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AKT-inhibition is a promising approach to improve T cell therapies; however, its effect on CD4+ T cells is insufficiently explored. Previously, we and others showed that AKT-inhibition during ex vivo CD8+ T cell expansion facilitates the generation of polyfunctional T cells with stem cell memory-like traits. However, most therapeutic T cell products are generated from lymphocytes, containing CD4+ T cells that can affect CD8+ T cells dependent on the Th-subset. Here, we investigated the effect of AKT-inhibition on CD4+ T cells, during separate as well as total T cell expansions. Interestingly, ex vivo AKT-inhibition preserved the early memory phenotype of CD4+ T cells based on higher CD62L, CXCR4 and CCR7 expression. However, in the presence of AKT-inhibition, Th-differentiation was skewed toward more Th2-associated at the expense of Th1-associated cells. Importantly, the favorable effect of AKT-inhibition on the functionality of CD8+ T cells drastically diminished in the presence of CD4+ T cells. Moreover, also the expansion method influenced the effect of AKT-inhibition on CD8+ T cells. These findings indicate that the effect of AKT-inhibition on CD8+ T cells is dependent on cell composition and expansion strategy, where presence of CD4+ T cells as well as polyclonal stimulation impede the favorable effect of AKT-inhibition.

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype. This research was funded by grants from Instituto de Salud Carlos III (ISCIII) PI14/01867, PI16/02024 and PI17/00701, TRASCAN (EPICA), CIBERONC (CB16/12/00489; Co-finance with FEDER funds), RTICC (RD12/0036/0068) and Departamento de Salud del Gobierno de Navarra 40/2016. N.M. is supported by a FEHH-Celgene research grant, M.P. was supported by a Sara Borrell fellowship CD12/00540 and RO was supported by Ministerio de Ciencia, Innovación y Universidades of Spain, Subprograma de Formación de Profesorado Universitario (FPU) award number FPU14/04331.

The advent of novel agents for multiple myeloma (MM) is cause for a re-examination of the incidence of second primary malignancies (SPM5). We examined the SPM rate in MM patients who were enrolled in the prospective observational CALM (Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma) study. Between 2008 and 2012, 3204 patients with MM underwent a first autologous hematopoietic stem cell transplantation. Plerixafor was used as a mobilizing agent for patients with poor (or potentially poor) stem cell mobilization as defined by the respective centers. A total of 135 patients developed SPM5, with a cumulative incidence of 5.3% (95% confidence interval, 4.4 to 6.3) at 72 months. Ninety-four patients developed solid tumors, 30 developed hematologic malignancies, and 11 developed an SPM of an unknown type. The cumulative incidence of known hematologic and solid malignancies were 1.4% and 3.6%, respectively, at 72 months. In a univariate analysis, use of radiotherapy, type of induction regimen, hematopoietic stem cell dose, poor mobilizer status, plerixafor use, and sex did not influence the cumulative incidence of SPMs. Only age over 65 years was statistically associated with an increased incidence. Overall, the incidence of SPMs was comparable to earlier estimations of SPMs in MM. (C) 2018 American Society for Blood and Marrow Transplantation.

Combining natural killer (NK) cell adoptive transfer with hypomethylating agents (HMAs) is an attractive therapeutic approach for patients with acute myeloid leukemia (AML). However, data regarding the impact of HMAs on NK cell functionality are mostly derived from in vitro studies with high nonclinical relevant drug concentrations. In the present study, we report a comparative study of azacitidine (AZA) and decitabine (DAC) in combination with allogeneic NK cells generated from CD34(+) hematopoietic stem and progenitor cells (HSPC-NK cells) in in vitro and in vivo AML models. In vitro, low-dose HMAs did not impair viability of HSPC-NK cells. Furthermore, low-dose DAC preserved HSPC-NK killing, proliferation, and interferon gamma production capacity, whereas AZA diminished their proliferation and reactivity. Importantly, we showed HMAs and HSPC-NK cells could potently work together to target AML cell lines and patient AML blasts. In vivo, both agents exerted a significant delay in AML progression in NOD/SCID/IL2Rg(null) mice, but the persistence of adoptively transferred HSPC-NK cells was not affected. Infused NK cells showed sustained expression of most activating receptors, upregulated NKp44 expression, and remarkable killer cell immunoglobulin-like receptor acquisition. Most importantly, only DAC potentiated HSPC-NK cell anti-leukemic activity in vivo. Besides upregulation of NKG2D- and DNAM-1-activating ligands on AML cells, DAC enhanced messenger RNA expression of inflammatory cytokines, perforin, and TRAIL by HSPC-NK cells. In addition, treatment resulted in increased numbers of HSPC-NK cells in the bone marrow compartment, suggesting that DAC could positively modulate NK cell activity, trafficking, and tumor targeting. These data provide a rationale to explore combination therapy of adoptive HSPC-NK cells and DAC in patients with AML.

Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8+ T cells of allo-SCT recipients using a 13-color flow cytometry panel, and to correlate these expression patterns to clinical outcomes. MiHA-reactive CD8+ T cells exhibited an early differentiated CD27++/CD28++ phenotype with low KLRG-1 and CD57 expression. These T cells also displayed increased expression of PD-1, TIM-3, and TIGIT compared with total effector memory T cells and CMV-specific CD8+ T cells in healthy donors and allo-SCT recipients. Remarkably, high coexpression of PD-1, TIGIT, and KLRG-1 on MiHA-reactive CD8+ T cells was associated with relapse after allo-SCT. Taken together, these findings indicate that MiHA-specific CD8+ T cells of relapsed patients have a distinctive coinhibitory expression signature compared with patients who stay in remission. This phenotype may serve as a potential monitoring tool in patients. Moreover, these findings suggest that PD-1 and TIGIT play important roles in regulating T cell-mediated tumor control, providing a rationale for immunotherapy with blocking antibodies to treat relapse after allo-SCT.

Melphalan at a dose of 200 mg/m2 is standard conditioning prior to autologous hematopoietic stem cell transplantation for multiple myeloma, but a dose of 140 mg/m2 is often used in clinical practice in patients perceived to be at risk of excess toxicity. To determine whether melphalan 200 mg/m2 and melphalan 140 mg/m2 are equally effective and tolerable in clinically relevant patient subgroups we analyzed 1964 first single autologous transplantation episodes using a series of Cox proportional-hazards models. Overall survival, progression-free survival, cumulative incidence of relapse, non-relapse mortality, hematopoietic recovery and second primary malignancy rates were not significantly different between the melphalan 140 mg/m2 (n=245) and melphalan 200 mg/m2 (n=1719) groups. Multivariable subgroup analysis showed that disease status at transplantation interacted with overall survival, progression-free survival, and cumulative incidence of relapse, with a significant advantage associated with melphalan 200 mg/m2 in patients transplanted in less than partial response (adjusted hazard ratios for melphalan 200 mg/m2versus melphalan 140 mg/m2: 0.5, 0.54, and 0.56). In contrast, transplantation in very good partial or complete response significantly favored melphalan 140 mg/m2 for overall survival (adjusted hazard ratio: 2.02). Age, renal function, prior proteasome inhibitor treatment, gender, or Karnofsky score did not interact with overall/progression-free survival or relapse rate in the melphalan dose groups. There were no significant survival or relapse rate differences between melphalan 200 mg/m2 and melphalan 140 mg/m2 patients with high-risk or standard-risk chromosomal abnormalities. In conclusion, remission status at the time of transplantation may favor the use of melphalan 200 mg/m2 or melphalan 140 mg/m2 for key transplant outcomes (NCT01362972).

Rationale and Aim: In patients with Myeloma, early relapse following Autologous Haematopoietic Cell Transplantation (Auto-HCT) is a poor prognostic marker. Two groups have published scoring systems to predict early relapse. The CIBMTR score is based on cytogenetics, the bone marrow plasma cell percentage at the time of Auto-HCT and serum albumin. The GIMEMA Simplified early relapse in multiple myeloma (S-ERMM) score is a cumulative score based on a raised serum lactate dehydrogenase (LDH), t(4;14), del17p, low albumin, bone marrow plasma percentage >60%, and lambda light chain. The aim of the current study was to develop a scoring system to predict early relapse post-Auto-HSCT-1 using readily available variables. Study design and statistics: Within the EBMT database, there were 8,206 patients meeting the following eligibility criteria: First auto transplant 2014-2019, Known sex, ISS at diagnosis, cytogenetics analysis at diagnosis, disease status at Auto-HCT, Interval diagnosis-Auto-HCT > 1 month and Results: Comparison of the training and validation cohorts revealed no relevant differences (Table 1). Importantly, OS and PFS of both cohorts were overlapping with the probability of PFS at 12 months being 83.3% and 86.8%, respectively. The cumulative incidence of relapse at 12 month was 15.7% and 12.1%, respectively. Among patients who relapsed early, this occurred at a median of 6.64 months (0.56-11.99) in the first cohort, and at 5.85 months (0.1- 11.99) in the second cohort. The final model included (1) disease status at Auto-HCT, (2) age at Auto-HCT, and (3) ISS at diagnosis. Considering the order of magnitude of the coefficients, the points attributed in the risk score were: 0 for CR or VGPR; 1 for PR or SD/MR; 3 for Rel/Prog; 0 / 1/ 2 respectively for ISS I / II / III and -1 for Age=75 yrs. The Hazard Ratio for a +1 point is 1.52 i.e. the risk of early relapse/death increased on average by 52% for each additional point in the score. The distribution of risk scores was as follows: Score= -2 (n=757), -1 (n=1,481), 0 (n=1,358), 1 (n=647), and 2 (n=146). The score allows separation of the PFS12 curves (Figure 1), with the lowest risk group (N=757) having a PFS at 12 months of 91%, and the highest risk group (N=146) having a PFS at 12 months of 65%. Despite some minor differences in the risk factors between the training and validation cohorts, the score has a similar average effect (HR=1.48 i.e. + 48% hazard for each additional point) and worked well in separating the curves, in particular in identifying the patients at high risk of early relapse. Discussion and conclusion: The new EBMT score to predict early relapse post-Auto-HCT uses the easily available variables of age and ISS stage at diagnosis as well as the dynamic variable of response to induction. With this simple approach, we were able to clearly identify patients at high risk of early relapse. To our surprise, older age emerged as a protective factor against relapse. This may reflect a relative selection bias in that older patients with higher risk disease may not have been selected for transplant. Impact of cytogenetics will be presented at the Congress. In conclusion, this novel scoring system is robust and easy to use in routine daily practice. Figure 1 Figure 1. Disclosures Beksac: Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Sanofi: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Oncopeptides: Consultancy. Blaise: Jazz Pharmaceuticals: Honoraria. Leleu: Karyopharm Therapeutics: Honoraria; AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; Merck: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Oncopeptides: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Forcade: Novartis: Consultancy, Other: Travel Support, Speakers Bureau; Gilead: Other: Travel Support, Speakers Bureau; Jazz: Other: Travel Support, Speakers Bureau; MSD: Other: Travel Support. Rabin: Janssen: Consultancy, Honoraria, Other: Travel support for meetings; BMS / Celgene: Consultancy, Honoraria, Other: Travel support for meetings; Takeda: Consultancy, Honoraria, Other: Travel support for meetings. Kobbe: Celgene: Research Funding. Sossa: Amgen: Research Funding. Hayden: Jansen, Takeda: Other: Travel, Accomodation, Expenses; Amgen: Honoraria. Schoenland: Pfizer: Honoraria; sanofi: Research Funding; janssen,Prothena,Takeda,: Consultancy, Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria.

