRD were conditioned with fludarabine, melphalan, and alemtuzumab, or fludarabine and busulfan. Pts with haplo-cord donors were conditioned with fludarabine, melphalan, and ATG. 5 pts had prior acute GVHD. Pts relapsed following alloHCT at a median of 453 days (range, 101-1021 days). A median of 2 cycles of pembrolizumab (range, 1-8) was administered. 3 pts are receiving ongoing treatment. 3 pts experienced a DLT due to an irAE (grade 3-4 pneumonitis 2 pts; grade 3 hyperthyroidism 1 pt), all of which occurred after 1-2 cycles of pem, and resolved after pem discontinuation and corticosteroid treatment. 1 pt experienced a TLT (grade 2 rash), but resumed pem treatment. Among all pts, irAEs of any grade occurred in 7 pts. 7 pts were evaluable for response. 3 pts (2 AML, 1 DLBCL) experienced progressive disease (PD), 2 pts (AML) had stable disease (SD), and 2 pts achieved CR (DLBCL, cHL). 1 pt with AML (myeloid sarcoma) in whom pem was discontinued for PD by PET/CT imaging had a concurrent tumor biopsy that revealed marked T cell infiltration and PD-L1 expression on a significant fraction of malignant myeloid cells, suggestive of possible inflammatory "pseudo-progression". 1 pt in CR developed therapy-related AML unrelated to pem. Notably, both patients with CR following pem had PD-L1 gene-amplified lymphomas by FISH, and diffuse PD-L1 protein expression on pre-treatment biopsies. Currently, 4 pts have died, all due to disease progression, and 7 are alive. A total of 26 patients are expected to be enrolled. Conclusions: Treatment with pem in the post-alloHCT disease relapse setting is feasible, but can induce early and severe irAEs, requiring vigilant monitoring. To date, objective responses were seen in 2/3 lymphoma patients treated with pem. In AML, pem may be less effective, where a best response of SD was observed in 2 pts, and possible "pseudo-progression" in a patient with myeloid sarcoma. This study continues to accrue pts, and correlative analyses are underway. To our knowledge, these are the first prospective data of PD-1 blockade therapy in the post-alloHCT setting. Disclosures Kline: iTeos: Research Funding; Merck: Honoraria, Research Funding. Liu:BMS: Research Funding. Curran:Merck: Research Funding. Stock:Jazz Pharmaceuticals: Consultancy. Smith:BMS: Consultancy; Portola: Honoraria. Bishop:Juneau Therapeutics: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; United Healthcare: Employment; Novartis Pharmaceuticals Corporation: Speakers Bureau.

Description: Introduction: Hematopoietic cell transplantation (HCT) advances in reduced intensity conditioning, donor identification, and supportive care have led to its increased use over the last few decades. HCT is a complex process that requires coordination at multiple levels, and there may be disparities in its utilization. To better understand these access disparities, we conducted a systematic review of studies that assessed barriers to referral and/or receipt of HCT. Additionally, we focused on a subgroup of older patients (aged ≥65 at transplant), who we hypothesized would be at higher risk for access barriers to HCT. Methods: A systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched for articles published in English from PubMed, Embase, Cumulative Index for Nursing and Allied Health, and Cochrane Central Register of Controlled Trials between the database inception and January 12th, 2018. Inclusion criteria were: 1) clinical trials, observational, qualitative, cross-sectional, or mixed-method study designs; 2) study assessed barriers to HCT or factors associated with referral for or receipt of HCT (except for country-specific economic factors as these are less likely to be targetable), 3) included patients ≥18 years with cancer. Narrative review articles and abstracts without full text were excluded. Two authors independently reviewed all titles and abstracts (N=3,262) and assessed studies for full-text eligibility (N=153). A third reviewer resolved any discrepancies. Eighteen studies met eligibility criteria and an additional 5 studies (not identified on our search strategy) were included on review of the bibliographies. Literature on subgroup of patients aged ≥65 was also assessed. Results: Among the 23 studies included, 16 were published after 2010. Studies were retrospective (N=18; 14 from registry data), cross-sectional (N=4; 2 from registry data), and