ALBERT

Description: Background IA is a major cause of morbidity and mortality for patients with hematological malignancies and has been mainly reported in patients with acute myeloblastic leukemia (AML) and stem cell transplantation. Much less is known about the role of IA during the treatment of lymphoproliferative diseases like ALL. Here, we retrospectively evaluated the characteristics of patients and the incidence of IA occurring during the induction course in adult ALL patients enrolled in the GRAALL-2005 trial. Methods We collected the data of 36 patients with IA during induction chemotherapy. All were included between May 2006 and October 2012 in the multicentric GRAALL-2005 phase III trial. According to ALL characteristics, these patients were treated in 3 different substudies: GRAALL, GRAALL-Rituximab (GRAALL-R) for CD20+ ALL, GRAAPH for Philadelphia (Ph) chromosome-positive ALL. IA was defined retrospectively using the EORTC modified criteria (De Pauw, CID 2008). Results Among the 969 patients enrolled, 36 (3.7%) developed IA during induction therapy. The median age was 30 years for all patients receiving induction and 47 years (range, 18 to 59) for patients with IA. We observed 18 IA (3%) by the GRAALL protocol (593 patients enrolled), 16 (8.3%) by the GRAALL-R protocol (191 patients enrolled), and 2 (0.7%) by the GRAAPH protocol (270 patients enrolled). In the GRAALL-R protocol, IA was diagnosed in 6 patients randomly assigned to receive rituximab and in 10 patients treated in the control group. The median time between first day of induction therapy and IA diagnosis was 20 days (range, -2 to 71). The median time between the first day of neutropenia and IA diagnosis was 18 days (range, 0 to 76). At the time of IA diagnosis, 13 patients were hospitalized in laminar airflow rooms, 10 patients in rooms with overpressure, 1 patient in a room with high-efficiency particulate filter, 5 patients in conventional rooms, 1 patient received home care and the type of hospitalization was unknown for the 6 remaining patients. Four patients with IA (11%) had received antifungal drug for invasive fungal infection (IFI) prophylaxis: one patient received fluconazole, one received caspofungin, and two received liposomal amphotericin B. All patients with IA presented pulmonary symptoms associated with a sinusal or cutaneous localization in 1 and 2 patients respectively. The diagnosis of IA was classified as possible in 7 episodes (19 %), probable in 22 episodes (61%), proven in 4 episodes (11%), and indeterminate in the remaining 3 episodes. Detection of Aspergillus antigen in serum by latex agglutination was positive in 24 cases (67%). Chest CT scans were taken for 33 patients (92%): nodules were found in 19 patients, halo sign in 20 patients, and “air crescent sign” in 1 patient. Bronchoalveolar lavage was performed in 11 patients (31%): culture was positive in 7 of them and Aspergillus antigen was positive in 2 of them. Biopsies where positive in 4 cases: in pulmonary biopsy in 3 patients and in cutaneous biopsy in 1 patient. Of all the Aspergillus isolates identified to the species level, Aspergillus fumigatus was isolated from 4 patients and Aspergillus flavus from 1 patient. Overall and IA-attributable 12-week mortality was 8 (0.8%) and 6 (16.7%) patients respectively. Conclusion IA is less frequently observed during induction therapy in adult ALL as compared to adult AML patients. However, the attributable mortality appears to be high in these patients. They are as at risk patients for IA and should be included in prophylactic and empirical antifungal clinical trials. Disclosures: No relevant conflicts of interest to declare.