Background: Splenomegaly is a marker of disease progression in MF; larger spleen size (SS) is correlated with poorer survival and debilitating MF symptoms. In a retrospective real-world study of 408 patients (pts) with MF treated with ruxolitinib (RUX), pts with SS ≥ 10 cm below the left costal margin (LCM) were significantly less likely to attain a spleen response than pts with SS < 10 cm (Palandri 2017); this finding has not been reported in clinical trials of RUX. FEDR is a JAK2-selective inhibitor approved in the US, EU, Canada, and elsewhere as first-line (1L) MF treatment (Tx) and in pts previously treated with RUX. FEDR was evaluated as 1L MF Tx in the phase 3, placebo (PBO)-controlled JAKARTA trial, and in the phase 2, single-arm JAKARTA2 trial in pts previously treated with RUX. Pts allocated to FEDR 400 mg/day (d) in these trials reported substantial reductions from baseline (BL) in spleen volume and MF symptom severity after 6 FEDR Tx cycles. It is important to determine whether spleen volume and symptom improvements during FEDR Tx are influenced by degree of pre-Tx splenomegaly. Objective: Investigate the clinical efficacy of FEDR 400 mg/d in pts in JAKARTA & JAKARTA2 with large spleens at BL. Methods: The JAKARTA trial assessed FEDR 400 mg/d, FEDR 500 mg/d, and placebo in pts with JAK-inhibitor-naïve MF, and the JAKARTA2 trial evaluated FEDR 400 mg/d (starting dose) in pts resistant/intolerant to prior RUX. Both studies enrolled pts with intermediate- or high-risk MF, SS > 5 cm from LCM by palpation, platelets ≥ 50 ×10 9/L, and ECOG PS ≤ 2. These analyses include pts in each trial allocated to receive FEDR 400 mg/d in continuous 28d Tx cycles. Too few pts had BL SS < 10 cm by palpation in JAKARTA (n = 21) and JAKARTA2 (n = 12) for meaningful comparison vs SS ≥ 10 cm. Thus, in these post hoc analyses we divided pts according to the median SS (mSS) at BL in each study , and assessed changes from BL in spleen volume and MFSAF total symptom score (TSS) at the end of cycle 6 (EOC6). Spleen volume was assessed by MRI/CT scan; MFSAF TSS was the sum of 6 MF symptom scores: night sweats, early satiety, pruritus, pain under ribs-left side, abdominal discomfort, and bone/muscle pain. Pts must have had spleen volume and/or TSS data at BL and EOC6. R esults: In JAKARTA, 96 pts were randomized to FEDR 400 mg/d; mSS at BL for all pts was 16 cm (range 5-40). Median (range) BL spleen volume was 1771 (316-3396) mL in the < mSS cohort and 3329 (983-6430) mL in the ≥ mSS cohort; median TSS was 13.0 and 17.6, respectively. Spleen volume data were available at BL and EOC6 for 37 (82%) and 38 (75%) pts in the < mSS and ≥ mSS cohorts, respectively. Median spleen volume reduction (SVR) at EOC6 was -38% [95%CI -43%, -31%] in the < mSS group and -40% [-40%, -28%] in the ≥ mSS group (Figure). Changes in MF symptom scores at EOC6 were similar in the < mSS (n = 37) and ≥ mSS (n = 34) cohorts, with median TSS reductions of -49% and -51%, respectively. For individual symptoms, median reductions in abdominal discomfort, bone/muscle pain, and early satiety were similar between BL SS cohorts, whereas changes were greater in the < mSS group for pruritus and pain under ribs-left side, and greater in the ≥ mSS group for night sweats. In JAKARTA2, 97 pts received FEDR 400 mg/d (starting dose); BL mSS for all pts was 18 cm (range 5-36). Median (range) BL spleen volumes were 1937 (737-4305) and 4002 (1821-7815) mL for pts with < mSS and ≥ mSS, respectively; and BL TSS was 17.2 (0.7-48.0) and 23.6 (1.0-44.0). Spleen volume and MFSAF TSS data were available at BL and EOC6 for 41 and 29 pts, respectively, in the < mSS cohort, and for 41 and 22 pts in the ≥ mSS group. At EOC6, median SVR from BL was -35% [95%CI -40%, -29%] for pts with < mSS at BL and -30% [-37%, -17%] for pts with ≥ mSS (Figure). Median TSS changes were -36% and -49% in the < mSS and ≥ mSS cohorts, respectively; pts with ≥ mSS at BL had similar or greater reductions from BL in 5/6 MFSAF symptoms (all except pruritus) vs those with < mSS. Conclusions: These analyses demonstrate that extent of splenomegaly at BL in JAKARTA and JAKARTA2 did not influence the likelihood of achieving improvements in spleen volume or MF symptom severity for pts receiving FEDR 400 mg/d as 1L MF Tx or as post-RUX salvage Tx. For pts who completed 6 FEDR Tx cycles, reductions in spleen volume and TSS at EOC6 in the ≥ mSS cohorts in both studies were similar to those in the < mSS cohorts, even though BL spleen volumes and TSS were higher in the ≥ mSS groups. Figure 1 Figure 1. Disclosures Kiladjian: Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Passamonti: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vannucchi: BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Talpaz: Imago: Consultancy; Celgene: Consultancy; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support . Cervantes: Bristol Myers Squibb: Consultancy, Honoraria. Harrison: Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Sierra Oncology: Honoraria; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Mesa: AOP: Consultancy; La Jolla Pharma: Consultancy; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Genentech: Research Funding; Samus: Research Funding; CTI: Research Funding; Celgene: Research Funding; Abbvie: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Gilead: Research Funding; CTI: Research Funding; Pharma: Consultancy; Promedior: Research Funding. Mascarenhas: Geron: Consultancy; Merus: Research Funding; Geron: Consultancy, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Galecto: Consultancy; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Forbius: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek: Promedior: Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corp: Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; Ital Pharma: Research Funding; Incyte Corporation: Consultancy, Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; Celgene: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Devos: Alexion, AstraZeneca Rare Disease Inc.: Consultancy; Incyte: Consultancy; AbbVie: Consultancy; Bristol Myers Squibb - Celegene: Consultancy; Novartis: Consultancy. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Zhang: Bristol Myers Squibb: Current Employment. Sy: Bristol Myers Squibb: Current Employment.

Background: A recent study from the Acute Leukemia Working Party of EBMT demonstrated that outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) for adults with acute lymphoblastic leukemia (ALL) have improved significantly over time and that total body irradiation (TBI) should be considered as the preferable type of myeloablative conditioning (MAC). This study, however, did not compare outcomes of allo-HCT in patients with CNS involvement (CNS-pos) vs. those without CNS disease (CNS-neg). Study population: Here, we evaluate post allo-HCT outcomes of 547 patients (CNS-pos at initial presentation=96, CNS-neg=451) who underwent the procedure in first complete remission (CR1) between 2009 and 2019 at an EBMT participating transplant center. The distribution of ALL subtypes were as follows: CNS-pos (Ph-neg B ALL=28%, Ph-pos B ALL=27%, and T-cell ALL=45%) and for CNS-neg (Ph-neg B ALL=21%, Ph-pos B ALL=44%, and T-cell ALL=35%), p=0.01. The primary endpoint was leukemia-free survival (LFS). Results: The median follow up was not statistically different between the CNS-pos (78.7 months) and the CNS-neg group (67.2 months), p=0.58. Patients in the CNS-pos group were younger (median age 31.3 vs. 39.7 years, p=0.004), received the procedure more recently (median year 2012 vs. 2010, p=0.003), were less likely to have a Karnofsky score of equal or higher than 90 (70.8% vs. 81.9%, p=0.017), or to have received peripheral blood stem cells (PBSC) (61.5% vs. 72.7%, p=0.028). The groups did not differ in regards to donor source (URD, 50% vs. 56.5%, p=0.24) or the intensity of the preparative regimen (MAC, 82.3% vs. 85.6%, p=0.41). In multivariate analysis, CNS-pos were associated with higher cumulative incidence of relapse (HR=1.58 (95%CI=1.06-2.35), P=0.025) and a trend for an inferior leukemia-free survival (LFS) (HR=1.38 (95%CI=0.99-1.92), p=0.057), but did not adversely impact overall survival (OS) (HR=1.28 (95%CI=0.89-1.85), p=0.18). A subgroup multivariate analysis limited to patients with CNS-pos showed that prescribing a TBI MAC regimen (vs. others) results in a lower cumulative incidence of relapse (HR=0.35 (95%CI=0.15-0.79), p=0.012) and better LFS (HR=0.43 (95%CI=0.22-0.83), p=0.01) and OS (HR=0.44 (95%CI=0.21-0.92), p=0.03). Use of PBSC (vs. BM) was also independently associated with better OS (HR=0.53 (95%CI=0.29-0.99), p=0.046). Conclusion: Notwithstanding the inherent limitations of registry data, particularly ascertaining the absence of CNS involvement in the CNS-neg group, our results show CNS involvement as an independent risk factor for relapse following allo-HCT. Our data support, nonetheless, the choice of a TBI-based MAC regimen in this group of patients but stresses the need for close monitoring of relapse after allo-HCT. Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Bazarbachi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hikma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees. Mielke: Immunicum: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Miltenyi: Other: Data safety monitoring board; Novartis: Speakers Bureau; Celgene/BMS: Speakers Bureau. Socie: Alexion: Research Funding. Huynh: Jazz Pharmaceuticals: Honoraria. Yakoub-Agha: Jazz Pharmaceuticals: Honoraria. Giebel: Janssen: Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau. Peric: Therakos, Servier, MSD, Astellas, Novartis, Abbvie, Pfizer: Honoraria. Mohty: Sanofi: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria; Takeda: Honoraria; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Adaptive Biotechnologies: Honoraria.