mixed-method (N=1), and primarily conducted in the US (N=21). Barriers were assessed at the patient level (N=19; sample size ranged from 350 to 38,420), healthcare professional level (N=3; 1 study assessed both patients and healthcare professionals), or country level (N=2). Fourteen studies included some information on age of the patients and 10 studies included some patients aged 60 and above. Seventeen studies only included patients with hematologic malignancies. Age was the most common barrier identified (N=16 out of 16 studies identified older age as a barrier). Fourteen studies showed that older age was associated with lower odds of referral for or receipt of HCT, and the remaining 2 studies provided descriptive data showing lower percentages of patients receiving HCT compared to the younger age groups. Table 1 shows other potential barriers or factors associated with lower referral for or receipt of HCT at the patient, disease, physician, and organizational levels. These included race (N=14 out of 16 studies identified non-white race as a barrier), insurance or financial capacity (N=11/12), comorbidity (N=8/9), gender (N=7/17; primarily female), disease status (N=5/5), patient preferences (N=5/5), time of diagnosis (N=5/5), cancer type (N=4/6), and socioeconomic status (N=4/5). Only one study evaluated factors associated with receipt of HCT in a subgroup of patients ≥65 years. Older age, female gender, and a diagnosis of leukemia other than acute myeloid leukemia were associated with lower odds of receiving HCT. Conclusions: There are limited prospective studies evaluating access barriers to HCT in adult patients with cancer. Older age is the most commonly reported barrier to both autologous and allogeneic HCT, although studies have not addressed specific mechanisms for this disparity. In addition, other potential barriers identified such as gender, race, insurance status, and comorbidity have not been well studied in the context of older age. While some barriers may be difficult to intervene upon (e.g. comorbidity, disease status, performance status), many are amenable to interventions (e.g. socioeconomic status, distance to transplant center, social support). With the increasing trend for HCT in older patients, there is a critical need for prospective studies that better describe these access barriers and their mechanisms in order to design future interventions to reduce disparities in HCT access. Figure. Figure. Disclosures Liesveld: Onconova: Other: DSMB; Abbvie: Honoraria. Aljitawi:Medpace: Consultancy; The University of Rochester Medical Center: Patents & Royalties: Pending patent related to decellularized Wharton's jelly matrix. Klepin:Genentech Inc: Consultancy. Stock:Jazz Pharmaceuticals: Consultancy. Wildes:Janssen: Research Funding. Majhail:Incyte: Honoraria; Anthem, Inc.: Consultancy; Atara: Honoraria.

Description: Background: Myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have poor outcomes with a median survival of 3 to 5 months. Approximately 20% of MPN-BP patients have a pathogenic mutation in IDH1 or IDH2. Ivosidenib and enasidenib, inhibitors of the IDH1 and IDH2 mutant enzymes respectively, provide a new treatment approach for high-risk IDH-mutated acute myeloid leukemia (AML). There are limited clinical trial data and real-world experience with IDH inhibitors in MPN-AP/BP. We hypothesized that patients with IDH-mutated MPN-AP/BP may benefit from IDH inhibitor therapy. We performed a single institution retrospective analysis of patients with AML arising from a prior chronic myeloid neoplasm treated with an IDH inhibitor and evaluated outcomes of the MPN-AP/BP patients. Methods: Retrospective chart review was done to identify patients with IDH1/2-mutated MPN AP/BP, AML arising from myelodysplastic syndrome (MDS-AML), or AML arising from CMML (CMML-AML), that were treated with ivosidenib or enasidenib from 1/1/2009-5/14/2019. Response was assessed using both the 2003 International Working Group AML (2003 IWG AML) criteria and 2017 European LeukemiaNet (ELN) criteria. For the MPN-AP/BP patients, response was also assessed using the 2012 Post-MPN AML Consortium (2012 MPN-BP) criteria (Mascarenhas et al. Leuk Res 2012). Overall survival from initiation of IDH inhibitor therapy and adverse event data were collected. Results: There were 96 patients with IDH1 or IDH2 mutations identified by analysis of Next Generation Sequencing (NGS) data. 15 of these patients underwent treatment with an IDH inhibitor and had an antecedent chronic myeloid neoplasm: 7 MPN-BP, 1 MPN-AP, 5 MDS-AML, and 2 CMML-AML. Median age was 69 years old with a median Charlson Comorbidity Index of 6. ELN risk criteria could be assessed in 13/15 patients; of those, 54% were adverse-risk. 13 IDH2 mutated patients received enasidenib as monotherapy (n=12) or combined with azacitidine (n=1). 