Description: Background : Bacterial infections (BI) are a major cause of morbidity and mortality in patients treated for hematological malignancies, especially those with acute myeloblastic leukemia or receiving allogeneic hematopoietic stem cell transplantation. Despite severe neutropenia and prolonged treatment with corticosteroids, there are little published data on BI during induction chemotherapy in adults with acute lymphoblastic leukemia (ALL). Between 2006 and 2014, 787 adult patients were included in the GRAALL-2005 study, a prospective, randomized and multicenter phase III trial for patients newly diagnosed patients with Philadelphia chromosome-negative B-cell precursor (BCP) or T-cell ALL. We retrospectively reviewed the occurrence of BI during induction treatment in these patients. Patients and Methods: The GRAALL-2005 study evaluated the value of hyperfractionated cyclophosphamide in the whole study population and of rituximab in patients with CD20+ BCP-ALL. All patients received a 5-drug induction therapy with corticosteroids (prednisone) for 21 days, associated with vincristine, daunorubicin, cyclophosphamide and L-asparaginase. A broad-spectrum antibiotic treatment effective on Gram-negative and positive germs was recommended when the neutrophil count was less than 0.5 G/L. Pneumocystis prophylaxis was made by trimethoprim/sulfamethoxazole or pentamidine. Results: During induction chemotherapy, 270 of the 787 patients (34.3%) experienced a total of 376 BI episodes (1.4 BI episodes per patient). The BI incidence rate was higher in the subgroup of patients combining hyperfractionated cyclophosphamide and rituximab as compared to those who received standard-dose cyclophosphamide and no rituximab (40.7% versus 29.5%; p=0.098). The median time from the first day of induction therapy to BI diagnosis was 10 days (range, 7-14). The infection was considered as serious in 58 patients, with a diagnosis of septic shocks in 57. Forty-one patients were transferred in intensive care unit. At 50 days after induction initiation, 22 patients had died from BI: 8.1% of patients with BI and 2.8% of all patients. Bloodstream was the most common site (82.7%), followed by gastrointestinal tract (6.5%) and lungs (6.5%). In less than 2% of cases, skin and soft tissues, central venous catheter, or urinary tract was concerned. Infections with Gram-positive cocci predominated as the etiology of microbiologically documented infections (46.9%), more specifically coagulase-negative Staphylococci. E. coli and Pseudomonas species were the most common Gram-negative organisms (40.5%). The patients received a median number of 3 antibiotics. The first-line was a monotherapy in 57% of cases, with the predominant use of betalactam. In one-third of the cases, it was betalactam in combination with aminoglycoside or glycopeptide. More than 2 antibiotics were prescribed in 12% of cases. Conclusion: Induction chemotherapy in adults with ALL is associated with a high incidence of bacterial infections and a significant related mortality. To our knowledge, this report is the only large adult ALL study dealing with bacterial infectious complications during induction chemotherapy. Despite an intensely myelosuppressive chemotherapy regimen, the infection-related mortality seems to be lower than that reported during induction in acute myeloid leukemia. Predictive risk factors for bacterial infections have to be analyzed, as well as prophylactic/empirical antibiotic strategies in order to improve care for this subset of patients. Disclosures No relevant conflicts of interest to declare.

Description: Introduction: CD38 is highly and uniformly expressed on myeloma cells (1). Daratumumab is a human anti-CD38 IgG1κ monoclonal antibody that has previously shown a favourable safety profile as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (2). This study further assesses the efficacy of Daratumumab in combination with Dexamethasone in heavily pre-treated myeloma patients that are refractory to Lenalidomide, Pomalidomide, and Bortezomib. Methods: This study is an ongoing, open-label phase II study of Daratumumab in combination with Dexamethasone (NCT02626481). Sixty-four, heavily pretreated Patients were recruited in thirty centres in France and Belgium from November 2015, to receive Daratumumab