Item does not contain fulltext High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) to rescue hematopoiesis is considered standard care for patients with a relapsed chemosensitive lymphoma, but diagnosis of lymphoma has been a risk factor for poor mobilization in several studies. The aim of this prospective noninterventional clinical audit was to review the mobilization strategies used by EBMT centers in relapsed lymphoma and to evaluate their efficacy. Between 2010 and 2014, 275 patients with relapsed lymphoma from 30 EBMT centers were prospectively registered. Almost all patients were mobilized with chemotherapy plus G-CSF (96%), but there was a large variation in chemotherapy schedules. Thirty (11%) of them were poor mobilizers (

Although high-dose therapy and autologous stem cell transplant combined with novel agents continues to be the hallmark of first-line treatment in newly diagnosed transplant-eligible multiple myeloma patients, the impact of tandem autologous or autologous/reduced-intensity allogeneic transplant for patients with extramedullary disease (EMD) and high-risk cytogenetics is not yet defined. Here, we analyzed clinical and cytogenetic data from 488 adult myeloma patients with EMD undergoing single autologous (n = 373), tandem autologous (n = 84), or autologous–allogeneic transplant (n = 31) between 2003 and 2015. At least 1 high-risk abnormality was present in 41% (n = 202), with del(17p) (40%) and t(4;14) (45%) the most frequent. More than 1 high-risk abnormality was found in 54%. High-risk cytogenetics showed worse 4-year overall survival (OS) and progression-free survival (PFS) of 54% and 29%, respectively, versus 78% and 49% for standard-risk cytogenetics (P < .001). Co-segregation of high-risk abnormalities did not seem to affect outcome. Regarding transplant regimen, OS and PFS were 70% and 43% for single autologous versus 83% and 52% for tandem autologous and 88% and 58% for autologous–allogeneic (P = .06 and P = .30). In multivariate analysis high-risk cytogenetics were associated with worse survival (hazard ratio [HR], 2.00; P = .003), whereas tandem autologous significantly improved outcome versus single autologous transplant (HRs, 46 and .64; P = .02 and P = .03). Autologous–allogeneic transplant did not significantly differ in outcome but appeared to improve survival, but results were limited because of small population (HR, 31). In conclusion, high-risk cytogenetics is frequently observed in newly diagnosed myeloma with EMD and significantly worsens outcome after single autologous, whereas a tandem autologous transplant strategy may overcome onset poor prognosis., SCOPUS: ar.j, info:eu-repo/semantics/published

Acute myeloid leukemia (AML) with FLT3-mutation carries a poor prognosis, and allogeneic stem cell transplantation (allo-SCT) is recommended at first complete remission (CR1). We assessed 462 adults (median age 50 years) with FLT3-mutated AML allografted between 2010 and 2015 from a matched related (40%), unrelated (49%), or haploidentical donor (11%). The median follow-up of alive patients was 39 months. Day-100 acute graft versus host disease (GVHD) grades II-IV and III-IV were encountered in 26% and 9%, whereas the 2-year incidence of chronic and extensive chronic GVHD were 34% and 16%, respectively. The 2-year incidences of relapse and nonrelapse mortality were 34% and 15%, respectively. The 2-year leukemia-free survival, overall survival (OS), and GVHD relapse-free survival (GRFS) were 51%, 59%, and 38%, respectively. In multivariate analysis, NPM1-mutation, transplantation in CR1, in vivo T-cell depletion, and posttransplant sorafenib improved OS, whereas more than one induction (late CR1) negatively affected OS. Similarly, NPM1-mutation, a haploidentical donor, T-cell depletion, and sorafenib maintenance improved GRFS, whereas late CR1 or persistent disease negatively affected it. In conclusion, FLT3-mutated AML remains a challenge even following allo-SCT. In vivo T-cell depletion and posttransplant sorafenib significantly improve OS and GRFS, and may be considered as standard of care. ispartof: Clin Hematol Int vol:1 issue:1 pages:58-74 ispartof: location:United States status: Published online

Tolerance induction through simultaneous hematopoietic stem cell and renal transplantation has shown promising results, but it is hampered by the toxicity of preconditioning therapies and graft‐versus‐host disease (GVHD). Moreover, renal function has never been compared to conventionally transplanted patients, thus, whether donor‐specific tolerance results in improved outcomes remains unanswered. We collected follow‐up data of published cases of renal transplantations after hematopoietic stem cell transplantation from the same donor and compared patient and transplant kidney survival as well as function with caliper‐matched living‐donor renal transplantations from the Austrian dialysis and transplant registry. Overall, 22 tolerant and 20 control patients were included (median observation period 10 years [range 11 months to 26 years]). In the tolerant group, no renal allograft loss was reported, whereas 3 were lost in the control group. Median creatinine levels were 85 μmol/l (interquartile range [IQR] 72‐99) in the tolerant cohort and 118 μmol/l (IQR 99‐143) in the control group. Mixed linear‐model showed around 29% lower average creatinine levels throughout follow‐up in the tolerant group (P, A long‐term follow‐up analysis shows stable renal graft function without immunosuppression and no graft loss in patients receiving renal transplantation after hematopoietic stem cell transplantation from the same donor.

Supplemental Digital Content is available in the text, Introduction: Recurrent ovarian carcinoma has dismal prognosis, but control of disease and prolonged survival are possible in some patients. The estimated 5-year survival is 46% for all stages of ovarian cancer, and only 28% for metastasized disease. Notably, the majority of women with ovarian cancer are diagnosed with stage III or IV disease with a high recurrence rate. As most women with relapsed or metastatic cancer will die of progressive disease, there is an urgent need for novel therapeutic strategies. The primary aim of our study is to evaluate safety and toxicity of intraperitoneal infusion of ex vivo-expanded natural killer cells (NK), generated from CD34+ umbilical cord blood (UCB) progenitor cells, with and without a preceding non-myeloablative immunosuppressive conditioning regimen in patients suffering from recurrent ovarian cancer. The secondary objectives are to compare the in vivo lifespan, expansion, and biological activity of intraperitoneally infused NK cell products with or without preparative chemotherapy, as well as evaluate effects on disease load. Methods: In this phase I safety trial, 12 patients who are suffering from recurrent ovarian cancer, detected by a significant rise in serum level of CA-125 on two successive time points, will be included. Prior to UCB-NK cell infusion, a laparoscopy is performed to place a catheter in the peritoneal cavity. The first cohort of three patients will receive a single intraperitoneal infusion of 1.5-3×109 UCB-NK cells, generated ex vivo from CD34+ hematopoietic progenitor cells obtained from an allogeneic UCB unit, without a preparative chemotherapy regimen. The second group of three patients will be treated with a similar dose of UCB-NK cells following a preparative four days non-myeloablative immunosuppressive conditioning regimen with cyclophosphamide and fludarabine (Cy/Flu). If no severe toxicity is seen in these 6 patients, an extension cohort of 6 patients will be included to answer the secondary objectives. Discussion: This study investigates the safety of a promising new cellular therapy in a group of patients with a poor prognosis. Demonstration of safety and in vivo expansion capacity of allogeneic UCB-NK cells in the absence of Cy/Flu pretreatment will provide rationale for UCB-NK cell infusion after regular second-line chemotherapy.

Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a complex therapy which can induce a multi-factorial cascade of complications, and potentially lead to patient death. The triggering event(s), sequence and severity of such complications can significantly differ between patients, but in many cases, a so-called "multi-organ failure" (MOF) is usually reported as the leading cause of death. However, a patient's clinical course can be very heterogeneous across and within cause-specific mortalities. Moreover, comorbidities present prior to alloHCT carry their own risks and represent additional confounding factors. Therefore, identification of the exact initial trigger or event leading to MOF in alloHCT patients is a critical step towards early intervention and improvement of patients' outcome. The goal of the current study was to establish and identify the exact cause of death in alloHCT patients where MOF was considered to be the main cause of death. Of note, we specifically focused on VOD/SOS because this life-threatening complication has a mortality exceeding 80% in severe cases, ending usually in MOF, and because VOD/SOS has subtle and dynamic evolution features which are not easy to capture, but could be potentially controlled by appropriate therapy (eg. defibrotide). Patients and Methods: For the purpose of this analysis, we randomly identified 241 adult patients (42% female; median age: 50 years; range 19-73) with acute leukemia (72% AML, 25% ALL, 3% other) allografted between 2010 and 2018 from a matched sibling (29%), unrelated (61%) or haploidentical donor (10%). All patients were reported to the EBMT registry to have died from MOF. Karnofsky score at time of alloHCT was >90 in 87% of patients. Seventy-three percent of patients underwent transplant in complete remission, and conditioning was myeloablative in 70%. Sixty patients (25%) received VOD/SOS prophylaxis treatment, mainly consisting of ursodiol and/or heparin. Patients' files were reviewed in detail in order to capture all early signs and symptoms which occurred prior to MOF, based on the classical Baltimore criteria, modified Seattle criteria, and/or the newly published EBMT criteria. These criteria included bilirubin levels, the presence of hepatomegaly or painful hepatomegaly, ascites, percentage weight gain, hemodynamic instability, and ultrasound/histologically proven VOD/SOS. Results: Using one or more of the above criteria defining VOD/SOS, we identified a total of 67 (28%) patients for whom VOD/SOS could be considered as the trigger for MOF and the leading cause of death. Interestingly, among these 67 patients, only 22 (33%) were originally reported by the centers as having developed VOD/SOS leading to MOF post-transplant. When comparing the group of 67 patients dying of VOD/SOS-related MOF and the remaining 174 patients dying of MOF not related to VOD/SOS (please see attached table), a multivariate regression analysis identified a significant increase in VOD/SOS incidence (odds ratio 3.9; 95%CI, 2.42-6.33; p Conclusion: The above results suggest that VOD/SOS-related MOF is an under-reported cause of death. It is actually a relatively frequent cause of MOF, accounting for at least 28% of deaths that would otherwise been attributed to MOF of unknown origin. While the MOF concept is a widely used cause of death after alloHCT, having precise categories of cause-specific death from MOF should allow (whenever possible), for earlier specific therapeutic intervention (eg. defibrotide), thus contributing to improved patient outcome. Table Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Schaap:Celgene: Consultancy; Novartis: Consultancy. Snowden:Jazz: Honoraria; IDMC: Honoraria; Mallinckrodt: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Background Myeloablative (MAC) and reduced-intensity conditioning (RIC) are established approaches for allogeneic stem cell transplantation (SCT) in acute myeloid leukemia (AML). Most deaths after MAC occur within the first 2 years after SCT, while patients surviving leukemia-free for 2 years can expect a favorable long-term outcome. However, there is paucity of data on the long-term outcome (beyond 10 years) and the pattern of late events following RIC due to the relative recent introduction of this approach. Methods We analyzed long-term outcomes in a cohort of 1423 AML patients, age ≥50 years, after SCT from HLA-matched siblings, during the years 1997–2005, median follow-up 8.3 years (0.1–17). Results The 10-year leukemia-free survival (LFS) was 31 % (95CI, 27–35) and 32 % (28–35) after MAC and RIC, respectively (P = 0.57). The 10-year GVHD/ relapse-free survival (GRFS), a surrogate for quality of life was 22 % (18–25) and 21 % (18–24), respectively (P = 0.79). The 10-year non-relapse mortality (NRM) was higher and relapse rate was lower after MAC, throughout the early and late post-transplant course. The 10-year LFS among 584 patients surviving leukemia-free 2 years after SCT was 71 % (65–76) and 73 % (67–78) after MAC and RIC, respectively (P = 0.76). Advanced leukemia at SCT was the major predictor of LFS subsequent to the 2-year landmark. Relapse was the major cause of late death after both regimens; however, NRM and in particular chronic graft-versus-host disease and second cancers were more common causes of late death after MAC. Conclusions Long-term LFS and GRFS are similar after RIC and MAC. Most events after RIC or MAC occur within the first 2 years after SCT. Patients who are leukemia-free 2 years after SCT can expect similar good subsequent outcome after both approaches. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0347-1) contains supplementary material, which is available to authorized users.