2 IDH1-mutated patients received ivosidenib as monotherapy (n=1) or combined with azacitidine (n=1). Of the 8 MPN-AP/BP patients, 6 received IDH inhibitor therapy in the front-line setting. Of the 7 patients with MDS-AML or CMML-AML, only 2 patients received IDH inhibitor therapy in the frontline setting. The overall response rate (ORR) to IDH inhibitor therapy for the 15 patients was 40% using both the 2003 IWG AML criteria and the 2017 ELN criteria. In the 8 patients with MPN-AP/BP, the ORR was 37.5% using both the 2003 IWG AML response criteria and the 2017 ELN criteria and was 75% when using the 2012 MPN-BP response criteria (Table 1). Median overall survival was not reached for the 3 MPN-BP patients reclassified as responders using 2012 MPN-BP criteria with median follow-up at time of data lock being 431 days (range, 67-1218+). Median duration of IDH inhibitor therapy in the whole 15 patient cohort was 126 days (range, 14-1218+) and 258 days (14-1218+) for MPN-BP patients. Median follow-up at time of data lock was 151 days for all patients and 272 days for MPN-BP patients. Within the MPN-AP/BP cohort, 3 are still on therapy at this time, 2 had stopped due to progression of disease, and 3 had stopped due to an adverse event or clinical deterioration (Figure 1). Median overall survival for all patients after initiation of IDH inhibitor therapy was 235 days (Figure 2). Median survival for patients with MPN-AP/BP (n=8) was not reached compared to 193 days for the 7 patients with MDS-AML or CMML-AML. The incidence of Grade 3 or greater adverse events was similar to the known AE profile of these agents. NGS analysis at time of progression to AML/accelerated phase identified JAK2 and SRSF2 mutations as the most frequent co-mutations (Table 2). Conclusions: Treatment with IDH inhibitor therapy in IDH-mutated MPN-AP/BP patients holds promise as a means of inducing durable responses that extend beyond historical survival data for MPN-BP. In addition, utilization of the 2012 MPN-BP criteria to assess response in this patient population can provide better insight into the benefit of this treatment strategy. Our single institutional experience merits confirmation in a larger group of patients with IDH1/2-mutated MPN-AP/BP. Disclosures Liu: Agios: Honoraria; Novartis: Other: PI of clinical trial; Arog: Other: PI of clinical trial; Karyopharm: Research Funding; BMS: Research Funding. Thirman:Celgene: Consultancy; Pharmacyclics: Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; Up to Date: Honoraria; Gilead: Research Funding; Janssen: Consultancy; Astra Zeneca: Consultancy; Roche/Genentech: Consultancy; AbbVie: Consultancy, Research Funding. Artz:Miltenyi: Research Funding. Larson:Celgene: Consultancy; Agios: Consultancy; Novartis: Honoraria, Other: Contracts for clinical trials. Stock:Kite, a Gilead Company: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Daiichi: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; UpToDate: Honoraria; Research to Practice: Honoraria. Segal:Astra Zeneca: Consultancy; Merck: Consultancy; BMS: Consultancy, Research Funding; AbbVie: Research Funding. Odenike:Agios: Research Funding; CTI/Baxalta: Research Funding; Gilead Sciences: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Oncotherapy: Research Funding; Astex Pharmaceuticals: Research Funding; Astra Zeneca: Research Funding; Janssen Oncology: Research Funding; NS Pharma: Research Funding. OffLabel Disclosure: We discuss the use of the IDH inhibitors ivosidenib and enasidenib in treatment of advanced-phase Ph-negative myeloproliferative neoplasms. Ivosidenib is currently approved for use in the frontline setting in IDH1-mutated AML patients 〉75 years old or with comorbidities precluding the use of intensive induction therapy. Ivosidenib is also approved in the relapsed/refractory setting for IDH1-mutated AML. Enasidenib is approved in the relapsed/refractory setting for IDH2-mutated AML.

