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Supplemental table 1: Sequence of hydrolysis probes and primers used for the ddPCR.

Purpose:Tyrosine kinase inhibitor (TKI) discontinuation is an emerging goal in chronic myelogenous leukemia (CML) management and several studies have demonstrated the feasibility of safely stopping imatinib. A sustained deep molecular response on long-term TKI is critical prior to attempting treatment-free remission. Reproducible results from several studies reported recently, failed to identify robust and reproducible predictive factors for the selection of the best candidates for successful TKI cessation.Patients and Methods:We conducted a prospective national phase II study evaluating the cessation of imatinib after at least 2 years of MR4.5 obtained on imatinib first-line in patients with chronic phase CML.Results:A total of 218 patients with de novo chronic phase CML were involved in the study. The median follow-up after imatinib cessation was 23.5 (1–64) months, 2 patients died from unrelated causes, and 107 experienced a confirmed increase in BCR-ABL1 levels defined as molecular recurrence. The molecular recurrence-free survival was 52% [95% confidence interval (CI), 45%–59%] at 6 months, and 50% (95% CI, 43%–57%) at 24 months. Droplet digital PCR (ddPCR) was used to evaluate more accurately low levels of BCR-ABL1 in 175 of 218 patients at imatinib cessation. To apply positive BCR-ABL1/ABL1 ratios on the international scale (IS), a conversion factor was calculated for ddPCR and the significant cut-off point was established at 0.0023%IS. In a multivariate analysis, the duration of TKI (≥74.8 months) and ddPCR (≥0.0023%IS) were the two identified predictive factors of molecular recurrence, with P = 0.0366 (HR, 0.635; 95% CI, 0.415–0.972] and P = 0.008 (HR, 0.556; 95% CI, 0.360–0.858), respectively.Conclusions:We conclude that the duration of TKI and residual leukemic cell load as determined by ddPCR are key factors for predicting successful treatment-free remission for patients with de novo chronic phase CML.See related commentary by Yan et al., p. 6561

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of BCR-ABL1 transcript as a result of reciprocal translocation between chromosome 9 and 22. The most common transcripts subtypes are e13a2 (b2a2) and e14a2 (b3a2). The prognostic impact of the type of BCR-ABL1 transcript has been the subject of controversies over time. In the imatinib era, several studies have suggested a deeper and faster response in patients expressing e14a2. However, the impact on response after first line therapy with a second-generation tyrosine kinase inhibitor, nilotinib, is unknown. We retrospectively evaluated 118 patients newly diagnosed with chronic phase CML and treated frontline with nilotinib inside or outside clinical trial in five French centers. Only patients expressing e14a2 or e13a2 transcripts alone were analyzed. At baseline, 55.3% expressed e14a2, 44.7% expressed e13a2. The median age was 51 years and median follow-up was 49 months. Relative risks of CML at diagnosis were similar according to the ELTS score (p = .87). Complete hematological response and complete cytogenetic response rates were similar among groups. Patients expressing e14a2 transcripts compared to e13a2 transcripts had deeper and faster molecular responses, when considering MMR (100% vs 84.1%, p = .007) with a median time of 6.7 and 17.1 months or MR4.5 (100% vs 59.9%, p = .005) with a median time of 39.7 and 70.9 months, respectively. A sustained treatment free remission was observed in 10/10 patients with e14a2 versus 1/3 with e13a2 transcript (p = .04). In conclusion, even treated with nilotinib first line, patients with chronic phase CML expressing BCR-ABL1 e13a2 transcript have a lower rate of deep molecular responses.

In a significant number of cases cancer therapy is followed by a resurgence of more aggressive tumors derived from immature cells. One example is acute myeloid leukemia (AML), where an accumulation of immature cells is responsible for relapse following treatment. We previously demonstrated in chronic myeloid leukemia that the bone morphogenetic proteins (BMP) pathway is involved in stem cell fate and contributes to transformation, expansion, and persistence of leukemic stem cells. Here, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in AML patients at diagnosis. BMP2 and BMP4 protein concentrations are elevated within patients’ bone marrow with a BMP4-dominant availability. This overproduction likely depends on the bone marrow microenvironment, since MNCs do not overexpress BMP4 transcripts. Intrinsically, the receptor BMPR1A transcript is increased in leukemic samples with more cells presenting this receptor at the membrane. This high expression of BMPR1A is further increased upon BMP4 exposure, specifically in AML cells. Downstream analysis demonstrated that BMP4 controls the expression of the survival factor ΔNp73 through its binding to BMPR1A. At the functional level, this results in the direct induction of NANOG expression and an increase of stem-like features in leukemic cells, as shown by ALDH and functional assays. In addition, we identified for the first time a strong correlation between ΔNp73, BMPR1A and NANOG expression with patient outcome. These results highlight a new signaling cascade initiated by tumor environment alterations leading to stem-cell features and poor patients’ outcome.

The response definitions proposed by the European Leukemia Net (ELN) have been recently modified. We evaluated the new criteria for de novo imatinib (400 mg/d) chronic phase chronic myeloid leukemia (CP-CML) patients. Response status according to the 2009 and 2013 criteria were determined in 180 unselected patients. Outcome of the subgroups of patients were then compared. The 180 patients were classified as optimal responders (OR2009; n = 113, 62.7%), suboptimal responders (SOR2009; n = 47, 26.1%) and failures (FAIL2009; n = 20, 11.1%) according to the 2009 ELN criteria and optimal responders (OR2013; n = 77, 42.7%), warnings (WAR2013; n = 59, 32.7%), and failures (FAIL2013; n = 44, 24.4%) according to the 2013 ELN criteria. No difference in terms of outcome was observed between OR2009 patients who became WAR2013 when compared with OR2013 patients. When compared with FAIL2009 patients, SOR2009 patients who became WAR2013 had better EFS, FFS, PFS, and OS. No difference was observed in PFS or OS in SOR2009 patients who became FAIL2013. The 2013 ELN response status criteria have improved patients classification in terms of response status. However, in our patient population this improvement is related to a better definition of failure rather than that of optimal response for CP-CML patients treated with IM frontline therapy. Am. J. Hematol. 90:37–41, 2015. © 2014 Wiley Periodicals, Inc.

Sustained imatinib treatment in chronic myeloid leukemia patients can result in complete molecular response allowing discontinuation without relapse. We set out to evaluate the frequency of complete molecular response in imatinib de novo chronic phase chronic myeloid leukemia patients, to identify base-line and under-treatment predictive factors of complete molecular response in patients achieving complete cytogenetic response, and to assess if complete molecular response is associated with a better outcome. A random selection of patients on front-line imatinib therapy (n=266) were considered for inclusion. Complete molecular response was confirmed and defined as MR 4.5 with undetectable BCR-ABL transcript levels. Median follow up was 4.43 years (range 0.79–10.8 years). Sixty-five patients (24%) achieved complete molecular response within a median time of 32.7 months. Absence of spleen enlargement at diagnosis, achieving complete cytogenetic response before 12 months of therapy, and major molecular response during the year following complete cytogenetic response was predictive of achieving further complete molecular response. Patients who achieved complete molecular response had better event-free and failure-free survivals than those with complete cytogenetic response irrespective of major molecular response status (95.2% vs. 64.7% vs. 27.7%, P=0.00124; 98.4% vs. 82.3% vs. 56%, P=0.0335), respectively. Overall survival was identical in the 3 groups. In addition to complete cytogenetic response and major molecular response, further deeper molecular response is associated with better event-free and failure-free survivals, and complete molecular response confers the best outcome.

