Citations

Abstract We conducted a two-stage Simon phase II, multi-center study in two groups: related and unrelated donor transplants. Based on the results of a previously conducted prospective study (MPD-RC 101, Rondelli et al, Blood, 2014) demonstrating relatively poor outcome in the unrelated donor arm due to high non-relapse mortality and graft failure (GF), we sought to improve this noted disparate outcome. The hypothesis driving this trial was that pre-transplant JAK1/2 inhibition would result in an increase in performance status, reduction in splenomegaly and inflammatory cytokine expression leading to improved HCT outcome. In the unrelated arm in the first 11 patients, the trial was to be terminated if 6 or more failures (GF or death due to any cause by 100 days post-transplant) were observed. In the related arm in the first 11 patients, the trial was to be terminated if 3 or more failures were observed. Key eligibility criteria included diagnosis of primary MF or post-PV MF or post-ET MF, age 18-70 years, and DIPSS int-2/high risk disease or int-1 risk disease with at least one additional risk factor. Patients could have received up to 6 months of ruxolitinib prior to enrollment provided that there was no evidence of loss of response to ruxolitinib during this period. Ruxolitinib was given for 56 days followed by a 4-day taper ending day -6. The conditioning regimen utilized was IV fludarabine 40 mg/m2 IV and IV busulfan 2.0 mg/KBW IV once daily for 4 days from days -5 to -2. GVHD prophylaxis consisted of cyclosporine or tacrolimus and methotrexate. Patients undergoing unrelated donor HCT also received low dose thymoglobulin (0.5 mg/KBW on day -3/2.0 mg/KBW on day -2 & day -1). The study has enrolled 21 patients (related, 7; unrelated, 14) with a median age of 59 years (range 39-70). 17 (81%) patients had palpable splenomegaly with median spleen size of 11 cm, and 16 patients had int-2/high risk disease. Of the 21 patients, 19 patients received transplantation (related 5/7 [71%], unrelated 14/14 [100%] underwent transplant). Two patients in the related arm did not proceed with transplantation as one progressed to acute myeloid leukemia (baseline blast count 14%) and another experienced sudden death of unknown cause the day after starting ruxolitinib. In addition, there was one GF in the related arm. Due to these 3 failures in the related arm, further enrollment was stopped in this arm per protocol criteria. In the unrelated arm, there were 4 failures (Table 1), and the study met the protocol criteria for further enrollment. Mean percent reduction from baseline to day -9 in palpable spleen length below the left costal margin was 30% (p=0.04) in 12 patients with palpable spleen. 5/12 (42%) had any reduction, and 4/12 (33%) had ≥50% reduction. From baseline to best score on day -9 or day -5, 11/19 (58%) patients with data had any improvement in MPN-SAF Total Symptom Score, and 7/19 (37%) had ≥50% reduction. Of the 19 patients undergoing transplant, ruxolitinib was tapered off successfully in all patients with no significant withdrawal syndrome or delay in transplant noted. In the pre-transplant phase, most common Grade 3 or higher toxicity considered to be related to ruxolitinib was anemia (6/21, 29%), and one patient had legionella pneumonia deemed not related to ruxolitinib. Median time to neutrophil recovery (> 0.5 x 109/L) and platelet recovery (>20 x 109/L) was 19 and 19.5 days. By day 100, 7/19 (37%) experienced Grade 2-4 acute GVHD (G2 in 5, G3 in 2). In the first 30 days post HCT, most common Grade 3 or higher toxicity was febrile neutropenia seen in 5/19 (26%) patients. In all 21 patients from time of registration with median follow-up of 5.8 months, 6-mo overall survival was 75% (95% CI 44-90%). For the 19 transplant recipients, 6-mo OS was 83% (95% CI 55-94%) from date of transplant. Conclusions: Stage 1 trial results highlight important observations. First, ruxolitinib may not be suitable for all myelofibrosis patients pre-transplant, eg, alternative approaches might be more appropriate in the context of accelerating disease. Second, we demonstrated a safe approach for tapering ruxolitinib prior to transplant which allowed patients to commence conditioning with reduced spleen size and symptoms. Third, pre-transplant ruxolitinib does not appear to have any adverse impact on early post-HCT outcomes following unrelated donor transplant, although Stage 2 enrollment will be required to better assess the potential benefits of this approach. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Research Funding. Yacoub:Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Alexion: Honoraria. Mesa:Promedior: Research Funding; Celgene: Research Funding; CTI: Research Funding; Gilead: Research Funding; Incyte: Research Funding; Galena: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Mead:Novartis: Honoraria, Research Funding, Speakers Bureau. Mascarenhas:Novartis: Other: DSMB , Research Funding; Roche: Research Funding; Promedior: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Incyte: Other: Clinical Trial Steereing Committee, Research Funding.