Description: Early trials evaluating nonmyeloablative allogeneic hematopoietic transplant (NST) for metastatic renal cell carcinoma (RCC) have reported widely discordant results. We performed a meta-analysis of the published literature to identify prognostic factors for NST. However, known RCC prognostic factors are not often detailed in these studies, hindering the identification of patient differences among studies. We explored the order of patient entry as a surrogate marker for patient selection, hypothesizing that patient selection, rather than treatment differences, accounted for early promising results. Patient specific data and adequate follow-up were available for 76 patients from six studies. The rank of patient entry on each individual trial was recorded as well as ≥ grade 2 acute graft-versus-host disease (aGVHD), recipient age, recipient sex, response (partial plus complete), and survival. Multivariable analyses for response and survival were modeled using logistic and cox proportional hazards regression, respectively. The mean overall response rate was 22/76 (29%), with responses across individual studies significantly varying from 0% to 57% P =.009 by Chi-square). Median Kaplan-Meier survival was 263 days. Neither age nor sex was significantly ( associated with response or survival. Acute GVHD occurred in 42% of individuals and correlated with response (OR=9.9, P =0.012) but not survival (HR=1.53, P=0.28). When adjusting by study, later patient entry rank reduced the probability of response (OR=0.30, P =0.007) and survival (HR=1.89, P =0.006). Alternatively, being among the first five patients enrolled in a given study relative to subsequent patients, increased the probability of response (OR=6.69, 95% CI 1.95–39.1, P=0.005), even when adjusting for aGVHD, and afforded a survival benefit (HR= 0.45, 95% CI 0.022 −0.92, P=0.028). The prognostic strength of patient entry rank strongly suggests “entry bias” in patient selection. This bias potentially accounts for the large variation in outcome among studies and for the promising results in early studies. Entry bias analysis offers a novel method to assess early phase trials for selection bias, when detailed individual prognostic information is lacking. Further study is warranted to determine to what extent, if any, entry bias occurs in other clinical trial settings. Figure Figure

Description: BK virus (BKV) is an important pathogen and cause of nephropathy in recipients of renal transplants, but its clinical significance in patients following hematopoetic stem cell transplantation (HSCT) is less well described. Over a 10 month period we prospectively measured BKV (by quantitative PCR) in the blood and urine of 103 patients who had undergone previous allogeneic HSCT [HLA-identical donor (n = 58), alternative donor (HLA-mismatched-related, matched-unrelated, or cord) (n = 45)] and who were receiving inpatient or outpatient post-transplant care. The median time from transplantation to the last follow-up virus sampling was 422 days (range = 12 to 3456 days), and the cohort included patients undergoing transplants as early as 1998 through 2007. BK viruria was manifest at any time during the period of measurement in 62% of the patients. Only 16% (16/103) developed BK viremia. All patients with BK viremia also had detectable BK viruria. In 38 patients who underwent BKV monitoring beginning immediately after transplant, development of BK viruria was an early phenomenon (median 26 days post-transplant, range = 4 to 274 days), while BK viremia occurred later (median 157 days post-transplant, range = 62 to 323 days). More recipients of alternative donor transplants compared to HLA-identical transplants developed BK viruria (75% vs 53%, P = 0.03) and BK viremia (24% vs 9%, P = 0.02). Given the tropism of BKV for the genitourinary tract and its association with hemorrhagic cystitis, urinalyses from all patients were analyzed for the presence and number of red blood cells (RBCs). Those patients with microscopic hematuria (81/103) had significantly higher levels of urinary BKV than patients without hematuria (P 〈 0.001), and there was a suggestion that the degree of hematuria was directly related to the amount of urinary virus, since a subset of patients with more pronounced hematuria (〉 5 RBCs per high-powered microscopic field) had higher levels of urinary BKV than those with only small numbers of urinary RBCs (P = 0.06). Blood BKV levels were not associated with hematuria. The presence of BK viremia and/or viruria were not significantly associated with renal function, as measured by the mean serum creatinine, although 2/16 patients with BK viremia developed biopsy proven BKV interstitial nephritis, with one requiring hemodialysis. In summary, BK viruria is a common early finding in patients undergoing allogeneic HSCT, especially in those who do not have HLA-identical donors. Our data support the claim that BKV urinary infection is associated with hematuria post-HSCT. BK viremia occurs later and less commonly. Investigation of a larger number of patients is warranted to establish the incidence of and risk factors for BKV nephropathy in the allogeneic HSCT setting.