and Dexamethasone. Daratumumab 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during Cycles three through six, and monthly in Cycle seven and beyond until disease progression or unacceptable toxicity. Patients were all refractory to Lenalidomide (Len), Pomalidomide (Pom) (defined by a progression within 60 days from last drug dosing) and Bortezomib (Bz) (defined by a progression within 6 months from last drug dosing). The primary objective was overall response rate as per the International Myeloma Working Group criteria. A planned safety and efficacy interim analysis was performed after the first 19 patients were enrolled. The last patient was enrolled on the 1stof August 2016. Results: Sixty-four patients were recruited onto the study. The median age (range) at screening was 61 (30-80). The median number (range) of prior lines of therapy was 6 (2-9). Sixty-seven percent of patient had previously received an autologous stem-cell transplant. At the time of screening, 20% of patients (n=13) had a t(4;14) and 12.5% (n=8) a del(17p). Planned interim analysis after the first 19 patients were enrolled did not find any unexpected toxicity. Safety and efficacy results (data cut May 15, 2016) of Daratumumab 16 mg/kg are presented here. No patient discontinued treatment due to Treatment Emergent Adverse Event such as infusion related reactions. Ten (15%) patients discontinued treatment due to disease progression after a median of one-cycle. The most common non-haematological TEAEs included infusion related (IRR, n=5, 8%), and fatigue (n=6, 9.3%). All patients with IRRs recovered and continued to receive treatment. Only six (9.5%) patients experienced hyperthermia. Thrombocytopenia and neutropenia were the most frequently reported grade 3 or 4 TEAE (11 and 5% respectively). Planned interim efficacy assessment showed a response rate (defined as a Partial Response (PR) or greater) in 3/19 patients at the end of the first cycle and 4/19 at the end of the second cycle, and a clinically relevant response (Stable Disease (SD) or greater) at the end of the second cycle for 11 of 19 patients, thus meeting the planed futility criteria and enabling the trial to go forward. As per the 15thof May, among the 40 evaluable patients (that had received at least 2 treatment cycles or progressed within the first) the overall response rate (3) was 25%, with eight (20%) partial responses (PR) and two (5%) very good partial responses (VGPRs) after a median of two cycles (range 1-5). An additional seven patients (17.5%) obtained a Minimal Response (MR) according to the EBMT criteria (4). This is consistent with prior results. Updated results will be presented at the time of ASH. Conclusions: Daratumumab in combination with Dexamethasone is a safe treatment option with a favourable benefit/risk profile for the treatment of triple relapsed or refractory (Len, Pom and Bz) myeloma patients. 1. Stevenson GT. CD38 as a Therapeutic Target. Mol Med. 2006;12(11-12):345-6. 2. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with Daratumumab Monotherapy in Multiple Myeloma. N Engl J Med. 2015 Sep 24;373(13):1207-19. 3. Kyle R, Rajkumar S. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leuk Off J Leuk Soc Am Leuk Res Fund UK. 2009 Jan;23(1):3-9. 4. Bladé J,et al. Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. Br J Haematol. 1998 Sep;102(5):1115-23. Disclosures Boyle: Novartis: Honoraria; Pfizer: Honoraria; Takeda: Honoraria; Janssen: Honoraria. Leleu:Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria; TEVA: Membership on an entity's Board of Directors or advisory committees. Hulin:Amgen: Honoraria; Janssen: Honoraria; Bristol: Honoraria; celgene: Honoraria; takeda: Honoraria. Moreau:Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria. Fohrer:amgen: Consultancy; celgne: Consultancy. Decaux:SIEMENS: Honoraria, Other: supply of free light chain assays , Research Funding; The Binding Site: Other: supply of free light chain assays , Research Funding. Avet-Loiseau:celgene: Consultancy; amgen: Consultancy; janssen: Consultancy; sanofi: Consultancy. Attal:celgene: Consultancy, Research Funding; amgen: Consultancy, Research Funding; janssen: Consultancy, Research Funding; sanofi: Consultancy. Facon:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel and expense, Speakers Bureau.