Contains fulltext : 172057.pdf (Publisher’s version ) (Closed access) Potent immunotherapies are urgently needed to boost antitumor immunity and control disease in cancer patients. As dendritic cells (DCs) are the most powerful APCs, they are an attractive means to reinvigorate T cell responses. An appealing strategy to use the effective Ag processing and presentation machinery, T cell stimulation and cross-talk capacity of natural DC subsets is in vivo tumor Ag delivery. In this context, endocytic C-type lectin receptors are attractive targeting molecules. In this study, we investigated whether CLEC12A efficiently delivers tumor Ags into human DC subsets, facilitating effective induction of CD4(+) and CD8(+) T cell responses. We confirmed that CLEC12A is selectively expressed by myeloid cells, including the myeloid DC subset (mDCs) and the plasmacytoid DC subset (pDCs). Moreover, we demonstrated that these DC subsets efficiently internalize CLEC12A, whereupon it quickly translocates to the early endosomes and subsequently routes to the lysosomes. Notably, CLEC12A Ab targeting did not negatively affect DC maturation or function. Furthermore, CLEC12A-mediated delivery of keyhole limpet hemocyanin resulted in enhanced proliferation and cytokine secretion by keyhole limpet hemocyanin-experienced CD4(+) T cells. Most importantly, CLEC12A-targeted delivery of HA-1 long peptide resulted in efficient Ag cross-presentation by mDCs and pDCs, leading to strong ex vivo activation of HA-1-specific CD8(+) T cells of patients after allogeneic stem cell transplantation. Collectively, these data indicate that CLEC12A is an effective new candidate with great potential for in vivo Ag delivery into mDCs and pDCs, thereby using the specialized functions and cross-talk capacity of these DC subsets to boost tumor-reactive T cell immunity in cancer patients.

Context: MF is characterized by anemia, progressive splenomegaly, and debilitating constitutional symptoms. Fedratinib is a selective JAK2 inhibitor approved in the US for adult patients with intermediate-2 or high-risk MF. Fedratinib was assessed in the phase III, placebo-controlled JAKARTA trial in patients with JAK-inhibitor-naive MF, and in the phase II single-arm JAKARTA2 trial in patients previously treated with ruxolitinib. Reduced splenomegaly and decreased symptom burden are each important goals of treatment but may not occur simultaneously. Objective: Assess the overall clinical benefit of fedratinib, as assessed by proportions of patients in JAKARTA and JAKARTA2 who achieved a spleen volume response, symptom response, or both, after 6 fedratinib treatment cycles. Methods: Both studies enrolled patients with intermediate- or high-risk MF, platelet counts ≥50 × 109/L, and ECOG PS ≤ 2. Efficacy endpoints included rates of spleen volume response (≥35% spleen volume reduction from baseline) and symptom response (≥50% reduction from baseline total symptom score [TSS] on the modified MFSAF) at the end of cycle 6 (EOC6). These analyses assess outcomes among patients in both studies who received fedratinib 400 mg/day and JAKARTA patients randomized to placebo, who had spleen volume and MFSAF TSS data available at baseline and EOC6. Results: In JAKARTA, 67/96 (70%) patients randomized to fedratinib 400 mg and 45/96 (47%) randomized to placebo had spleen volume and MFSAF assessments at baseline and EOC6. Overall, 76% (51/67) of fedratinib-treated patients achieved a spleen volume (n=40 [60%]) or symptom (n=35 [52%]) response, including 24 patients (36%) who achieved both responses. In the placebo arm, 8/45 patients (18%) achieved a spleen volume (n=1) or symptom (n=7) response; no patient attained both responses. In JAKARTA2, 42/97 patients (43%) who received fedratinib 400 mg/day (starting dose) had spleen volume and symptom assessments at baseline and EOC6. Of them, 81% (34/42) achieved a spleen (n=24 [57%]) or symptom response (n=20 [48%]), including 10 patients (24%) who achieved both. Conclusion: A majority of patients with MF who completed 6 fedratinib treatment cycles in JAKARTA or JAKARTA2 experienced a clinical benefit in terms of spleen volume reductions or symptom responses, and one-fourth to one-third of these patients achieved both responses.

Introduction: The prognosis of patients diagnosed with blast crisis (BC) chronic myeloid leukemia (CML) is dismal. Allogeneic stem cell transplantation (alloSCT) represents the only curative treatment option. In the current tyrosine kinase inhibitor (TKI) era, however, data on transplant outcomes in patients with BC CML, particularly those with active BC at transplant, are scarce. We hereby report on a multicentre, EBMT-registry based retrospective study of adult patients allografted for BC CML focusing on patients with active disease at transplant and pre-transplant prognostic factors. Patients and methods: Patients with BC CML at transplant (i.e. prior to the start of the conditioning) who underwent alloSCT after the year 2004 within the EBMT database were identified. Next, transplant centers were asked to report the exact disease status at transplant (including blood count, blast count in peripheral blood and bone marrow, achievement and type of remission with corresponding assessment dates, and the reason to proceed with alloSCT in BC CML). A total of 170 patients allografted for BC CML between 2004 and 2016 had complete data for analysis. Overall survival (OS) and leukemia-free survival (LFS) were calculated from date of alloSCT to the appropriate endpoint. For multivariable analysis of predictors of OS and LFS, Cox proportional hazard regression models were performed. Confounding prognostic factors (full models) were: age, disease status prior to alloSCT, Karnofsky performance status (KPS) prior to transplant, interval from diagnosis to transplant, year of transplant, stem cell source, conditioning intensity, donor type, and donor/recipient sex match. All patients provided informed consent for data collection and analysis. Results: Median age at alloSCT was 45 years (range [r], 18-75). Median time from diagnosis to alloSCT was 13.9 months (r, 1.6-367.4). Median follow-up time was 54.7 months (r, 0.1-135.2). Stem cell source was peripheral blood, bone marrow and cord blood in 145 (85%), 18 (11%) and 7 (4%) patients, respectively. Donor types were: unrelated (UD), matched related, and mismatched related in 91 (54%), 64 (38%), and 15 (9%) patients, respectively. Conditioning was myeloablative in 108 (64%) of patients. KPS at alloSCT was ≤80% in 31% of patients. Information on BCR-ABL mutations was available for 41 patients; T315I was present in 28 patients. After thorough analysis of disease parameters, a total of 95 patients had any kind of remission of BC CML (including secondary chronic phase) prior to transplant (termed BC in remission); 75 patients had active BC CML prior to transplant (termed BC active). Main reason for proceeding with alloSCT despite active disease was resistance/refractoriness towards TKI in combination with polychemotherapy. Extramedullary disease was documented in 4 patients. In uni- and multivariable analyses of the entire cohort, besides low KPS, only disease status prior to transplant was significantly associated with shorter OS and LFS (for BC active: HR 2.00, 95%CI 1.35-2.96, p=0.001 and HR 1.80 95%CI 1.27-2.57, p=0.001, respectively). Accordingly, for patients allografted for active BC estimated 3-year OS and LFS was rather short (23.8% 95%CI 13.6-34.0 and 11.6% 95%CI 3.0-20.2, respectively) and significantly lower as compared to patients allografted for BC in remission (3-year OS and LFS: 51.1% 95%CI 40.5-61.7 and 33.8% 95% CI 23.6-44.0, respectively) (Figure 1A and B). Consequently, prognostic factors for survival were analyzed separately according to disease status at alloSCT (slim models, Table 1). For patients with BC in remission at transplant advanced age, lower KPS, shorter interval from diagnosis to transplant, myeloablative conditioning, and UD transplant were risk factors for inferior survival, whereas in patients allografted for active BC, only UD transplant was associated with prolonged LFS and with a trend towards improved OS (Table 1). Conclusion: Survival of BC CML patients after alloSCT in the TKI era remains poor unless disease remission could be achieved. In patients who achieve remission prior to alloSCT, conventional prognostic indicators remain the determinants of transplant outcomes. In patients with active BC CML, UD transplantation appears to be associated with a survival advantage in our study. Disclosures Finke: Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding; Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding. Tischer:Jazz Pharmaceuticals: Other: Jazz Advisory Board. Mayer:Eisai: Research Funding; Roche: Research Funding; Affimed: Research Funding; Novartis: Research Funding; Johnson & Johnson: Research Funding. Byrne:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Chalandon:Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel costs.

The aim of the study was to assess the role of allogeneic stem cell transplantation (SCT) in patients diagnosed with BCR-ABL1-positive acute myeloid leukemia (AML). Fifty-seven patients (median age, 48 years, range: 19-67) with BCR-ABL1 positive AML undergoing SCT were identified. The majority of the patients (70%) received a TKI before the transplant. At SCT 48 patients were in CR (45 in CR1), while 9 patients were transplanted in a more advanced stage of the disease. MRD was negative (BCR-ABL1/ABL

Purpose Total-body irradiation (TBI) is a major constituent of myeloablative conditioning regimens. The standard technique consists of 12 Gy in 6 fractions over a period of 3 days. The Standard-fractionation compAred to one-daily fRaction total body irrAdiation prior to tranSplant In LEUkemia patieNts (SARASIN) study aimed to compare standard fractionation with once-daily fractionation before transplant in leukemia. Methods and Materials We retrospectively compared TBI regimens delivered in 2993 patients from the European Society for Blood and Marrow Transplantation database, who underwent transplantation between 2000 and 2014 for acute lymphoblastic leukemia (ALL, n = 1729) or acute myeloid leukemia (AML, n = 1264). TBI was delivered as either 12 Gy in 6 fractions (group 1, considered the reference group; 1362 ALL and 857 AML patients), 9 to 12 Gy in 2 fractions (group 2, 173 ALL and 256 AML patients), or 12 Gy in 3 to 4 fractions (group 3, 194 ALL and 151 AML patients). Results The median follow-up was 60 and 84 months in ALL and AML patients, respectively. At 5 years, the leukemia-free survival rate, overall survival rate, relapse incidence, and nonrelapse mortality rate were 46.6%, 50.4%, 28.8%, and 24.6%, respectively, in ALL patients and 46.6%, 48.9%, 29.7%, and 23.6%, respectively, in AML patients. In multivariate analyses, the outcomes of groups 2 and 3 were not statistically different from those in group 1. The cumulative incidence of secondary malignancies (SMs) was significantly higher in group 2 (7.2%; P Conclusions We showed that the 12-Gy fractionated TBI dose delivered either in 2 fractions or in 1 fraction per day over a period of 3 to 4 days resulted in nonsignificant differences in disease control and survival. However, 1-day fractionation may be associated with a higher risk of mucositis and hemorrhagic cystitis. The absence of a significant difference in the SM incidence in the non–T-cell–depleted group should be interpreted with caution in the context of a retrospective study design. Our findings are important to consider for radiation therapy department organization. In-depth analyses of other nonlethal toxicities and late effects are required.