Description: There are limited data regarding the incidence or prognostic value of cytogenetic abnormalities in pts with leukemic relapse after allogeneic hematopoietic cell transplantation (HCT). Between 2002 and 2005, 70 consecutive pts with high risk AML or MDS were transplanted with a reduced intensity preparative regimen of fludarabine 30 mg/m2/day IV (150 mg/m2 total), alemtuzumab SC 20 mg/day IV (100 mg total) D-7 to D-3, and melphalan 140 mg/m2 IV D-2, with tacrolimus given for post-transplantation immunosuppression. Twenty-five pts relapsed or progressed; 21 had AML, 3 had MDS and 1 had mast cell leukemia. Twenty-two pts had cytogenetic analysis available prior to HCT and at relapse. Cytogenetic abnormalities were present in 12/22 (55%) pts prior to HCT. The median OS was 184 days (95% CI: 81 – 300) after relapse. Four pts with cytogenetic abnormalities prior to HCT reverted to a normal karyotype at relapse. Ten pts had no changes in their cytogenetics from HCT to relapse; they either remained normal or retained the same abnormality. Eight pts developed a new clonal abnormality at relapse, and had a median OS of 106 days (95% CI: 30 – 322). There was a non-significant trend toward inferior OS among pts with new abnormalities compared to the other groups (HR = 1.74, 95% CI 0.69 – 4.44, P = 0.24). The higher than previously reported rate of clonal evolution (8/22, 36%) may be due to the high prevalence of refractory disease at HCT in this cohort, more refined cytogenetic analysis, or regimen related factors (e.g. reduced intensity conditioning). The same clonal abnormality with or without new changes occurred in 7/22 pts. Thus, minimal residual disease monitoring in the subset of pts harboring pre-HCT karyotypic derangements may be a viable strategy for early detection and intervention. Our data suggest that clonal evolution at relapse of AML and MDS after HCT is relatively frequent, and in this small series, a trend toward worse outcomes exists for pts who develop new cytogenetic abnormalities. Larger studies are warranted to more completely characterize the prognostic value of cytogenetics and karyotypic evolution at relapse after HCT. Cytogenetic abnormalities for AML/MDS relapsing after HCT (N = 22) Pre HCT* Relapse *History of cytogenetic abnormality any time before HCT **Clonal evolution in 8/22 (36%) No 10 (45%) No 7 (32%) Yes (New)** 3 (14%) Yes 12 (55%) No 4 (18%) Yes (Same) 3 (14%) Yes (New)** 5 (27%)

Description: HCT entails substantial TRM justifying continued efforts to better risk stratify patients. Single institutional studies have suggested several clinically available biomarkers of CRP, ferritin and albumin influence TRM if not overall survival (OS). We sought to confirm the independent prognostic value of these biomarkers in a large multi-institutional cohort. The study population consisted of 784 adults with AML in remission (80%) or MDS (20%) undergoing unrelated donor HCT between 2008 and 2010 and available cryopreserved samples through the Center for International Blood and Marrow Transplant Research (CIBMTR) repository. CRP and ferritin were centrally quantified by ELISA from cryopreserved plasma whereas albumin levels obtained from center reported data. Correlation studies for biomarkers required log transformation of CRP and ferritin to produce a normal distribution. Multivariate models were fitted separately for each biomarker applying protocol specified thresholds generated from the literature of CRP 〉 10 mg/L, ferritin 〉 2500 ng/mL, albumin 〈 3.5 g/dL on TRM. Further analysis explored optimal cutpoints for this cohort for all significant clinical variables for TRM. HCT characteristics included a median age of 50 (range 18-78) years, HCT-CI (co-morbidity index) 3 or more in 35%, single allele/antigen mismatch (7/8) in 23%, PB as stem cell source in 83%, and myeloablative conditioning in 72%. Biomarker data were available in 783, 781 and 695 cases for CRP, ferritin and albumin respectively. The median values and ranges for each biomarker were as follows: 5.0 mg/L (0.3 - 316) for CRP, 1148 ng/mL (51 – 14,298) for ferritin and 3.6 g/dL (0.6-5.3) for albumin. Log transformed CRP and ferritin showed a modest correlation (r=0.35, P2500 ng/mL 93 (12) 1.26 0.84 – 1.88 0.27 1.15 0.86 – 1.54 0.35 Albumin 〈 3.5 g/dL 290 (42) 1.48 1.10 – 2.0 0.010 1.39 1.13 – 1.72 0.002 Optimal threshold, combined model ** CRP 〉3.67 mg/L 497 (64) 1.56 1.11 – 2.19 0.010 1.24 1.00 – 1.55 0.054 Log(Ferritin), linear n/a 1.20 0.99 – 1.46 0.07 1.20 1.04 – 1.38 0.010