AbstractMyeloproliferative Neoplasms (MPN) course can be complicated by thrombosis involving unusual sites as the splanchnic veins (SVT). Their management is challenging, given their composite vascular risk. We performed a retrospective, cohort study in the framework of the International Working Group for MPN Research and Treatment (IWG‐MRT), and AIRC‐Gruppo Italiano Malattie Mieloproliferative (AGIMM). A total of 518 MPN‐SVT cases were collected and compared with 1628 unselected, control MPN population, matched for disease subtype. Those with MPN‐SVT were younger (median 44 years) and enriched in females compared to controls; PV (37.1%) and ET (34.4%) were the most frequent diagnoses. JAK2V617F mutation was highly prevalent (90.2%), and 38.6% of cases had an additional hypercoagulable disorder. SVT recurrence rate was 1.6 per 100 patient‐years. Vitamin K‐antagonists (VKA) halved the incidence of recurrence (OR 0.48), unlike cytoreduction (OR 0.96), and were not associated with overall or gastrointestinal bleeding in multivariable analysis. Esophageal varices were the only independent predictor for major bleeding (OR 17.4). Among MPN‐SVT, risk of subsequent vascular events was skewed towards venous thromboses compared to controls. However, MPN‐SVT clinical course was overall benign: SVT were enriched in PMF with lower IPSS, resulting in significantly longer survival than controls; survival was not affected in PV and slightly reduced in ET. MPN‐U with SVT (n = 55) showed a particularly indolent phenotype, with no signs of disease evolution. In the to‐date largest, contemporary cohort of MPN‐SVT, VKA were confirmed effective in preventing recurrence, unlike cytoreduction, and safe; the major risk factor for bleeding was esophageal varices that therefore represent a major therapeutic target.

Background Left ventricular ( LV ) recovery in takotsubo syndrome ( TTS ) occurs over a wide‐ranging interval, varying from hours to weeks. We sought to investigate the clinical predictors and prognostic impact of recovery time for TTS patients. Methods and Results TTS patients from the International Takotsubo Registry were included in this study. Cut‐off for early LV recovery was determined to be 10 days after the acute event. Multivariable logistic regression was used to assess factors associated with the absence of early recovery. In‐hospital outcomes and 1‐year mortality were compared for patients with versus without early recovery. We analyzed 406 patients with comprehensive and serial imaging data regarding time to recovery. Of these, 191 (47.0%) had early LV recovery and 215 (53.0%) demonstrated late LV improvement. Patients without early recovery were more often male (12.6% versus 5.2%; P =0.011) and presented more frequently with typical TTS (76.3% versus 67.0%, P =0.040). Cardiac and inflammatory markers were higher in patients without early recovery than in those with early recovery. Patients without early recovery showed unfavorable 1‐year outcome compared with patients with early recovery ( P =0.003). On multiple logistic regression, male sex, LV ejection fraction <45%, and acute neurologic disorders were associated with the absence of early recovery. Conclusions TTS patients without early LV recovery have different clinical characteristics and less favorable 1‐year outcome compared with patients with early recovery. The factors associated with the absence of early recovery included male sex, reduced LV ejection fraction, and acute neurologic events. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifier: NCT 01947621.