The deletion (5q) karyotype (del [5q]) in patients with myelodysplastic syndrome (MDS) is the most common karyotypic abnormality in de novo MDS. An increased number of blasts and additional karyotypic abnormalities (del [5q]+) are associated with a poor outcome. We analyzed the outcome of allogeneic hematopoietic cell transplants (HCT) in patients suffering from MDS with only del (5q) or del (5q)+ . A total of 162 patients, of median age 54 years (range, 9 to 73), having MDS and del (5q) abnormalities received HCT from identical siblings (n = 87) or unrelated donors (n = 75). The cumulative incidence of nonrelapse mortality and relapse incidence at 4 years was 29% (95% CI, 22 to 36) and 46% (95% CI, 38 to 54), whereas the estimated 4 year survival, relapse-free and overall, was 25% (95% CI, 18 to 33) and 30% (95% CI, 23 to 38), respectively. In a multivariate analysis patients with del (5q) and a blast excess displayed poorer survival (hazard ratio, 2.38; 95% CI, 1.44 to 3.93; P

Contains fulltext : 152789.pdf (Publisher’s version ) (Closed access) Early natural killer (NK)-cell repopulation after allogeneic stem cell transplantation (allo-SCT) has been associated with reduced relapse rates without an increased risk of graft-versus-host disease, indicating that donor NK cells have specific antileukemic activity. Therefore, adoptive transfer of donor NK cells is an attractive strategy to reduce relapse rates after allo-SCT. Since NK cells of donor origin will not be rejected, multiple NK-cell infusions could be administered in this setting. However, isolation of high numbers of functional NK cells from transplant donors is challenging. Hence, we developed a cytokine-based ex vivo culture protocol to generate high numbers of functional NK cells from granulocyte colony-stimulating factor (G-CSF)-mobilized CD34(+) hematopoietic stem and progenitor cells (HSPCs). In this study, we demonstrate that addition of aryl hydrocarbon receptor antagonist StemRegenin1 (SR1) to our culture protocol potently enhances expansion of CD34(+) HSPCs and induces expression of NK-cell-associated transcription factors promoting NK-cell differentiation. As a result, high numbers of NK cells with an active phenotype can be generated using this culture protocol. These SR1-generated NK cells exert efficient cytolytic activity and interferon-gamma production toward acute myeloid leukemia and multiple myeloma cells. Importantly, we observed that NK-cell proliferation and function are not inhibited by cyclosporin A, an immunosuppressive drug often used after allo-SCT. These findings demonstrate that SR1 can be exploited to generate high numbers of functional NK cells from G-CSF-mobilized CD34(+) HSPCs, providing great promise for effective NK-cell-based immunotherapy after allo-SCT.

YARS2 variants have previously been described in patients with myopathy, lactic acidosis and sideroblastic anemia 2 (MLASA2). YARS2 encodes the mitochondrial tyrosyl-tRNA synthetase, which is responsible for conjugating tyrosine to its cognate mt-tRNA for mitochondrial protein synthesis. Here we describe 14 individuals from 11 families presenting with sideroblastic anemia and YARS2 variants that we identified using a sideroblastic anemia gene panel or exome sequencing. The phenotype of these patients ranged from MLASA to isolated congenital sideroblastic anemia. As in previous cases, inter- and intra-familial phenotypic variability was observed, however, this report includes the first cases with isolated sideroblastic anemia and patients with biallelic YARS2 variants that have no clinically ascertainable phenotype. We identified ten novel YARS2 variants and three previously reported variants. In vitro amino-acylation assays of five novel missense variants showed that three had less effect on the catalytic activity of YARS2 than the most commonly reported variant, p.(Phe52Leu), associated with MLASA2, which may explain the milder phenotypes in patients with these variants. However, the other two missense variants had a more severe effect on YARS2 catalytic efficiency. Several patients carried the common YARS2 c.572 G>T, p.(Gly191Val) variant (minor allele frequency =0.1259) in trans with a rare deleterious YARS2 variant. We have previously shown that the p.(Gly191Val) variant reduces YARS2 catalytic activity. Consequently, we suggest that biallelic YARS2 variants, including severe loss-of-function alleles in trans of the common p.(Gly191Val) variant, should be considered as a cause of isolated congenital sideroblastic anemia, as well as the MLASA syndromic phenotype.

Allogeneic stem cell transplantation (allo-SCT) can be a curative treatment for patients with a hematologic malignancy due to alloreactive T cell responses recognizing minor histocompatibility antigens (MiHA). Yet tumor immune escape mechanisms can cause failure of T cell immunity, leading to relapse. Tumor cells display low expression of costimulatory molecules and can up-regulate coinhibitory molecules that inhibit T cell functionality on ligation with their counter-receptors on the tumor-reactive T cells. The aim of this explorative study was to evaluate immune checkpoint expression profiles on T cell subsets and on cytomegalovirus (CMV)- and/or MiHA-reactive CD8

Item does not contain fulltext BACKGROUND: Myelofibrosis is a chronic myeloproliferative neoplasm characterised by splenomegaly, cytopenias, bone marrow fibrosis, and debilitating symptoms including fatigue, weight loss, and bone pain. Mutations in Janus kinase-2 (JAK2) occur in approximately 50% of patients. The only approved JAK2 inhibitor for myelofibrosis is the dual JAK1 and JAK2 inhibitor, ruxolitinib. 58-71% of patients treated with ruxolitinib in clinical trials so far have not achieved the primary endpoint of 35% or more reduction in spleen volume from baseline assessed by MRI or CT. Furthermore, more than 50% of patients discontinue ruxolitinib treatment after 3-5 years. On the basis of this unmet need, we investigated the efficacy and safety of fedratinib, a JAK2-selective inhibitor, in patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis. METHODS: This single-arm, open-label, non-randomised, phase 2, multicentre study, done at 31 sites in nine countries, enrolled adult patients with a current diagnosis of intermediate or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis, or post-essential thrombocythaemia myelofibrosis, found to be ruxolitinib resistant or intolerant after at least 14 days of treatment. Other main inclusion criteria were palpable splenomegaly (>/=5 cm below the left costal margin), Eastern Cooperative Oncology Group performance status of 2 or less, and life expectancy of 6 months or less. Patients received oral fedratinib at a starting dose of 400 mg once per day, for six consecutive 28-day cycles. The primary endpoint was spleen response (defined as the proportion of patients with a >/=35% reduction in spleen volume as determined by blinded CT and MRI at a central imaging laboratory). We did the primary analysis in the per-protocol population only (patients treated with fedratinib, for whom a baseline and at least one post-baseline spleen volume measurement was available) and the safety analysis in all patients receiving at least one dose of fedratinib. This trial was registered with ClinicalTrials.gov, number NCT01523171. FINDINGS: Between May 8, 2012, and Aug 29, 2013, 97 patients were enrolled and received at least one dose of fedratinib. Of 83 assessable patients, 46 (55%, 95% CI 44-66) achieved a spleen response. Common grade 3-4 adverse events included anaemia (37 [38%] of 97 patients) and thrombocytopenia (21 [22%] of 97), with 18 (19%) patients discontinuing due to adverse events. Seven (7%) patients died during the study, but none of the deaths was drug related. Suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination. INTERPRETATION: This phase 2 study met its primary endpoint, suggesting that patients with ruxolitinib-resistant or ruxolitinib-intolerant myelofibrosis might achieve significant clinical benefit with fedratinib, albeit at the cost of some potential toxicity, which requires further evaluation. Fedratinib development in this setting is currently being assessed. FUNDING: Sanofi.

Contains fulltext : 182504.pdf (Publisher’s version ) (Closed access) Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) is the only curative option for several hematological malignancies. Unfortunately, allo-SCT is often associated with GvHD, and patients often relapse. We therefore aim to improve the graft-versus-tumor effect, without increasing the risk of GvHD, by targeting hematopoietic lineage-restricted and tumor-associated minor histocompatibility antigens using peptide-loaded dendritic cell (DC) vaccinations. In the present multicenter study, we report the feasibility, safety and efficacy of this concept. We treated nine multiple myeloma patients with persistent or relapsed disease after allo-SCT and a previous DLI, with donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI. Vaccinations were well tolerated and no occurrence of GvHD was observed. In five out of nine patients, we were able to show the induction of mHag-specific CD8+ T cells in peripheral blood. Five out of nine patients, of which four developed mHag-specific T cells, showed stable disease (SD) for 3.5-10 months. This study shows that mHag-based donor monocyte-derived DC vaccination combined with DLI is safe, feasible and capable of inducing objective mHag-specific T-cell responses. Future research should focus on further improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses.

Purpose: Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units. Experimental Design: Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30 × 106/kg body weight) after lymphodepleting chemotherapy without cytokine boosting. Results: HSPC-NK cell products contained a median of 75% highly activated NK cells, with Conclusions: These findings indicate that HSPC-NK cell adoptive transfer is a promising, potential “off-the-shelf” translational immunotherapy approach in AML. Clin Cancer Res; 23(15); 4107–18. ©2017 AACR.

Contains fulltext : 136942.pdf (Publisher’s version ) (Closed access) The superiority of dendritic cells (DCs) as antigen-presenting cells has been exploited in numerous clinical trials, where generally monocyte-derived DCs (Mo-DCs) are injected to induce immunity in patients with cancer or infectious diseases. Despite promising expansion of antigen-specific T cells, the clinical responses following vaccination have been limited, indicating that further improvements of DC vaccine potency are necessary. Pre-clinical studies suggest that vaccination with combination of primary DC subsets, such as myeloid and plasmacytoid blood DCs (mDCs and pDCs, respectively), may result in stronger clinical responses. However, it is a challenge to obtain high enough numbers of primary DCs for immunotherapy, since their frequency in blood is very low. We therefore explored the possibility to generate them from hematopoietic progenitor cells (HPCs). Here, we show that by inhibiting the aryl hydrocarbon receptor with its antagonist StemRegenin 1 (SR1), clinical-scale numbers of functional BDCA2+BDCA4+ pDCs, BDCA1+ mDCs, and BDCA3+DNGR1+ mDCs can be efficiently generated from human CD34+ HPCs. The ex vivo-generated DCs were phenotypically and functionally comparable to peripheral blood DCs. They secreted high levels of pro-inflammatory cytokines such as interferon (IFN)-alpha, interleukin (IL)-12, and tumor necrosis factor (TNF)-alpha and upregulated co-stimulatory molecules and maturation markers following stimulation with Toll-like receptor (TLR) ligands. Further, they induced potent allogeneic T-cell responses and activated antigen-experienced T cells. These findings demonstrate that SR1 can be exploited to generate high numbers of functional pDCs and mDCs from CD34+ HPCs, providing an alternative option to Mo-DCs for immunotherapy of patients with cancer or infections.