We prospectively evaluated in high-risk myeloma patients the efficacy and toxicity of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) followed by reduced-intensity conditioning (RIC) and allogeneic (allo)-HSCT with bortezomib and donor lymphocyte infusions introduction after allo-HSCT (group 1). Results were compared with results from tandem auto-RIC-allo-HSCT without bortezomib (group 2). Groups 1 and 2 were compared to matched patients not receiving allo-HSCT from the Intergroupe Francophone du Myelome prospective studies. Allo-HSCT groups included 25 patients (12 in group 1, 13 in group 2). All patients engrafted. There were 8 acute GVHD (7 grade II [3 in group 1], 1 grade III in group 1)] and 11 chronic GVHD (3 limited [in group 1], 8 extensive [1 in group 1]). Matched population included 36 controls for group 1 and 39 for group 2. After a median follow-up of 55 months (range, 3–142 months), median overall survival was not reached in group 1 versus 65 months (51-not reached [NR]) in its matched group ( p = 0.027); it was 96 months (49-NR) in group 2 versus 91 months (32-NR) in its matched group ( p = 0.77). Median progression-free survival was 49 months (29-NR) in group 1 and was 25 months (range, 21–35 months) in its matched group ( p = 0.0045); it was 31 months (22-NR) in group 2 and 28 months (range, 21–40 months) in its matched group ( p = 0.0776). Tandem auto-RIC–allo-HSCT including new molecules and immunomodulation after transplantation could be used as a first-line treatment for high-risk myeloma patients.

After allogeneic hematopoietic stem cell transplantation (HSCT), BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication. Although supportive measures have been the standard of care for many years, several studies suggested the efficacy of cidofovir. The aim of this study was to assess the safety profile and efficacy of cidofovir. A retrospective study was conducted on all patients treated with cidofovir in our HSCT unit between March 2011 and May 2013. Data for efficacy (partial [PR] or complete response [CR]), prescription (dose, frequency, number of doses, and administration route), and toxicity were collected from published reports and medical files. Renal toxicity was evaluated using creatinine clearance calculated with the Cockcroft and Gault formula. A parallel literature search using PubMed (last search, May 2015) was performed. From March 2011 to June 2013, 27 of 181 patients undergoing allogeneic HSCT in our department received cidofovir for BKV-HC: 24 (88.9%) intravenously, 1 intravesically, and 2 via both routes. Mean dose was 5 mg/kg per administration, for a median of 4 injections (range, 1 to 11), from twice a week to once every 2 weeks. CR was achieved in 22 patients (81.5%), PR in 2, and no response in 2 patients. Eight patients presented renal failure (29.6%): 6 moderate (creatinine clearance 60 mL/min) and 2 severe (creatinine clearance 30 mLmin). Mean decrease in creatinine clearance after cidofovir was 27% (35 mL/min; range, 2 to 159). In 3 cases renal insufficiency and hematologic toxicity led to discontinuation of treatment or switch to intravesical instillation. For 3 patients cidofovir dose was reduced because of nephrotoxicity. Thirteen studies have reported on the use of cidofovir for BKV-HC (204 patients) since 2005. Intravenous cidofovir was used for 91.3% of patients, with doses ranging from .5 to 5 mg/kg. The main toxicity reported was renal failure (9% to 50% in 9 studies). Between 60% and 100% of CRs were observed independently of cidofovir dose or administration route. Cidofovir is an effective therapy for BKV-HC but requires very precise renal function management to avoid toxicity. Cidofovir treatment modalities (high dose, intravesical instillation, or low dose [≤1 mg/kg]) needs to be investigated in randomized controlled trials.

BACKGROUND: Despite frequent anemia and multiple transfusions in patients undergoing chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia , recommendations for use of erythropoiesis-stimulating agents (ESAs) in these populations are still missing. The primary objective was the effect of ESA administration on patient's quality of life (QoL). Secondary objectives were hemoglobin (Hb) recovery, red blood cell (RBC) transfusions, overall survival, and event-free survival. METHODS: Adult patients with Hb ≤ 11 g/dL after consolidation chemotherapy for acute myeloid leukemia (group 1), or after allo-HSCT for any hematological diseases (group 2), were prospectively included. ESA was administered subcutaneously once per week during a maximum period of 6 months and was stopped when Hb level reached 12 g/dL. A paired-matched analysis using a historical control group was performed for secondary endpoints. Fifty-two patients were included in group 1, and 55 patients were in group 2. RESULTS: For the global population, a significant improvement of QoL was noticed with ESA use; 83% (group 1) and 71% (group 2) of patients achieved an Hb level ≥ 12 g/dL without transfusion requirement. The pair-matched analysis showed a reduction of 4 RBC units per patient in group 1 (P = .0002) and 3 RBC units per patient in group 2 (P = .04). No significant difference in terms of thromboembolic events, overall survival, and event-free survival was observed between ESA and control groups. A RBC transfusion median savings of €1712 per patient was estimated in each group. CONCLUSIONS: ESAs have a clinical and economic benefit on Hb recovery, could improve a patient's QoL, and lead to a significant reduction in number of RBC transfusions with no effect on survival. Cancer 2013. © 2012 American Cancer Society.