Description: Introduction Multiple myeloma (MM) is characterized by a proliferation of plasma cells with a strong dependence on the bone marrow (BM) microenvironment. However, in some MM patients this proliferation escapes the BM resulting in extramedullary disease (EMD) with two types of involvement: 1) paraskeletal (PS) and 2) extramedullary (EM), involving either skin/lymph nodes (EMS) or organs (EMO). EMD is considered to be associated with poor prognosis. Autologous stem cell transplantation (ASCT) in MM is standard therapy in first line therapy in eligible patients, but only limited reports on outcome of EMD after ASCT exist. Methods Within the European Society for Blood and Marrow Transplantation (EBMT) registry, 4658 patients (female n=1898, male n=2760) who received upfront ASCT were reported between January 2005 and December 2014 with available data on EM involvement at time of diagnosis. 3802 patients had no EMD (MM group), while 677 had PS and 179 EM involvement, including EMS (n=68) or EMO (n=111). The median age of the patients was 59 years (range 22 - 77). The stage according ISS at diagnosis was I (n=1229), II (n=1174) and III (n=865). All patients received an upfront single (n=4250) or tandem (n=408) ASCT. Salmon and Durie classification stage B was seen more frequently in EM (31%), than in MM (17%) or PS (16%) (p〈 0.001). More EM had ≥ 2 different sites of involvement than PS patients (20% versus 4%, p〈 0.001). Tandem ASCT was applied to 15% in the PS group compared to 8% in the MM and 10% in the EM group (p〈 0.001). Primary end point was 5 year progression-free survival (PFS). Results At ASCT 18% of MM patients achieved a complete remission (CR) compared to 20% of PS and 12% of EM patients (p=0.058). MM and PS patients showed similar 5 year PFS (28% versus 29%, p= 0.74) in the univariate analysis with a median PFS of 31 versus 33 months. In contrast, EM patients had a significant worse median PFS (21.5 months) and 5 year probability (22%) than MM patients (28%) as well as PS patients (29%) (p〈 0.001). Five year probability of OS were higher in MM compared to PS (67% versus 63%, p=0.05) and to EM (67% versus 49%, p〈 0.001). Furthermore, the difference in 5 year OS between PS and EM involvement reached statistical significance (63% versus 49%, p〈 0.001). When analyzing PFS according to the number of sites involved, the median PFS in PS patients was 35 for 1 versus 24 months for ≥ 2 sites and in EM patients 24 versus 17 months (p=0.003). Other significant factors for worse PFS in the univariate analysis were: IgA-type (p〈 0.001), Salmon and Durie stage B (p〈 0.001), ISS II and III (p〈 0.001, respectively), while favorable factors were CR (p〈 0.001) and female sex (p〈 0.001). In a subanalysis comparing EMS and EMO, the median PFS was significantly worse for EMS than EMO (20 versus 25 months, p=0.024). Cox proportional hazards regression considering independent factors for worse PFS yielded: EM (HR 2.88, 95% CI 1.90 - 4.37), IgA (HR 1.31, 95% CI 1.15 - 1.48) as well as Salmon and Durie stage B (HR 1.26, 95% CI 1.06 - 1.51), while improved PFS was seen for CR (HR 0.47, 95% CI 0.36 - 0.61) and ISS I (HR 0.70, 95% CI 0.60 - 0.83). Conclusion This EBMT registry study demonstrates that EMD manifestation in patients with MM is an independent risk factor for worse outcome after ASCT. Within the EMD group, non-paraskeletal extramedullary manifestation, EMS and involvement of 2 or more sites resulted in worse PFS. Disclosures Leleu: TEVA: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Delforge:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Kröger:Riemser: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding.