Item does not contain fulltext Effective T-cell therapy against cancer is dependent on the formation of long-lived, stem cell-like T cells with the ability to self-renew and differentiate into potent effector cells. Here, we investigated the in vivo existence of stem cell-like antigen-specific T cells in allogeneic stem cell transplantation (allo-SCT) patients and their ex vivo generation for additive treatment posttransplant. Early after allo-SCT, CD8(+) stem cell memory T cells targeting minor histocompatibility antigens (MiHAs) expressed by recipient tumor cells were not detectable, emphasizing the need for improved additive MiHA-specific T-cell therapy. Importantly, MiHA-specific CD8(+) T cells with an early CCR7(+)CD62L(+)CD45RO(+)CD27(+)CD28(+)CD95(+) memory-like phenotype and gene signature could be expanded from naive precursors by inhibiting Akt signaling during ex vivo priming and expansion. This resulted in a MiHA-specific CD8(+) T-cell population containing a high proportion of stem cell-like T cells compared with terminal differentiated effector T cells in control cultures. Importantly, these Akt-inhibited MiHA-specific CD8(+) T cells showed a superior expansion capacity in vitro and in immunodeficient mice and induced a superior antitumor effect in intrafemural multiple myeloma-bearing mice. These findings provide a rationale for clinical exploitation of ex vivo-generated Akt-inhibited MiHA-specific CD8(+) T cells in additive immunotherapy to prevent or treat relapse in allo-SCT patients.

Introduction: Patients (pts) with myelofibrosis (MF) experience a broad array of symptoms that negatively affect HRQoL. Fedratinib (FEDR) is an oral, selective inhibitor of JAK2 that was investigated in the randomized, placebo (PBO)-controlled, phase III JAKARTA study in adult pts with intermediate- or high-risk primary or secondary MF and no prior ruxolitinib exposure. Here we report the effect of FEDR 400 mg (starting dose) vs. PBO on pt-reported MF-associated symptoms and HRQoL in the JAKARTA study. Methods: Pt-reported symptoms were assessed daily during the week before day 1 of each cycle and at the end of cycle 6 (EOC6) using the modified Myelofibrosis Symptom Assessment Form (MFSAF), which comprises 6 key MF symptoms (night sweats, early satiety, pruritus, pain under ribs on the left side, abdominal discomfort, bone/muscle pain), each scored from 0 (absent) to 10 (worst imaginable). Total symptom score (TSS), ranging from 0-60, was estimated by averaging daily TSS (sum of the individual symptom scores) during the week of each scheduled assessment. HRQoL was assessed at cycle 1 day 1 (C1D1) and EOC6 using the EuroQoL-5D 3-level (EQ-5D-3L), a generic, self-administered questionnaire with 5 dimensions (mobility, self-care, pain, usual activities, anxiety/depression). Health utility scores were derived using UK population preferences, with a range from -0.594 to 1.0. A higher EQ-5D-3L utility score represents a better health state. All pts randomized to FEDR 400 mg/day or PBO with an evaluable assessment at BL (defined as available daily TSS on the MFSAF for ≥5 of 7 days in the week before C1D1; and non-missing values on the EQ-5D-3L at C1D1) were included in analyses. Cross-sectional assessment of changes from BL at post-BL visits was performed. Differences in mean changes from BL at post-BL visits between Tx groups were compared using a pooled 2-sample, 2-sided t-test. Effect sizes (95% confidence intervals [CI]) for between-group differences in mean changes from BL were also estimated using Hedges' g. Effect sizes between 0.2 (small) and 0.5 (medium) are a commonly used ballpark threshold for clinically meaningful differences between Tx groups. Responder analyses were performed using logistic regression, controlling for BL scores. On the MFSAF, symptom response was defined as a ≥50% reduction in TSS from BL. Pts with a TSS of 0 at BL were excluded from responder analyses. For EQ-5D-3L, a ≥0.08-point change from BL in health utility was used to define clinically meaningful improvement at EOC6. Pts with missing values at post-BL visits were considered non-responders in the responder analyses. Results: The MFSAF evaluable population comprised 91/96 FEDR 400 mg pts (95%) and 85/96 PBO pts (89%). BL characteristics were comparable between Tx arms. At BL, mean TSS was 17.6 and 14.7 for FEDR and PBO, respectively. Clinically meaningful and statistically significant between-group differences in favor of FEDR were generally observed for all individual MFSAF symptoms and across all visits (above medium effect size: night sweats, abdominal discomfort, early satiety, pain under ribs on left side; above small effect size: bone/muscle pain, pruritis). Mean TSS change significantly favored FEDR vs. PBO across all assessments, with clinically meaningful medium effect sizes (Figure A). Symptom response rate at EOC6 was significantly greater with FEDR (40.4%) than with PBO (8.6%)(odds ratio [OR] 6.97 [95%CI 2.87, 16.9]; P EQ-5D-3L health utility scores at BL were similar between Tx arms (0.70 and 0.72 with FEDR and PBO, respectively). The difference in mean change from BL at EOC6 in EQ-5D-3L health utility was also clinically meaningful in favor of FEDR, with an effect size of 0.37 (95%CI 0.08, 0.66). The proportion of pts with clinically meaningful improvement in EQ-5D-3L health utility at EOC6 was significantly higher with FEDR, at 23.2% vs. 6.5% in the PBO arm (OR 5.12 [95%CI 1.81, 14.48]; P=0.002). Conclusions: FEDR 400 mg provided clinically meaningful and statistically significant improvement in TSS across the 6 MF-relevant symptoms, and broader HRQoL, as measured by health utility, vs. PBO in MF pts with no prior exposure to ruxolitinib. HRQoL benefits of FEDR were observed across clinically relevant pt subgroups, suggesting minimal heterogeneity of Tx effect. Disclosures Mesa: Shire: Honoraria; Promedior: Research Funding; Sierra Oncology: Consultancy; Celgene Corporation: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; PharmaEssentia: Research Funding; Gilead Sciences: Research Funding; Genentech: Consultancy; NS Pharma: Research Funding; Galena Biopharma: Consultancy; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; AbbVie: Research Funding; Baxalta: Consultancy; Genotech: Research Funding; LaJolla: Consultancy; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Pfizer: Research Funding; CTI: Research Funding; Samus: Research Funding. Schaap:Novartis: Consultancy; Celgene: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Kiladjian:AOP Orphan: Honoraria, Research Funding; Celgene: Consultancy; Novartis: Honoraria, Research Funding. Passamonti:Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:Constellation: Research Funding; Asana: Research Funding; Promedior: Research Funding; Gilead: Research Funding; Celgene: Consultancy, Other: Travel; NS Pharma: Research Funding; Stemline: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Janssen: Research Funding; CTI: Research Funding; BMS: Consultancy; Samus: Research Funding. Verstovsek:Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Rose:Celgene Corporation: Employment, Equity Ownership. Tang:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene: Employment, Equity Ownership. Brownstein:Celgene: Employment, Equity Ownership. Guo:Evidera: Employment. Ye:Evidera: Employment. Harrison:AOP: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.

Introduction: Cytopenias are a leading cause of ruxolitinib (RUX) discontinuation for patients (pts) with myelofibrosis (MF). Though RUX 5 mg BID is recommended for pts with platelet (PLT) counts of 50 to Methods: JAKARTA and JAKARTA2 enrolled adult pts with intermediate- or high-risk MF, PLT counts ≥50 × 109/L, and ECOG PS scores ≤2. These analyses include pts in both studies who received FEDR 400 mg QD (starting dose), and JAKARTA pts randomized to PBO. Outcomes are also assessed for a subgroup of JAKARTA2 pts who met new, more stringent criteria for RUX relapsed/refractory (R/R) or intolerant ("Stringent Criteria Cohort"). RUX R/R required ≥3 mo RUX Tx with an initial response followed by spleen regrowth or suboptimal response; RUX intolerance required ≥28 d of RUX Tx with development of RBC transfusion requirement or grade ≥3 cytopenias, hematoma, or hemorrhage. Endpoints of this analysis were spleen volume response rate (SVRR; the proportion of pts who achieved ≥35% spleen volume reductions) and symptom response rate (RR; ≥50% reduction in total symptom score [TSS] on the modified Myelofibrosis Symptom Assessment Form [MFSAF] from BL to end of cycle 6 [EOC6]). SVRR analyses were intention-to-treat (ITT); pts missing data at EOC6 were considered nonresponders. Results: In JAKARTA, the overall SVRR at EOC6 in the FEDR 400 mg and PBO arms was 47% and 1%, respectively (P In the BL PLT 99%. At EOC6, rates of grade 3-4 thrombocytopenia (preferred term) for all pts in the JAKARTA FEDR 400 mg and PBO arms were 5% and 6%, respectively; in the subgroup of pts with BL PLT counts In JAKARTA2, median prior RUX Tx duration for all pts (N=97) was 10.7 mo. SVRR overall was 31% (Figure) and symptom RR was 27%. Median duration of spleen volume response was not reached at study termination. Among pts with BL PLT counts Median duration of FEDR Tx in pts with BL PLT counts Conclusion: Pts with MF who entered JAKARTA or JAKARTA2 with PLT counts Disclosures Harrison: Celgene: Honoraria, Speakers Bureau; AOP: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; CTI: Speakers Bureau; Promedior: Honoraria; Janssen: Speakers Bureau; Sierra Oncology: Honoraria; Shire: Speakers Bureau; Roche: Honoraria; Incyte: Speakers Bureau; Gilead: Speakers Bureau. Schaap:Celgene: Consultancy; Novartis: Consultancy. Vannucchi:Celgene: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kiladjian:AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Consultancy. Passamonti:Roche: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zweegman:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:BMS: Consultancy; Stemline: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Other: Travel; Incyte: Research Funding; Constellation: Research Funding; Asana: Research Funding; Gilead: Research Funding; CTI: Research Funding; NS Pharma: Research Funding; Samus: Research Funding; Novartis: Research Funding; Janssen: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Rose:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene: Employment, Equity Ownership. Berry:Celgene: Employment, Equity Ownership. Brownstein:Celgene: Employment, Equity Ownership. Mesa:AbbVie: Research Funding; NS Pharma: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; CTI: Research Funding; Galena Biopharma: Consultancy; Shire: Honoraria; Genentech: Consultancy; LaJolla: Consultancy; PharmaEssentia: Research Funding; Genotech: Research Funding; Celgene Corporation: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; Baxalta: Consultancy; Promedior: Research Funding; Pfizer: Research Funding; Sierra Oncology: Consultancy; Gilead Sciences: Research Funding; Samus: Research Funding.