Background: In the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT), donor and/or recipient cytomegalovirus (CMV) seropositivity is still associated with a lower overall survival (OS) despite current strategies to decrease CMV disease incidence. However, recent studies have suggested that early CMV reactivation decreases the risk of disease relapse after allo-HSCT. Other reactivations like Epstein-Barr virus (EBV) and BK virus (BKV) with an adverse impact on OS have not been evaluated in the same context. The aim of our study was to evaluate the impact of early CMV, EBV and BK-V reactivation after allo-HSCT on the relapse incidence. Patients and methods: We evaluated 292 allo-HSCT in adults recipients with acute myeloid leukemia (n=114), acute lymphoid leukemia (n=60), multiple myeloma (n=41), non-Hodgkin lymphoma (n=27), myelodysplastic syndrome (n=18), Hodgkin's disease (n=14), myeloproliferative neoplasms (n=13), and chronic lymphoid leukemia (n=7) treated at the University Hospital Centre of Lyon between years 2008 and 2013. At transplantation, 77% of patients were in complete response (CR) or chronic phase and 23% in less than CR. One hundred and thirty-two (45%) patients received bone marrow, 119 peripheral blood stem cells, 41 cord blood, conditioning regimen was myeloablative (MAC) in 163 (56%) cases. Antithymocyte globulin was used in conditioning regimen for GVHD prophylaxis in 70% of patients. After allo-HSCT, patients underwent twice weekly screening for CMV and EBV reactivation using a RQ-PCR until day 90 whereas BKV was screened in case of urinary symptoms and/or hematuria. CMV and EBV reactivation was defined as any level of DNAemia ≥ 1000 copies/mL, the diagnosis of BKV reactivation was relied on the presence of hemorrhagic cystitis with positive BKV viruria and/or viremia. Results: In the global population, the cumulative incidence of CMV, EBV, BKV reactivations by day 90 was 29.1% (95%CI: 24-34), 33.9% (95%CI: 29-39), and 16.8% (95% CI: 13-21) with a median occurrence time after allo-HSCT of 40 days, 41 days, and 36 days respectively. The cumulative incidence of relapse at 2 and 4 years was 26% (21-31%) and 29% (24-34%) respectively with a cumulative incidence of NRM of 16% (12-21) and 24% (19-29) respectively. Among the 99 patients with EBV reactivation, 32 (32.3%) needed treatment with rituximab. In univariate analysis, disease status at transplantation and type of conditioning were significantly impacting relapse incidence. In multivariate analysis, when adjusting on type of conditioning regimen and disease status at transplantation, patients with CMV reactivation had significantly lower rate of relapse, HR=0.81, 95% CI: 0.67-0.98, p=0.03, this was the same for those with EBV reactivation, HR=0.86, 95%CI: 0.72-1), p=0.05, as well as for BKV, HR=0.79, 95%CI: 0.66-0.95, p=0.012. In addition, we found that patients who had a simultaneous reactivation of CMV and EBV were at higher risk of relapse, HR=4.2, 95%CI: 1.9-8.1, p=0.002. Conclusion: We confirmed the positive impact viral reactivation after allo-HSCT on relapse incidence, which could be explained as a stimulation of both function and amplification of NK compartment. Our finding about viral co-reactivation that includes EBV with a higher risk of relapse should be further explored and carefully interpreted as this might come from EBV treatment by rituximab that impairs the immunological system by impacting the GVL effect and therefore leads to more relapse. Disclosures Michallet: Octapharma: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy; Novartis: Research Funding.

Introduction: Tyrosine kinase inhibitor (TKI) discontinuation is being investigated in pts with CML-CP with sustained DMR (defined here as MR4.5 or BCR-ABL1 ≤ 0.0032% on the International Scale [IS]), with the goal of treatment-free remission (TFR). Successful TFR has been reported previously for pts enrolled in DASFREE (CA180-406/NCT01850004), which showed that 48% of CML-CP pts with DMR for ≥ 1 year were able to stop dasatinib and maintain major molecular response (MMR) 12 months after discontinuation. Here we present updated results from pts followed for a minimum of 18 months, in order to understand the durability of TFR beyond 12 months. Methods: DASFREE is a phase 2, open-label, single-arm study in adult pts with CML-CP on dasatinib for ≥ 2 years as 1st-line or subsequent therapy. Eligible pts had dasatinib-induced DMR (MR4.5) confirmed at a local lab for ≥ 1 year prior to enrollment, with a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 months of starting dasatinib. MR4.5 was confirmed at a central lab twice within 3 months prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after discontinuation every month in the 1st year, then every 3 months. Pts resumed dasatinib at their previous dose if MMR was lost. The primary endpoint is the rate of MMR 12 months after dasatinib discontinuation. Secondary endpoints include BCR-ABL1 kinetics, molecular relapse-free survival (MRFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase [AP/BP] CML), rate of transformation to AP/BP, progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and MMR after reinitiating dasatinib. Results: In total, 84 pts enrolled between February 2014 and June 2016 discontinued dasatinib; all had ≥ 18 months of follow-up after discontinuation at the time of this analysis. Pt characteristics were previously reported (the majority [64%] had low Sokal scores; no pt had prior interferon; 37 pts were on 1st-line dasatinib, 47 on subsequent lines of dasatinib). At 18 months after discontinuation, the RFS rate was 48% (95% CI 37-58) in all pts (Figure), 54% (95% CI 38, 70) in 1st-line pts, and 42% (95% CI 28, 57) in pts who received subsequent-line therapy. With longer follow-up, 1 additional pt lost MMR at 18 months following discontinuation. Of the 45 pts who lost MMR and restarted treatment, 44 regained MMR (1 pt discontinued after only 1 molecular assessment) in a median of 2 months (range 1-4) and 42 regained MR4.5 in a median of 3 months (range 2-18). Analyses of baseline pt characteristics revealed that for the 40 pts who did not lose MMR after discontinuation, 15 (37.5%) were able to maintain MR4.5. Additionally, the median time in prior MR4.5 was 28 months (range 13-116) for all pts, and was similar for 1st-line pts who maintained (27 months [range 13-56]) or lost MMR (27 months [range 15-68]) at 12 months. With longer follow-up, AEs (any cause) identified were consistent with previous reports and were found to be similar on and off treatment: 8 (10%) pts off treatment and 8 (18%) pts on treatment experienced grade 3/4 AEs of any cause after restarting dasatinib (4.4% were drug related). No transformation events or deaths occurred. Of the 13 reported withdrawal events occurring in 8 (9.5%) pts, 10 were resolved (5 off treatment, 5 resolved after restarting treatment due to loss of MMR) after a median of 5 months (range 1-12) after onset. One pt discontinued after restarting dasatinib due to malignancy unrelated to treatment. In addition to efficacy and safety data, multivariate analyses evaluating prognostic factors for MMR will be presented. Conclusions: Additional follow-up of pts enrolled in DASFREE revealed that TFR remained durable at 18 months after discontinuing dasatinib. AEs reported here were consistent with the known safety profile of dasatinib, and withdrawal was well tolerated. Collectively, this trial, the largest dasatinib discontinuation trial to date, continues to support the feasibility and practicality of TFR in pts with CML-CP in DMR treated with dasatinib in the 1st line and beyond. Figure. Figure. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. García Gutiérrez:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau. Larson:Bristol-Myers Squibb: Consultancy; Takeda: Speakers Bureau. Saussele:Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria. Rea:Incyte: Honoraria; Bristol-Myers Squibb: 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; Pfizer: Honoraria. Mahon:Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Levy:Takeda (Millennium Pharmaceuticals, Inc.): Consultancy. Gómez-Casares:Novartis: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Incyte: Speakers Bureau. Pane:Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Incyte: Consultancy. Nicolini:Incyte: Consultancy, Honoraria, Speakers Bureau; Sun Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Mauro:Pfizer: Consultancy; Takeda: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding. Sy:Bristol-Myers Squibb: Employment. Martin Regueira:Bristol-Myers Squibb: Employment, Equity Ownership. Lipton:ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Introduction: Graft-versus-host disease (GVHD), and complications of its treatment are the major causes of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). With the use of standard GVHD prophylaxis with classical administration of Anti-thymocyte globulin (ATG), calcineurin inhibitors (CNIs) and methotrexate, the incidence of acute and chronic forms of GVHD remains not negligible. Extracorporeal photopheresis (ECP) has shown very promising results as curative strategy for GVHD but also when used prophylactically. The primary objective of this observational study was to perform an exhaustive description concerning patients receiving ECP after steroid resistance for either acute or chronic GVHD following allo-HCT, secondary objectives were to evaluate the efficacy and long-term outcomes. Patients and methods: We included 82 patients who underwent allo-HCT between years 2001 and 2016, 50 (61%) were males, median age at allo-HCT was 52 years (20-67). Major diagnoses were acute leukemias (45%), myelodysplastic syndromes (17%) and multiple myeloma (11%). Before transplantation, 43 (52%) patients were in complete remission or in chronic phase. Donors were identical siblings in 51% of patients, matched unrelated in 24%, mismatched unrelated in 24% and haploidentical in 1%. Hematopoietic Stem Cell source was peripheral blood in 65%, bone marrow in 27% and cord blood in 8%. Conditioning regimens were non myeloablative in 63% cases and myeloablative in 37%. ATG was used during conditioning in 63% of patients. GVHD prophylaxis consisted on cyclosporine A (CsA) alone in 21% of patients, CsA + mycophenolate mofetil in 27%, CsA + methotrexate in 26%, the rest received other combinations. In acute GVHD, first treatment consisted in methyl-prednisolone 2mg/Kg/day in combination with CNIs; and in chronic GVHD, it was methyl-prednisolone 0.5 - 1 mg/Kg/day + CNIs. ECP was performed using peripheral venous access. ECP was initiated after transplantation either for acute GVHD [N=28 (34%), 9 grade II, 3 grade III and 16 grade IV] affecting skin alone (N=5), gut alone (N=14), gut + liver (N=8); or for chronic GVHD [N=54 (66%), 19 (35%) limited and 35 (65%) extensive]. A total of 3300 ECP sessions were performed, majority were twice a week; the median number of sessions/patient was 21 (min: 2, max: 131) for a median duration of 4.2 months (range: 0.5-73). ECP response evaluation was assessed after 4 weeks of treatment, patients were considered responding to ECP if more than 50% resolution of clinical GVHD manifestation of the organ involved was registered. Results: Among the 28 patients treated for acute GHVD, one was not evaluable because of disease progression and early death, 11/27 (41%) were responders to ECP and 16/27 (59%) were not responders and died later from GVHD associated to other complications. Among the 54 patients with chronic GVHD, 32/54 (59%) were responders. Of note, in both forms of acute and chronic GVHD, responding patients had more skin forms whereas non-responding patients has more organ-involved forms especially liver and gut. After a median follow-up of 26 months, 32 (39%) patients are alive and 50 (61%) died, 43 from TRM causes (17 in the aGVHD group and 26 in the cGVHD group). Patients with acute GVHD had a median OS of 6 months with a survival probability at 2 years of 31% [95%CI: 14-56], those with chronic GVHD had a median OS of 36 months with a survival probability at 2 years of 55% [95%CI: 40-78]. Patients with chronic GVHD had better PFS probability at 2 years with 55% (95% CI: 43-70) versus 27% (95% CI: 14-51) for those with acute GVHD, p=0.007. In stepwise multivariate analysis, acute GVHD grade III-IV, significantly impacted on OS (HR=7.77, 95%CI: 1.7-34), p=0.007, while ATG and also aGVHD grade III-IV, negatively impacted PFS, HR=2, 95%CI: 1.02-4.12, p=0.04, and HR=5.88, 95%CI: 1.7-20, p=0.005 respectively. Conclusion: We confirm that ECP is an effective treatment for GVHD in a good proportion of patients with overall response rate of 59%. Interestingly, we observed a better PFS in patients receiving ECP for longer time as in the case of chronic GVHD, which could be related to the GVL effect itself but also a possible involvement of the ECP. As patients with advanced phase of GVHD were poor responders, we suggest that an early use of ECP in the acute phase of the inflammation before organ damage, could lead to optimal results. Disclosures Michallet: Novartis: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy. Nicolini:Incyte: Consultancy, Honoraria, Speakers Bureau; Sun Pharma: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau.