Objective This study aims to (1) determine and validate living cartilage allograft transplantation as a novel source for viable osteochondral allograft (OCA) tissues and (2) perform histologic and viability comparisons of living donor cartilage tissues to currently available clinical-grade standard processed grafts. Design Using healthy cartilage from well-preserved contralateral compartments in 27 patients undergoing total knee arthroplasty (TKA) and 10 clinical-grade OCA specimens obtained immediately following operative implantation, standard and living donor OCA quality was evaluated at the time of harvest and following up to 3 weeks of storage on the basis of macroscopic International Cartilage Repair Society grade, histology, and viability. Results Osteochondral samples demonstrated a consistent decrease in viability and histologic quality over the first 3 weeks of storage at 37°C, supporting the utility of an OCA paradigm shift toward early implantation, as was the clinical standard up until recent adoption of transplantation at 14 to 35 days following donor procurement. Samples from the 10 clinical-grade OCAs, implanted at an average of 23 days following graft harvest demonstrated a mean viable cell density of 45.6% at implantation, significantly lower ( P < 0.01) than the 93.6% viability observed in living donor allograft tissues. Conclusions Osteochondral tissue viability and histologic quality progressively decreases with ex vivo storage, even when kept at physiologic temperatures. Currently available clinical OCAs are stored for 2 to 5 weeks prior to implantation and demonstrate inferior viability to that of fresh osteochondral tissues that can be made available through the use of a living donor cartilage program.

Abstract Abstract 277 Background: Current information on the natural history of polycythemia vera (PV) is mostly derived from early studies based on the PV Study Group diagnostic criteria. The World Health Organization (WHO) diagnostic approach to PV is currently the gold standard. The main objective of the current study was to describe survival, disease complication rates and risk factors in WHO-defined PV. Methods: Under the auspices of an International Working Group, seven international centers of excellence for myeloproliferative neoplasms submitted a total of 1,430 patients, locally diagnosed with “WHO-defined PV”. The two principle investigators (AT and TB) reviewed all the cases and selected 1,263 patients who were age 18 years or older, diagnosed after 1970, and whose submitted data included diagnostically essential information. Results I: Presenting Features: Median age was 60 years (range, 18–95; 51% females). The number of patients diagnosed between 1970–1990, 1991–2000, and 2001–2011 were 136 (11%), 337 (27%) and 790 (62%), respectively. Arterial/venous thrombosis history before or at diagnosis was documented in 142/73 and 80/42 patients, respectively. Other features at diagnosis included pruritus (37%), microvascular disturbances (29%), palpable splenomegaly (37%), abnormal karyotype (13%), and leukoerythroblastosis (6%). History of hypertension (45%), hyperlipidemia (17%), diabetes (9%), and tobacco use (15%) was also obtained. Results II: Clinical Course: To date, 228 (18%) deaths, 42 (3%) leukemic progressions, and 101 (8%) fibrotic transformations have been recorded. Post-diagnosis arterial or venous thrombosis occurred in 139 (11%) and 85 (7%) patients, respectively. Cytoreductive therapy had not been used in 342 (27%) patients whereas 154 (12%) patients were exposed to two or more cytoreductive drugs. Results III: Risk Factors: Multivariable analysis identified advanced age, leukocytosis, venous thrombosis history and abnormal karyotype as significant (p<0.01) risk factors for overall survival (OS). Receiver operating characteristic (ROC) plots delineated ages 69 (AUC 0.83) and 59 (AUC 0.61) years and leukocyte count 13 × 109/L (AUC=0.61) as the best discriminant levels in this regard; HR (95% CI) were 11.4 (7.7–16.9) for age ≥70 years, 3.8 (2.6–5.7) for age 60–69 years, and 2.0 (1.5–2.6) for leukocyte count ≥15 × 109/L. Results IV: Risk Stratification: HR-based risk scores were assigned to age ≥70 years (3 points), age 60–69 years (2 points) and leukocyte count ≥15 × 109/L (one point), in order to create four risk groups: low (zero points; n=492; median survival 322 months), intermediate-1 (one or 2 points; n=353; median survival 208 months; HR 3.8, 95% CI 2.5–5.8), intermediate-2 (3 points; n=286; median survival 132 months; HR 10.7, 95% CI 6.9–16.5), and high (4 points; n=56; median survival 90 months; HR 22.7, 95% CI 13.9–37.1) (Figure 1). Similar results were obtained when analysis was restricted to the 1,011 JAK2 mutation-positive patients (Figure 2). The particular risk model was equally robust in predicting leukemia-free survival (p=0.001). Conclusions: Age and leukocyte count matter the most in predicting survival in PV. The current study suggests additional prognostic value from karyotype and venous thrombosis history. Disclosures: Vannucchi: Novartis: Honoraria. Gisslinger:Novartis: Speakers Bureau; Celgene Austria: Speakers Bureau; AOP-Orphan: Speakers Bureau.