Background: Treatment (Tx) options for patients (pts) with MF are limited following RUX failure. Fedratinib (FEDR) is an oral, selective inhibitor of JAK2. The phase II JAKARTA2 study of FEDR in pts with MF previously treated with RUX was initiated shortly after RUX was approved, and at the time there were no well-established criteria for RUX failure. Pt eligibility for JAKARTA2 was determined per investigator assessment. JAKARTA2 findings were originally reported using a last-observation-carried-forward (LOCF) analysis method in the "Per Protocol" population (pts with a baseline [BL] and ≥1 post-BL spleen assessment) (Harrison, Lancet Haematol,2017). Since JAKARTA2 was conducted, clinical experience with RUX has better informed criteria for RUX failure. Objective: To evaluate FEDR safety and efficacy using intention-to-treat (ITT) analyses for all pts enrolled in JAKARTA2 (ITT Population), and for a subgroup of pts who met more stringent definitions for RUX relapsed, refractory, or intolerant ("Stringent Criteria Cohort") than used in the original analysis. Methods: Adult pts with intermediate- or high-risk primary, post-polycythemia vera, or post-essential thrombocythemia MF, platelet counts ≥50 × 109/L, and ECOG PS scores 0-2 were enrolled. Pts were assessed by investigators to be RUX-resistant after receiving ≥14 days of prior RUX therapy, or RUX-intolerant due to toxicity following any duration of RUX exposure. The Stringent Criteria Cohort comprised pts who met the following criteria for RUX relapsed, refractory or intolerant: relapsed/refractory required ≥3 mo of prior RUX Tx with an initial response followed by spleen regrowth or suboptimal response; RUX intolerance required ≥28 days of RUX Tx with development of RBC transfusion requirement or grade ≥3 cytopenias, hematoma, or hemorrhage. Initial FEDR dose was 400 mg/day in 28-day cycles. The primary endpoint was spleen volume response rate (SVRR); ie, the proportion of pts who achieved a ≥35% spleen volume reduction from BL to end of cycle 6 (EOC6). LOCF analysis was not used; pts missing an EOC6 spleen volume measure were deemed nonresponders. Results: In the ITT Population (N=97), median age was 67 yrs (range 38-83) and 55% of pts had primary MF. Outcomes of prior RUX therapy are shown in the Table. In the ITT Population, 64 pts (66%) were resistant and 32 (33%) were intolerant to RUX per investigators. Median BL spleen volume was 2894 mL (~14× normal). Median prior RUX exposure was 11.7 mo in RUX-resistant pts and 7.0 mo in RUX-intolerant pts. Median duration of FEDR Tx on-study was 24.4 weeks. SVRR at EOC6 in the ITT Population was 31% (95%CI 22, 41), with similar rates between RUX-resistant pts (33% [22, 46]) and RUX-intolerant pts (28% [14, 47]). All but 1 pt with EOC6 data (n=51) had some degree of spleen volume reduction (Figure). The Stringent Criteria Cohort included 79/97 pts (81%) who met stringent definitions of RUX relapsed (n=18, 23%), refractory (n=47, 60%), or intolerant (n=14, 18%) (Table), with median prior RUX exposures of 11.8, 11.4, and 8.7 mo, respectively. Median duration of FEDR Tx was 24.3 weeks. SVRR in the Stringent Criteria Cohort overall was 30% (95%CI 21, 42). SVRR in RUX relapsed, refractory, and intolerant pts was 28% (95%CI 10, 54), 32% (19, 47), and 29% (8, 58), respectively. All pts with available assessments (n=41) had spleen volume reductions from BL at EOC6 (Figure). In the Stringent Criteria Cohort, adverse events (AEs) were reported with generally similar frequency among RUX relapsed, refractory, and intolerant pts, with rates of grade 3-4 anemia of 44%, 49%, and 29%, respectively; and grade 3-4 thrombocytopenia of 28%, 19%, and 14%. Proportions of RUX relapsed, refractory, or intolerant pts who discontinued FEDR Tx due to an AE were 22%, 17%, and 29%, respectively. Conclusion: Tx with FEDR in JAKARTA2 pts, who had substantial prior exposure to RUX, was associated with a robust spleen response rate, similar to or higher than rates seen with other JAK inhibitors when used as front-line Tx for MF (Harrison, NEJM, 2012; Mesa, Lancet Haematol, 2017; Mesa, JCO, 2017). About one-third of pts in JAKARTA2 achieved a spleen volume response and most pts had some degree of spleen volume reduction during FEDR Tx, regardless of whether they were relapsed, refractory, or intolerant to RUX. Long-term FEDR Tx in pts previously exposed to RUX is currently under study in 2 ongoing phase III studies (NCT03755518, NCT03952039). Disclosures Harrison: Shire: Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Promedior: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte: Speakers Bureau; AOP: Honoraria; Roche: Honoraria; Janssen: Speakers Bureau; Sierra Oncology: Honoraria; Gilead: Speakers Bureau; CTI: Speakers Bureau. Schaap:Novartis: Consultancy; Celgene: Consultancy. Vannucchi:ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Jourdan:Celgene: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schouten:Novartis: Honoraria; Sanofi: Honoraria; Gilead: Honoraria; Alexion: Honoraria, Other: Travel expenses. Passamonti:Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Celgene Corporation: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:Novartis: Research Funding; Samus: Research Funding; Janssen: Research Funding; CTI: Research Funding; Stemline: Research Funding; Gilead: Research Funding; Constellation: Research Funding; NS Pharma: Research Funding; Incyte: Research Funding; BMS: Consultancy; Celgene: Consultancy, Other: Travel; Asana: Research Funding; Promedior: Research Funding. Verstovsek:Incyte: Research Funding; NS Pharma: Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Rose:Celgene Corporation: Employment, Equity Ownership. Shen:Celgene: Employment, Equity Ownership. Berry:Celgene: Employment, Equity Ownership. Brownstein:Celgene: Employment, Equity Ownership. Mesa:Gilead Sciences: Research Funding; Pfizer: Research Funding; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; CTI: Research Funding; AbbVie: Research Funding; Genotech: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; Galena Biopharma: Consultancy; NS Pharma: Research Funding; LaJolla: Consultancy; Samus: Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Shire: Honoraria; Baxalta: Consultancy; Sierra Oncology: Consultancy; Celgene Corporation: Research Funding; Promedior: Research Funding; Genentech: Consultancy; PharmaEssentia: Research Funding.

Introduction: Myelofibrosis (MF) is characterized by bone marrow fibrosis, splenomegaly, cytopenias, and poor survival. Ruxolitinib (RUX) is currently the only approved treatment (Tx) for intermediate- or high-risk MF. Clinical outcomes after RUX exposure are poor and no other Tx is available. Fedratinib (FEDR) is an oral, selective inhibitor of JAK2 investigated in the single-arm, phase II JAKARTA2 study in patients (pts) with intermediate- or high-risk MF previously exposed to RUX. The effect of FEDR on pt-reported MF-associated symptoms and HRQoL in JAKARTA2 was assessed. Methods: All pts received FEDR at a starting dose of 400 mg/day in 28-day Tx cycles. Pt-reported symptoms were assessed daily during the week before day 1 of each Tx cycle and at the end of cycle 6 (EOC6) using the modified Myelofibrosis Symptom Assessment Form (MFSAF). The MFSAF comprises 6 key MF symptoms (night sweats, pruritus, early satiety, pain under ribs on the left side, abdominal discomfort, bone or muscle pain), each scored from 0 (absent) to 10 (worst imaginable). Total symptom score (TSS), ranging from 0-60, was estimated by averaging daily TSS (sum of all individual symptom scores) during the week of each scheduled assessment. The EORTC Quality of Life Core 30 Questionnaire (QLQ-C30) measures QoL in pts with cancer. The QLQ-C30 has 15 HRQoL domains, including global health status/QoL and multiple functional and symptom domains. Domains are scored from 0-100; higher scores indicate better QoL or functioning, but worse symptomology. The QLQ-C30 was administered on day 1 of each cycle and at EOC6. The Patient's Global Impression of Change (PGIC) evaluates pt perceptions of MF symptom severity over time, providing an overall sense of whether Tx is beneficial. Answers range from 1 (very much improved) to 7 (very much worse). The PGIC was administered on day 1 of cycles 4 and 6 and at EOC6. The MFSAF and QLQ-C30 populations comprised all treated pts with an evaluable pt-reported outcome assessment measure at BL (defined as TSS data for ≥5 of 7 days on the MFSAF in the week before C1D1; and ≥15 of 30 items on the QLQ-C30 answered at BL). The PGIC population included all treated pts. Change from BL at each post-BL visit and corresponding effect size (95% confidence intervals [CI]) were estimated using Hedges' g. An effect size of 0.5 (medium; ie, half of the standard deviation) is a commonly used threshold for the clinical meaningfulness of a change from BL at a given visit when a threshold is not well established. Symptom response rate (≥50% reduction in TSS from BL) was estimated at each post-BL visit among pts with TSS >0 at BL and compared among clinically relevant pt subgroups. Pts with missing post-BL values were deemed nonresponders. Proportions of pts with clinically meaningful improvements in domains of the QLQ-C30 (≥10-point change from BL) were also evaluated across visits and compared between subgroups. Results: The MFSAF evaluable population included 90/97 (93%) JAKARTA2 pts. Mean TSS at BL was 21. Clinically meaningful improvements from BL were observed across visits in TSS (Fig. A) and in most individual symptoms scores: effect sizes at EOC6 were -0.68 for TSS, -0.69 for early satiety, -0.68 for night sweats, -0.59 for pain under ribs on left side, -0.47 for abdominal discomfort, -0.43 for pruritis, and -0.28 for bone or muscle pain. Overall, 26.7% of pts had a symptom response. TSS improvements were observed across pt subgroups (Fig. B). Pts had worse mean scores at BL across most QLQ-C30 domains than age- and gender-matched general populations. Most QLQ-C30 domains showed clinically meaningful (≥10-point change) improvement from BL across all or most post-BL visits in global health status/QoL, physical functioning, role functioning, fatigue, pain, dyspnea, insomnia, and appetite loss. About 44% (95%CI 30, 59), 53% (38, 68), and 39% (25, 54) of pts had clinically meaningful improvements at EOC6 in the global health status/QoL, physical functioning, and role functioning domains, respectively. Minimal heterogeneity of Tx effect was seen in subgroup analyses of global QoL. Most ongoing pts (>80%) reported overall symptom improvement on the PGIC. Conclusion: Tx with FEDR in pts previously exposed to RUX resulted in clinically meaningful improvement from BL in global QoL and functional status, in addition to MF-associated symptoms. Global QoL and MF-associated symptom improvement was shown across clinically relevant pt subgroups. Disclosures Harrison: Promedior: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau; AOP: Honoraria; Celgene: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; Shire: Speakers Bureau; Janssen: Speakers Bureau; CTI: Speakers Bureau; Gilead: Speakers Bureau; Incyte: Speakers Bureau. Schaap:Celgene: Consultancy; Novartis: Consultancy. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ITALFARMACO: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Kiladjian:Celgene: Consultancy; Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding. Jourdan:Novartis: Honoraria; Astellas: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Silver:PharmEssentia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Schouten:Gilead: Honoraria; Alexion: Honoraria, Other: Travel expenses; Sanofi: Honoraria; Novartis: Honoraria. Passamonti:Celgene Corporation: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz:NS Pharma: Research Funding; Celgene: Consultancy, Other: Travel; Stemline: Research Funding; Promedior: Research Funding; Samus: Research Funding; BMS: Consultancy; Gilead: Research Funding; Asana: Research Funding; Incyte: Research Funding; CTI: Research Funding; Janssen: Research Funding; Constellation: Research Funding; Novartis: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Rose:Celgene Corporation: Employment, Equity Ownership. Tang:Celgene Corporation: Employment, Equity Ownership. Hu:Celgene: Employment, Equity Ownership. Guo:Evidera: Employment. Liao:Evidera: Employment. Brownstein:Celgene: Employment, Equity Ownership. Mesa:PharmaEssentia: Research Funding; CTI: Research Funding; Pfizer: Research Funding; LaJolla: Consultancy; Samus: Research Funding; Genotech: Research Funding; Galena Biopharma: Consultancy; Promedior: Research Funding; Shire: Honoraria; Genentech: Consultancy; NS Pharma: Research Funding; Incyte: Other: travel, accommodations, expenses, Research Funding; AOP Orphan Pharmaceuticals: Honoraria, Other: travel, accommodations, expenses; Baxalta: Consultancy; Gilead Sciences: Research Funding; Sierra Oncology: Consultancy; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses; AbbVie: Research Funding; Celgene Corporation: Research Funding.