Introduction Since recently, HLA typing of CP-CML patients (pts) ≤65 years old was still recommended in at diagnosis and treated by Imatinib (IM) first-line, especially in case of baseline warnings (Baccarani et al. 2006/2009/2013), in the aim of performing allo-transplant if TKI failure occurs. Additionally, HLA molecules are processing BCR-ABL peptides at the surface of leukemic cells and trigger immune response, exploitable in autologous (Bocchia Lancet 2005) and allogeneic (Fefer NEJM 1979; Kolb Blood 1995) settings, including in residual disease conditions. The performance of antigen processing might differ according to the type of HLA molecules involved, but this remains largely debatable. Aims 1) To analyse the frequency of HLA subtypes in CP-CML pts as compared to those of the general population. 2) To investigate if IM first-line response differ according to the HLA subtypes, suggesting an involvement of the autologous immune system in the response observed. Methods We retrospectively analyzed a cohort of newly diagnosed CP-CML pts treated with IM first-line 400 mg alone and HLA typed (generic and/or allelic) in our center between years 2000 and2018. All pts were followed according to the ELN recommendations 2006/2010/2013. Clinical data were extracted from medical files, and responses were analysed with standard methods. Molecular results were ELN standardised since 2003, and were expressed as BCR-ABLIS in %. Overall survival (OS), progression-free survival (PFS), failure-free survival (FFS: progression to advanced phases death, loss of CHR, CCyR, or MMR, discontinuation of IM for toxicity, primary cytogenetic resistance) were analysed since IM initiation in intention-to-treat. Results Eighty-three pts have been included, with a median age of 47.5 (11-64.8) years at diagnosis, with 58% males and 42% females. Sokal score (n=80) was low in 44%, intermediate in 42% and high in 14%. ACA were present at diagnosis in 7% of pts (NA in 3), 2 pts had a cryptic Ph, and 2 a variant Ph. Major BCR transcripts were found in 96.4% pts, and atypical transcripts in 3.6%. We compared the frequencies of HLA A, B, C and DR in our 83 CP-CML to those of 5,225 unrelated bone marrow donors (UBMD) typed in the registry of the Rhône-Alpes region (35 million inhabitants). We could demonstrate that the HLA B13, B28, B51, B53 were significantly over-represented in the CP-CML population vs UBMD (4.24 vs 2.02%; 3.63 vs 2.48%, 11.5 vs 8.53%, 1.82 vs 0.88, overall p value = 0.007, Monte-Carlo test) as well as C05 (13.75 vs 8.39%, p=0.044) respectively. In addition, HLA B27, B45 and B55 were underrepresented in CP-CML pts vs UBMD (0.60 vs 3.43%, 0 vs 0.6%, 0.6 vs 1.66%, p=0.007, Monte-Carlo test). There was no difference for HLA A, and DR antigens. All pts got IM (Glivec®) 400 mg daily since diagnosis. The median follow-up after IM initiation was 111.5 (7.6-203) months. CHR was reached after a median of 1 (0-3.5) month, Conclusions CP-CML seems overrepresented in some particular HLA subtypes, and the sensitivity of the disease to IM seems improved in the HLA DRB1 07 allele although not significant. Whether this is related to the biological function of HLA molecules at the surface of CML cells or to a specific genetic background of these pts needs to be determined. These findings need to be confirmed in larger ongoing series. Disclosures Nicolini: Sun Pharma: Consultancy; Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau. Hayette:Incyte: Consultancy. Michallet:Octapharma: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy; Novartis: Research Funding.