Abstract Abstract 3891 Poster Board III-827 Age over 65 years, hemoglobin level lower than 10 g/dL, WBC count greater than 25 × 109/L, peripheral blood blasts equal to or greater than 1%, and presence of constitutional symptoms provide a reliable prediction of survival in patients with primary myelofibrosis (PMF) at diagnosis [Cervantes et al. Blood. 2009 Mar 26;113(13):2895-901]. In fact, based on the presence of 0 (low risk), 1 (intermediate risk-1), 2 (intermediate risk-2) or greater than or equal to 3 (high risk) of the above factors, 4 risk groups with no overlapping in their survival curves were defined. To investigate whether the acquisition of these prognostic factors during follow-up may predict survival anytime, we studied 525 PMF patients regularly followed at each participating Institution from 1980 to 2008. The study was carried out within the IWG-MRT, and an ad hoc database was developed for data collection. Patients with post-polycythemia vera and post-essential thrombocythemia myelofibrosis, and patients with pre-fibrotic myelofibrosis were excluded from this study. Overall, 68 patients (26% of subjects who were below the age of 65 at diagnosis) passed the 65-year age threshold during the study period, 158 (47% of patients without this risk factor at diagnosis) developed anemia, 72 (15% of patients without this risk factor at diagnosis) presented marked leukocytosis, 102 (27% of patients without this risk factor at diagnosis) had more than 1% peripheral blast cells, and 54 (14% of patients without these symptoms at diagnosis) had constitutional symptoms. All variables resulted significant when analyzed as time-dependent covariates in a multivariable Cox proportional hazard regression model, and all of them were therefore included in the subsequent models. Each variable was assigned an integer weight close to the corresponding hazard ratio (HR), and the sum of values obtained was used to allocate the patients into 4 risk categories (low, intermediate-1, intermediate-2, high). We developed 2 separate models, one for all patients (DIPSS) and the other one for patients below the age of 65 (age-adjusted DIPSS), both applicable during the course of the disease. Cumulative survival can be estimated with the Kaplan Meier method. The increased risk of death when changing risk category was estimated as HR. According to DIPSS, the HR was: 4.13 (95% CI: 1.73-9.82; P < .001) if the risk category shifted from low to intermediate-1, 4.61 (95% CI: 3.18-9.82; P < .001) from intermediate-1 to intermediate-2, and 2.54 (95% CI: 1.94-3.31; P < .001) from intermediate-2 to high. According to age-adjusted DIPSS, the HR was 3.97 (95% CI: 1.5-10.5, P = .005) if the risk category shifted from low to intermediate-1, 2.84 (95% CI: 1.46-5.54; P = .002) from intermediate-1 to intermediate-2, and 1.81 (95% CI: 1.08-3.04; P = .025) from intermediate-2 to high. In conclusion, this study shows that age over 65 years, hemoglobin level lower than 10 g/dL, WBC count greater than 25 × 109/L, peripheral blood blasts equal to or greater than 1%, and the presence of constitutional symptoms predict survival independently and in a time-dependent manner in patients with PMF. Both DIPSS and age-adjusted DIPSS allow a reliable prognostic assessment of PMF patients at any time during the clinical course of the disease, and are therefore useful for clinical decision making. Disclosures: No relevant conflicts of interest to declare.