Item does not contain fulltext The introduction of autologous stem cell transplantation (SCT) and novel drugs has improved overall survival in multiple myeloma (MM) patients. However, minimal residual disease (MRD) remains and most patients eventually relapse. Myeloma plasma cells express tumor-associated antigens (TAA), which are interesting targets for immunotherapy. In this phase 1 study, we investigated the safety and immunological effects of TAA-mRNA-loaded dendritic cell (DC) vaccination for treatment for MRD in MM after SCT. Mature monocyte-derived DCs were pulsed with keyhole limpet hemocyanin (KLH) and electroporated with MAGE3, Survivin or B-cell maturation antigen (BCMA) mRNA. Twelve patients were vaccinated three times with intravenous (5-22 x 10(6) DCs) and intradermal vaccines (4-11 x 10(6) DCs), at biweekly intervals. Immunological responses were monitored in blood and delayed-type hypersensitivity (DTH) biopsies. All patients developed strong anti-KLH T-cell responses, but not KLH antibodies. In 2 patients, vaccine-specific T cells were detected in DTH biopsies. In one patient, we found MAGE3-specific CD4(+) and CD8(+) T cells, and CD3(+) T cells reactive against BCMA and Survivin. In the other patient, we detected low numbers of MAGE3 and BCMA-reactive CD8(+) T cells. Vaccination was well tolerated with limited toxicity. These findings illustrate that TAA-mRNA-electroporated mature DCs are capable of inducing TAA-T-cell responses in MM patients after SCT. 01 augustus 2013

BACKGROUNDLeukemia recurrence is a major cause of treatment failure after autologous stem cell transplantation for acute myeloid leukemia (AML). It usually occurs within the first 2 years after transplantation. The goal of the current retrospective study was to assess the follow-up of and characterize risk factors for outcome among patients who survived free of disease recurrence after this period. METHODSThe analysis included 3567 adults (median age, 45 years) with AML who underwent autografting during the first (86% of patients) or second (14% of patients) complete remission between 1990 and 2008. The stem cell source was the bone marrow in 32% of patients or the peripheral blood in 68% of patients. The median follow-up was 6.9 years. RESULTSAt 5 years and 10 years after transplantation, the probability of leukemia-free survival was 86% and 76%, respectively; the recurrence incidence was 11% and 16%, respectively; and the nonrecurrence mortality rate was 3% and 8%, respectively. The observed survival was decreased compared with the expected survival of the general European population. In a multivariate analysis, decreased probability of leukemia-free survival was demonstrated for patients who underwent peripheral blood autologous stem cell transplantation; had French-American-British subtypes M0, M6, or M7; and were of an older age. The same factors were found to be associated with an increased risk of disease recurrence. Nonrecurrence mortality was found to be affected by older age. CONCLUSIONSThe results of the current analysis indicate that late recurrences remain a major concern after autologous stem cell transplantation among patients with AML, indicating the need for close monitoring of minimal residual disease and additional leukemic control measures after transplantation. Cancer 2016;122:1880-7. (c) 2016 American Cancer Society. Late disease recurrence remains a major concern for long-term survivors of autologous stem cell transplantation for acute myeloid leukemia. This indicates the need for close monitoring of minimal residual disease and additional leukemic control measures after transplantation.

Item does not contain fulltext Steroid-refractory acute graft-versus-host disease (aGVHD) remains an important cause of morbidity and mortality after allogeneic stem cell transplantation (SCT). A protocol on the management of aGVHD was introduced in our center that incorporated a prospective study on combination therapy with inolimomab (anti-IL-2Ralpha) and etanercept (anti-tumor necrosis factor-alpha) for steroid-refractory aGVHD. We evaluated the efficacy and safety in 21 consecutively treated patients. The patients had developed refractory aGVHD after SCT (n = 16) or donor lymphocyte infusion (n = 5), and aGVHD was classified as severe in all patients, mostly due to gastrointestinal involvement stages 2 to 4. No drug-related side effects were observed apart from the infections expected to occur in these severely immunocompromised patients. Overall response at day 28 of second-line therapy was 48% (10/21), with 6 and 4 patients achieving a complete and partial response, respectively. Eventually, 19 patients died (90%), with early mortality (

Item does not contain fulltext We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.

Item does not contain fulltext Dendritic cell (DC)-based vaccination boosting antigen-specific immunity is being explored for the treatment of cancer and chronic viral infections. Although DC-based immunotherapy can induce immunological responses, its clinical benefit has been limited, indicating that further improvement of DC vaccine potency is essential. In this study, we explored the generation of a clinical-grade applicable DC vaccine with improved immunogenic potential by combining PD-1 ligand siRNA and target antigen mRNA delivery. We demonstrated that PD-L1 and PD-L2 siRNA delivery using DLin-KC2-DMA-containing lipid nanoparticles (LNP) mediated efficient and specific knockdown of PD-L expression on human monocyte-derived DC. The established siRNA-LNP transfection method did not affect DC phenotype or migratory capacity and resulted in acceptable DC viability. Furthermore, we showed that siRNA-LNP transfection can be successfully combined with both target antigen peptide loading and mRNA electroporation. Finally, we demonstrated that these PD-L-silenced DC loaded with antigen mRNA superiorly boost ex vivo antigen-specific CD8(+) T cell responses from transplanted cancer patients. Together, these findings indicate that our PD-L siRNA-LNP-modified DC are attractive cells for clinical-grade production and in vivo application to induce and boost immune responses not only in transplanted cancer patients, but likely also in other settings. 01 februari 2013

Item does not contain fulltext Graft-versus-host disease (GVHD) and fungal infections are frequent complications after allogeneic hematopoietic stem cell transplantation (HSCT). Single nucleotide polymorphisms (SNPs) in genes of the immune system can influence the inflammatory cascade and T cell-driven alloimmune reactions after HSCT, and thus increasing the incidence of GVHD and infectious complications. Here, we investigated the effect of SNPs in IL-23R and CCR6 on posttransplantation outcome in 161 recipients of partially T cell-depleted HSCT. Remarkably, IL-23R SNPs were not associated with clinical outcome, but we found that disparities in the CCR6 tagSNP rs2301436 and SNP rs3093023 are independently associated with the occurrence of chronic GVHD (cGVHD) and invasive fungal disease. In multivariate analysis, patients receiving a transplant from a homozygous rs2301436 G allele donor showed less cGVHD (odds ratio [OR]: 0.16; P = .002), as was the case for a homozygous donor rs3093023 G allele (OR: 0.24; P = .005). In parallel, the GG genotype at rs2301436 in donors was associated with a higher incidence of invasive fungal disease at day 100 after HSCT (OR: 3.59; P = .008). This study shows that CCR6 SNPs can be used to predict clinical outcome, and that polymorphisms in the CCR6 gene may influence T cell-mediated immune reactions after HSCT.

Contains fulltext : 97194.pdf (Publisher’s version ) (Closed access) Tumor relapses remain a serious problem after allogeneic stem cell transplantation (alloSCT), despite the long-term persistence of minor histocompatibility antigen (MiHA)-specific memory CD8(+) T cells specific for the tumor. We hypothesized that these memory T cells may lose their function over time in transplanted patients. Here, we offer functional and mechanistic support for this hypothesis, based on immune inhibition by programmed death-1 (PD-1) expressed on MiHA-specific CD8(+) T cells and the associated role of the PD-1 ligand PD-L1 on myeloid leukemia cells, especially under inflammatory conditions. PD-L1 was highly upregulated on immature human leukemic progenitor cells, whereas costimulatory molecules such as CD80 and CD86 were not expressed. Thus, immature leukemic progenitor cells seemed to evade the immune system by inhibiting T-cell function via the PD-1/PD-L1 pathway. Blocking PD-1 signaling using human antibodies led to elevated proliferation and IFN-gamma production of MiHA-specific T cells cocultured with PD-L1-expressing leukemia cells. Moreover, patients with relapsed leukemia after initial MiHA-specific T-cell responses displayed high PD-L1 expression on CD34(+) leukemia cells and increased PD-1 levels on MiHA-specific CD8(+) T cells. Importantly, blocking PD-1/PD-L1 interactions augment proliferation of MiHA-specific CD8(+) memory T cells from relapsed patients. Taken together, our findings indicate that the PD-1/PD-L pathway can be hijacked as an immune escape mechanism in hematological malignancies. Furthermore, they suggest that blocking the PD-1 immune checkpoint offers an appealing immunotherapeutic strategy following alloSCT in patients with recurrent or relapsed disease.