Background The objective of the study was to assess the impact of the relocation of an adult hematological intensive care unit on invasive aspergillosis (IA) incidence. Methods A quasi-experimental study, including a control group and an intervention group that both underwent pretest and posttest evaluations, was conducted in the 3 adult hematological intensive care units (each composed of 14 single rooms) in a university hospital from 14 April 2005 through 1 February 2006. One of these units was relocated from the main building to an adjoining modular construction. In this unit, 4 rooms were equipped with laminar airflow before relocation; all rooms were equipped with positive pressure isolation after relocation. The 2 other units (control group), each containing 8 rooms with laminar airflow, did not undergo environmental modification. The diagnostic criteria for IA were based on the criteria of the European Organization for Research and Treatment of Cancer. Results In total, 356 hospitalized patients were included. Of the 21 cases of IA, 18 were nosocomial, and 3 were of undetermined origin. In the relocated unit, the incidence of IA decreased from 13.2% (9 patients) before relocation to 1.6% (1 patient) after relocation (P=.018). Eight of the 9 patients with IA before relocation stayed in rooms without specific air treatment. The rate of IA did not change in the control group. Patient characteristics were similar in each unit before and after relocation. Conclusion We detected a straightforward association between environmental modification and decreased IA incidence, which emphasizes the use of an environmental strategy, including high-efficiency air filtration, in the prevention of IA.

In order to study efficacy, toxicity and the long-term results of donor lymphocyte infusions (DLI), we retrospectively analyzed DLI given for relapse after conventional allogeneic hematopoietic stem cell transplantation (HSCT) in 30 patients with a median delay of 107.5 months after transplant and 58 months after DLI. After DLI, 15 patients established full donor chimerism, three patients developed grade III and one grade IV acute GVHD. A total of 15 patients achieved a disease response. Among the 14 patients with chronic myeloid leukemia (CML), 11 are alive at the last follow-up: five are in complete molecular response (CMR) and two in complete cytogenetic response (CCR) with no other intervention after DLI, three in CMR after imatinib mesylate given after DLI and one in complete hematological response after imatinib mesylate and reduced-intensity conditioning allogeneic SCT performed after DLI. At the time of the last follow-up, 19 (63%) patients died and 11 (37%) remain alive. The 3-year probability of survival for the entire population, CML patients and non-CML patients, was 60, 93, 62% after transplantation, and 48, 80 and 48% after DLI, respectively. A multivariate analysis demonstrated a significantly worse survival rate after transplantation for female recipients, advanced disease and acute leukemia before transplantation.

Treatment of a severe extensive cutaneous chronic GVHD after allo-HSCT using glycerolyzed skin allografts and cultured epidermis from the same donor

A pilot study of continuous imatinib vs pulsed imatinib with or without G-CSF in CML patients who have achieved a complete cytogenetic response

In order to determine whether doses of cyclosporine and methylprednisolone used for prophylaxis and therapy of acute graft-versus-host disease (GVHD) have any influence on relapse and survival following allogeneic bone marrow transplantation (BMT), we studied 176 adult patients with hematologic malignancies, who underwent a first allogeneic transplant from an HLA-identical sibling donor. Two methods of management of acute GVHD used in two different centers were compared: group I included 62 patients who had 'standard' management of GVHD including prophylaxis with 1-3 mg/kg/day of cyclosporine and treatment with 2 mg/kg/day of methylprednisolone when acute GVHD developed; group II included 114 patients who received 'intensive' management of GVHD including prophylaxis with 5 mg/kg/day of cyclosporine and treatment with high-dose methylprednisolone (8-20 mg/kg/day for 3 days) at the onset of GVHD. The overall incidence of GVHD was the same in both groups. However, acute GVHD was more severe in group I than in group II (P < 0.0001), with consequently less resolution of GVHD after treatment in group I (61%) than in group II (80%) (P = 0.06). Overall survival and disease-free survival (DFS) did not differ between the two groups. However, actuarial risk of disease relapse was significantly higher in group II than in group I (36% vs 17%, P = 0.02). In a multivariate analysis taking into account known factors influencing GVHD and relapse, only type of GVHD management and age were significantly predictive for the occurrence of GVHD, while only type of GVHD management and pathology other than chronic myeloid leukemia (CML) were predictive for relapse. This study demonstrates that intensity of GVHD prophylaxis and therapy can influence the graft-versus-leukemia effect by decreasing severity of GVHD but at the price of increasing relapse rate post transplant.

A fatal nosocomial infection withLegionella pneumophilaserogroup 5 occurred in a patient with leukemia. Isolates recovered from both the potable water supply and the patient showed an identical genomic profile. With no other exposure identified, the water from the washbasin was evidently the source of infection.

Identification of a rare e8a2 BCR-ABL fusion gene in three novel chronic myeloid leukemia patients treated with imatinib

To the editor: Dasatinib is a tyrosine kinase inhibitor licensed in the treatment of chronic myeloid leukemia (CML) known to exert immunomodulatory effects in vitro and in vivo.[1][1] We report on 9 chronic phase CML patients who developed follicular lymphoid hyperplasia (FLH) apparently caused by

Secondary Philadelphia chromosome after non-myeloablative peripheral blood stem cell transplantation for a myelodysplastic syndrome in transformation

Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach for a wide range of hematologic malignancies. However, the period of prolonged immunodeficiency after this procedure results in significant morbidity and mortality from infectious complications. Epstein-Barr virus (EBV) is a latent γ-herpes virus with B lymphocyte-specific tropism that infects more than 90% of healthy individuals. Following allo-HSCT, EBV reactivation and EBV-related proliferations may be associated with a spectrum of clinical presentations, going from fever to lymphoproliferative diseases (LPD), which arise as a consequence of an outgrowth of B cells latently infected with EBV in the setting of loss or suppression of normal cytotoxic T-cell surveillance. Reduction in immunosuppression and/or pre-emptive therapy with rituximab are strategies nowadays employed to prevent or to treat EBV-associated LPD, which have led to a significant improvement in patient outcome. While the role of T cells and NK cells in graft-versus-leukemia (GVL) immune responses has been established, recent studies have shown a potential contribution of B cells on GVL responses. In this context, the impact of the use of monoclonal antibodies targeting B cells lines on disease control has not been evaluated yet. The aim of this study is to evaluate the incidence of EBV reactivation in patients with hematological malignancies after allo-HSCT, the use of rituximab for its treatment and its impact on the transplantation outcomes. Patients and methods: We evaluated 359 consecutive patients with hematological malignancies who received allo-HSCT and were followed in our center between January 2008 and June 2015; there were 218 (61%) males and 141 (39%) females with a median age of 48 years (range: 18-70), 182 (51%) had acute myeloid leukemia, 44 (12%) multiple myeloma, 34 (9%) myelodysplastic syndrome, 30 (8%) Non-Hodgkin lymphoma, 7 (2%) chronic lymphocytic leukemia, 21 (6%) myeloproliferative syndrome, 14 (4%) Hodgkin disease, 13 (4%) chronic myeloid leukemia and 14 (4%) aplastic anemia. At transplantation, 227 (63%) patients were in complete response (CR) or chronic phase (CP) and 132 (37%) were in less than CR or CP. For conditioning regimen, 171 (48%) were myeloablative and 188 (52%) were reduced intensity. EBV DNA levels in blood were detected by quantitative real-time polymerase chain reaction (RQ-PCR) after weekly monitoring up to 3 months after allo-HSCT. EBV-DNA was considered positive when the copies exceeded 1000 copies/ml. EBV therapeutic intervention, firstly concerned gradual reduction of the doses of immunosuppressive drugs, and then rituximab infusion (375 mg/m², four injections weekly) was administered when the copies exceeded 10 000 copies/ml. Results: Among 359 patients, 222 patients had EBV reactivation after a median time of 1.3 months (0.7-2.5) after allo-HSCT with a cumulative incidence of 48 % (47-50) at 3 months. Among the 222 patients with EBV reactivation, only 35 (15.7%) needed treatment with rituximab. Rituximab was introduced after a median time of 55 days after transplantation with a median number of 5 infusions and a median dose of 2025 mg/m². EBV treatment was successful in all patients, none progressed to LPD. The cumulative incidence of relapse at one and two years for the whole population was 27% (26-28) and 34% (33-35) respectively and the cumulative incidence of transplant-related mortality (TRM) was 22% (21-23) and 25% (24-26) respectively. The multivariate analysis taking into account the type of disease, the type of conditioning, the use of ATG, the disease status at transplantation, the presence of GVHD and the EBV reactivation with/without rituximab, showed that the presence of EBV reactivation was associated with a significant lower relapse rate, HR= 0.52 [0.35-1], p=0.05. The use of rituximab did not compromise the GVL effect and thus had not impact on relapse or overall survival. Conclusion: We showed a positive impact of EBV reactivation on relapse incidence which could be explained as a stimulation of both function and amplification of NK compartment. The strict monitoring of the viral load and therapeutic intervention using rituximab enable a full viral control without any progression into LPD and without any compromise on GVL effect. Figure 1. Figure 1. Disclosures Michallet: Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Astellas Pharma: Consultancy, Honoraria; MSD: Consultancy, Honoraria; Genzyme: Consultancy, Honoraria. Nicolini:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background: Prior clinical trials demonstrated that 33-61% of patients with CML maintain disease control following TKI discontinuation in the 1st line and beyond (Thielen, Eur J Cancer. 2013; Mahon, Lancet Oncol. 2010; Hochhaus, ASCO 2016; Hughes, ASCO 2016; Imagawa, Lancet Haematol. 2015). Patients who relapsed after discontinuation regained major molecular response (MMR) upon retreatment. Dasatinib, a 2nd generation TKI, induces fast and deep molecular responses, making it an effective option for patients in view of a possible TFR. Here, we report interim results from the phase 2 DASFREE study, investigating TFR with dasatinib in the 1st and 2nd line settings. Methods: DASFREE (CA180-406/NCT01850004) is a phase 2 open-label, single-arm study in adults with CML-CP who were on dasatinib for ≥2 yr as 1st line or subsequent therapy, had confirmed dasatinib-induced DMR (defined as MR4.5, BCR-ABL1 ≤0.0032% [IS]) for ≥1 yr prior to enrollment, and achieved a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 mo of starting dasatinib. Prescreening for MR4.5 was done at a local lab, with confirmation at a central lab twice over a 3-mo interval prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after treatment discontinuation every mo in the 1st yr, then every 3 mo. If loss of MMR occurred, patients resumed dasatinib at the previous dose. The primary endpoint is MMR rate at 1 yr after dasatinib discontinuation. Secondary endpoints include kinetics of loss of response, event-free survival (EFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase CML), progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and molecular response rates after reinitiating dasatinib. All patients will be followed for up to 5 yr. This analysis reflects a planned interim assessment of patients followed for TFR for ≥1 yr. Results: Currently, 71 patients are enrolled out of 79 planned. Thirty patients (14 male; median age 51 yr [range: 29-76]; Sokal scores: 60% low, 27% intermediate, 3% high, 10% unknown) followed for ≥1 yr after dasatinib discontinuation were included in this interim analysis. MMR rate at 1 yr following discontinuation was 63% (95% CI: 46-81). EFS rate at 1 yr following discontinuation was 63% (95% CI: 44-78; Figure). RFS rate at 1 yr following discontinuation will be presented. Eleven of 30 patients lost MMR, with a median time to loss of MMR of 4 mo (range: 1-8). Median time on dasatinib prior to discontinuation was 40 mo (range: 26-114) for patients who lost MMR and 55 mo (range: 31-87) for patients who retained MMR. Eleven patients who lost MMR restarted dasatinib therapy: 10 regained MMR, and 1 patient chose to restart therapy at a nonstudy site, discontinued study, and was lost to follow-up. The kinetics of molecular relapse, the number of patients that regained DMR, and the time to regain MMR or DMR will be presented. No transformation events or deaths were observed at the time of this analysis. After discontinuation, 5 patients had musculoskeletal AEs; in 2 patients (with 3 events) these AEs were attributed to withdrawal from dasatinib by investigators. Additional AEs following discontinuation included hypertension (17%) and skin disorders (13%). For patients who restarted dasatinib, AEs were consistent with the known safety profile, and none of the on-treatment AEs resulted in discontinuation. Conclusions: This interim analysis of the first 30 patients enrolled in DASFREE demonstrated patients with dasatinib-induced DMR treated in the 1st and 2nd line had high rates of success at maintaining remission after treatment was discontinued (63% MMR and EFS at 1 yr), and there was rescue of molecular response in all patients once dasatinib was reinitiated. There is a suggested correlation between time on dasatinib prior to discontinuation and maintaining MMR. Dasatinib withdrawal appears to be tolerable, as there was a low incidence of withdrawal symptoms. These data build upon the growing body of evidence supporting the feasibility of TFR in patients with CML-CP and demonstrate that with frequent monitoring of BCR-ABL1, patients treated with dasatinib in the 1st and 2nd line can successfully discontinue treatment. Longer-term follow-up is ongoing. Figure Figure. Disclosures Shah: Bristol-Myers Squibb, ARIAD, Pfizer, Daiichi-Sankyo, Plexxikon: Research Funding. Paquette:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau. Müller:Ariad, BMS, Novartis, Pfizer: Honoraria; Ariad, BMS, Novartis, Pfizer: Consultancy; Institute for Hematology and Oncology, IHO GmbH: Employment, Equity Ownership. Saussele:Novartis, BMS, Ariad, Pfizer: Honoraria; Novartis, BMS: Research Funding. Garcìa-Gutiérrez:Novartis, BMS, Ariad and Pfizer: Consultancy; Novartis, BMS, Ariad and Pfizer: Research Funding. Nicolini:Ariad: 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, Research Funding; BMS: Consultancy, Honoraria. Mauro:ARIAD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Mahon:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Rea:Novartis: Honoraria; Ariad: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Martin-Regueira:Bristol-Myers Squibb: Employment. Subar:Bristol Myers-Squibb: Employment. Li:Bristol-Myers Squibb: Employment. Lipton:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Background: Reduced-intensity conditioning (RIC) regimens have led to a dramatic reduction of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The concept of RIC is to deliver adequate immunosuppression with manageable graft-versus-host disease (GVHD) and the eventual development of a potent graft-versus-leukemia effect. Nevertheless, GVHD prophylaxis remains a challenging task after allo-HSCT. While the combination of cyclosporine A (CsA) and a short course of methotrexate (Mtx) after transplantation is considered as the gold standard for GVHD prophylaxis after conventional myeloablative allo-HSCT from HLA-identical siblings, there is no consensus on the optimal preventive GVHD prophylaxis after RIC allo-HSCT. On the other hand, recent and ongoing studies are evaluating a promising GVHD prophylaxis strategy using post-transplantation cyclophosphamide (PTCy). The aim of this study is to evaluate the impact of different GVHD prophylaxis used after RIC allo-HSCT in patients receiving peripheral blood stem cells (PBSC) from unrelated donors for hematological malignancies. Patients and methods: We evaluated 127 consecutive patients with hematological malignancies who received RIC allo-HSCT and were followed in our center between January 2008 and January 2016; 74 (58%) were males, median age was 58 years (range: 18-70), 52 (41%) had acute myeloid leukemia, 36 (28%) myelodysplastic syndrome, 12 (10%) myeloproliferative syndrome, 9 (7%) Non-Hodgkin lymphoma, 9 (7%) chronic lymphocytic leukemia, 6 (5%) multiple myeloma and 3 (2%) chronic myeloid leukemia. At transplantation, 65 (51%) patients were in complete response (CR) or chronic phase (CP). RIC regimen consisted on fludarabine, intermediate doses of IV busulfan and anti-thymocyte golbulins (ATG) (Thymoblobulin) in 56 (44%) patients and a sequential FLAMSA regimen in 71 (56%) patients and who also received similar doses of ATG (Thymoglobulin). PBSC donors were 10/10 HLA matched in 81 (64%) patients and 9/10 HLA mismatched in 46 (36%) patients. Patients were divided according to GVHD prophylaxis into 3 groups: group 1 consisted on CsA alone with 23 (18%) patients, group 2 include patients who received either CsA + mycophenolate mofetil (MMF), n= 64 (50%) or CsA + Mtx, n= 20 (16%) or CsA + cyclophosphamide n= 5 (4%), and group 3 included patients receiving CsA + MMF + tacrolimus n= 15 (12%) patients. Results: After transplantation, all patients in group 1 engrafted after a median of 17 (3-25) days, 81/89 (91%) engrafted in group 2 after a median of 17 (5-58) days and 14/15 (94%) engrafted in group 3 after a median of 16 (9-24) days. We did not observe any significant impact of the type of GVHD prophylaxis on the 100-day incidence of grade II to IV acute GVHD, which occurred in 6/15 (40%), 34/81 (42%) and 7/14 (50%) for the groups 1, 2 and 3 respectively (p=0.18). Grade III-IV acute GVHD occurred in 3 (20%), 24 (29%) and 5 (33%) in the three groups respectively (p=0.11). Similarly, cumulative incidence of 1 year chronic GVHD was not different between groups 1, 2 and 3 reaching 46%, 43% and 46% respectively (p=0.6) among them 3/15 (20%), 18 (22%) and 3/14 (21%) patients had an extensive form. After a median follow-up of 22 months for surviving patients, although there was no significant difference between the three groups in terms of non-relapse mortality, we observed more infection-related mortality with 45% and 83% in groups 2 and 3 respectively compared to 47% in group 1. The cumulative incidence of relapse at 2 years was 22%, 31 and 26% for the three groups respectively (p=0.23). Overall survival rates at two years were 43%, 31% and 44 % for groups 1, 2 and 3 respectively (p=0.42). The multivariate analysis taking into account the type of disease, donor HLA matching, disease status at transplantation, type of RIC and the type of prophylaxis, showed that the incidence of acute GVHD was influenced only by the use of FLAMSA regimen from mismatched donors, HR= 2.2 [1.3-3.1], p=0.05 which had also the same impact on the occurrence of chronic GVHD. Conclusion: Despite its limitations and the need for prospective randomized studies, the results of our study suggest that in the RIC allo-HSCT from unrelated donors, the different GVHD prophylaxis associations lead to similar GVHD outcomes. Patients with more immunosuppressive drugs had a higher incidence of infection-related mortality and in which PTCy could be a better option. Disclosures Nicolini: BMS: Consultancy, Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Background: ENESTop (NCT01698905) is an ongoing, single-arm, phase 2 study evaluating treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) who achieved sustained molecular response 4.5 (MR4.5; BCR-ABL1 ≤ 0.0032% on the International Scale [BCR-ABL1IS]) on second-line nilotinib (NIL). In the primary analysis, 57.9% (95% CI, 48.8%-66.7%) of pts who stopped NIL maintained TFR (no loss of major molecular response [MMR; ie, BCR-ABL1IS > 0.1%], confirmed loss of MR4 [ie, consecutive BCR-ABL1IS > 0.01%], or treatment reinitiation) at 48 weeks. Adverse events (AEs) were reported in 73.8% of pts during the first 48 weeks of TFR vs 77.0% during the year prior to stopping treatment. The incidence of musculoskeletal pain-related AEs was higher during TFR (42.1% vs 14.3%). To assess the potential effect of stopping NIL on quality of life (QOL), pt-reported outcomes were assessed before and during TFR. Methods: ENESTop enrolled adult pts with CML-CP with ≥ 3 years of prior tyrosine kinase inhibitor (TKI) therapy (> 4 weeks of imatinib [IM], then ≥ 2 years of NIL). Pts must have achieved sustained MR4.5 on NIL after switching from IM. Enrolled pts entered a 1-year NIL treatment consolidation phase; those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) entered the TFR phase and stopped NIL. Pts with loss of MMR or confirmed loss of MR4 during the TFR phase reinitiated NIL. QOL was assessed via questionnaires completed by pts at specified time points. The MD Anderson Symptom Inventory for CML (MDASI-CML) questionnaire assessed, for a defined set of symptoms, the levels of severity and interference with daily life on a scale of 0 to 10, with 0 being the lowest level. The EQ-5D-5L questionnaire assessed problems experienced by pts (no, slight, moderate, severe, or extreme [ie, interfering with functioning] problems) in 5 dimensions: mobility, self-care, usual activities, anxiety/depression, and pain/discomfort; additionally, overall level of health was assessed on a scale of 0 to 100 using the EQ VAS, with 0 being the lowest level. Results: Of 163 enrolled pts, 126 met the criteria for stopping NIL in the TFR phase; of these 126, 53 had loss of MMR or confirmed loss of MR4, of whom 51 reinitiated NIL. Among pts who completed each questionnaire at week 48 of the consolidation phase, week 12 of the TFR phase, or week 48 of the TFR phase, mean MDASI-CML severity scores were 1.7, 1.5, and 1.2, respectively; mean MDASI-CML interference scores were 1.7, 1.6, and 1.4, respectively; and mean EQ VAS scores were 82.2, 78.8, and 82.3, respectively (Table). Among pts with sustained TFR and scores at both week 48 of the consolidation phase and week 12 or 48 of the TFR phase, minimal changes were observed in MDASI-CML and EQ VAS scores during TFR vs week 48 of the consolidation phase. Among pts who reinitiated NIL, mean MDASI-CML severity and interference scores and mean EQ VAS scores at 24 weeks after the start of retreatment were 1.6, 1.5, and 78.8, respectively; changes in scores between week 24 after treatment reinitiation and week 48 of the consolidation phase were minimal among pts with scores at both time points. Among pts who completed the EQ-5D-5L questionnaire, the proportions who reported problems (any level of severity) in the 5 dimensions were generally similar across time points, although problems with mobility and pain/discomfort were more common during TFR vs week 48 of the consolidation phase, particularly at week 12 of the TFR phase (Table). Conclusion: Changes in QOL after stopping NIL, as assessed using these questionnaires, were minimal. This may be related to pts having a relatively high QOL prior to stopping treatment given that they had tolerated ≥ 3 years of TKI therapy, including ≥ 2 years of NIL, prior to enrollment. Despite the higher incidence of musculoskeletal pain-related AEs observed during TFR (42.1% vs 14.3%), the overall QOL was generally similar between the TFR and consolidation phases. This suggests that these AEs did not have a significant negative impact on QOL. Longer follow-up in ENESTop will be needed to further evaluate trends in QOL after stopping second-line NIL. Disclosures Mahon: NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; ARIAD: Honoraria; PFIZER: Honoraria. Boquimpani:BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Novartis pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Turkina:Novartis Pharma: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Moiraghi:NOVARTIS: Speakers Bureau; BMS: Speakers Bureau. Nicolini:Ariad: 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, Research Funding; BMS: Consultancy, Honoraria. Sacha:Pfizer: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Brandt:Novartis: Employment. Gnanasakthy:Novartis: Consultancy, Equity Ownership, Research Funding. Jin:Novartis: Employment, Equity Ownership. Hughes:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

To the editor: Recent results from the STop IMatinib (STIM) trial suggest that imatinib may be safely discontinued in some chronic myeloid leukemia (CML) patients with long-lasting complete molecular response (CMR).[1][1] However, 60% of patients experienced molecular recurrence (MR; detection of

Anti–human leukocyte antigen (HLA) antibodies are associated with several complications in solid organ transplantations, but their impact after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is not yet well defined. To evaluate the relevance of anti-HLA antibodies, we have retrospectively analyzed 107 peripheral blood allo-HSCTs after reduced-intensity conditioning regimen between 2005 and 2010. Acute myeloid leukemia and multiple myeloma were the most frequent malignancies in the cohort. The detection of anti-HLA antibodies was systematically performed in all patients before transplantation. Anti-HLA antibodies were present in 24 patients (22%). There was no significant impact of anti-HLA antibodies on engraftment, incidence of relapse, and incidence of acute graft-vs-host disease. The presence of anti-HLA antibodies was associated with significantly worse overall survival ( p = 0.006) and event-free survival ( p = 0.024) after stratification on sex. The 3-year probability of overall survival was 34% without anti-HLA antibodies and 16% in their presence. Patients with anti-HLA antibodies had a higher transplant-related mortality associated with life-threatening vascular complications. Our study supports that anti-HLA antibodies should be tested and considered as an important impacting factor for transplantation outcomes after reduced-intensity conditioning allo-HSCT. We recommend its consideration before allo-HSCT in the donor–recipient selection parameters.

International audience; Invasive aspergillosis (IA) is an important cause of morbidity and mortality in neutropenic patients with hematological malignancies. To investigate the immediate and mid-term benefits of posaconazole prophylaxis in AML patients undergoing first induction chemotherapy and to study the infection risk factors, we prospectively studied the IA incidence in these patients at our hospital between years 2007 and 2008; then we compared them to a matched control group without prophylaxis. There were 55 and 66 patients in each group respectively. At day 32 post-induction, two probable cases (3.6%) were scored in the prophylaxis group compared to 8 cases (12.1%) in the control group (4 possible and 4 probable). At day 100, it reached 7.27% and 15.5% respectively. Kaplan-Meier analysis at day 100 showed lower mortality rate in the prophylaxis group compared to the control group [3.64% (n = 2, none due to IA) and 10.61% (n = 7, four due to IA) respectively, P = 0.002]. Multivariate analysis showed age and lack of response to induction as independent infection risk factors. Posaconazole prophylaxis resulted in lower incidence of IA and significantly improved survival. Patient's age and response to induction treatment are two independent infection risk factors, and need more attention during future clinical trials linked to antifungal prophylaxis.

Imatinib has transformed the prognosis and the management of chronic myeloid leukemia (CML) and has probably changed the patterns of mortality rates. We explored this change at each disease severity level (Sokal score) through a flexible statistical modeling of the effect of the year of diagnosis on the excess mortality rate. The study included 691 chronic-phase patients from Nord-Pas-de-Calais French CML registry diagnosed from 1990 to 2007. Imatinib was given to 93% of the patients diagnosed after 2000. Comparing the 1990-1994, 1995-1999, and 2000-2007 periods of diagnosis, the 5-year relative survival improved from 64% to 66% and 88%. The year of diagnosis was associated with a significant reduction of the excess mortality, but only in patients with intermediate to high Sokal scores. In high-risk patients diagnosed in the early 1990s, a peak of excess mortality was observed during the second year of follow-up. That peak decreased progressively over the years of diagnosis until disappearing in patients diagnosed after 2000. This study showed different effects according to Sokal scores of the use of imatinib on mortality in patients with chronic-phase CML and showed that since 2000 the pattern of mortality of high-risk patients became similar to that of intermediate-risk ones.

Acquired molecular abnormalities (mutations or chromosomal translocations) of the RUNX1 transcription factor gene are frequent in acute myeloblastic leukemias (AMLs) and in therapy-related myelodysplastic syndromes, but rarely in acute lymphoblastic leukemias (ALLs) and chronic myelogenous leukemias (CMLs). Among 18 BCR-ABL+ leukemias presenting acquired trisomy of chromosome 21, we report a high frequency (33%) of recurrent point mutations (4 in myeloid blast crisis [BC] CML and one in chronic phase CML) within the DNA-binding region of RUNX1. We did not found any mutation in de novo BCR-ABL+ ALLs or lymphoid BC CML. Emergence of the RUNX1 mutations was detected at diagnosis or before the acquisition of trisomy 21 during disease progression. In addition, we also report a high frequency of cryptic chromosomal RUNX1 translocation to a novel recently described gene partner, PRDM16 on chromosome 1p36, for 3 (21.4%) of 14 investigated patients: 2 myeloid BC CMLs and, for the first time, 1 therapy-related BCR-ABL+ ALL. Two patients presented both RUNX1 mutations and RUNX1-PRDM16 fusion. These events are associated with a short survival and support the concept of a cooperative effect of BCR-ABL with molecular RUNX1 abnormalities on the differentiation arrest phenotype observed during progression of CML and in BCR-ABL+ ALL.

Imatinib mesylate has become the gold standard front-line treatment of chronic myelogenous leukemia through its ability to inhibit ABL tyrosine kinase. Resistance to this inhibition may occur. We investigated the role of the K247R polymorphism in persistent sensitivity.