Description: Background Philadelphia negative myeloproliferative or myeloproliferative/myelodysplastic neoplasms may evolve towards secondary acute myeloid leukemia (AML). The prognosis of such secondary leukemia is very poor. At present, there are only a few reports assessing the outcome of adult patients with a philadelphia negative myeloproliferative or myeloproliferative/myelodysplastic neoplasm in blast phase (MPN-BP) who received allogeneic stem cell transplantation (allo-SCT). Patients and Methods in this retrospective study, inclusion criteria were: (i) adult patients with a MPN-BP (ii) who received first allo-SCT (iii) between 2000 and 2010 (iv) irrespective of the stem cell source or conditioning regimen. MPN with

Description: Abstract 3921 Introduction: Hairy cell leukemia (HCL) is a rare hematologic disorder, and the place of emerging treatments, such as BRAF inhibitors, remains to be defined. We conducted a large, multi-center, retrospective survey in France to determine the frequency of malignancy in HCL patients (pts) and their families, and to analyze the long-term effects of the established purine nucleotide analogs (PNA) cladribine (C) and pentostatin (P). Methods: Physician members of the Société Française d'Hématologie were surveyed on their management of HCL pts over the past 30 years. Clinicians completed a form that collected data concerning personal and familial medical history of pts, with particular focus on hematologic malignancies, solid tumors, clinical and biological presentation at HCL diagnosis, therapeutic options, response to treatment, time to relapse, secondary malignancies and cause of death. Results: The survey included 36 French clinical centers and 487 HCL cases (mean patient age 59y; range 29–90y). In the centers surveyed, HCL diagnosis was established after examination of peripheral blood and/or bone marrow and by immunophenotyping. Solid tumors and hematologic malignancies were present before HCL diagnosis in 45 cases (9.2%). A further 38 pts (7.8%) with pre-existing cancers were diagnosed with HCL after a median time of 89mo (range 1–529mo). At diagnosis, three HCL pts presented with follicular lymphoma, monoclonal gammopathy of undetermined significance, or large cell B cell lymphoma. Four pts developed HCL within a median time of 33mo (range 30–38mo) after diagnosis of B-cell lymphoproliferative disorders. In 93 pts (19.1%), at least one family member developed neoplasia: solid tumors=75 pts (15.4%); acute or chronic hematologic malignancies=18 pts (3.7%) with one familial HCL case. Twenty-three pts (4.7%) received no treatment for a median follow-up of 32mo (1–293). Three hundred and forty-five pts (70.8%) received just one first-line treatment (C=68.1%, P=23.8%, interferon [IFN]=3.8%, other=4.3%), and 119 pts (16.6%) received two-to-seven lines of therapy. After first-line treatment, complete responses were observed in 365 pts (74.9%; P=85.1%, C=85.0%, IFN=61.1%). Median duration of response was 41 months (1–270; C=40.5mo [1–188; 234 pts], P=43.0mo [1–209; 80 pts], IFN=74mo [24–270; 13 pts], other=21mo [2–186; 15 pts]). After second line treatment, the median duration of response decreased to 33mo (1–261; 80 pts) (C=27mo [1–159; 39 pts], P=38.5mo [0–206; 24 pts]) and also tended to differ according to first-line regimen (Table). After third-line treatment, the median duration of response decreased again to 24mo (2–224; 24 pts) (C=46mo [2–92], P=20mo [2–166], other=22mo [2–224]). After 60 months follow-up (range 1–384mo), overall survival at 5 years was 95%. Twenty-nine pts (6%) had died (11 deaths were HCL-related), and a further 53 pts (10.9%) developed second malignancies (39 solid tumors and 14 hematologic malignancies). Second malignancies occurred 6 months after HCL diagnosis in 50 pts. Conclusions: This study highlights the high frequency of cancers in HCL pts and their family members, suggesting a role for genetic factors in the development of the disease. The survey also confirms the high efficacy of PNA, and we therefore need to be cautious in adopting innovative new therapies treatment such as BRAF inhibitors or immunotoxins into first-line care. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4761 Background Indolent lymphoma cannot be cured in elderly patients. Applied treatments therefore aim at reaching the best response with as little as possible adverse effects to ensure the best survival. Because of their toxicities, multiagent cytotoxic chemotherapies are usually not applicable to elderly patients. The addition of rituximab to combination chemotherapy has improved treatment outcomes of indolent lymphomas. We used our experience of high intermittent dose of Chlorambucil in CLL1 to control indolent lymphoma in combination with rituximab in elderly patients. The aim of this study was to evaluate, in a retrospective manner, the efficacy and toxicity of this strategy. Methods Patients aged over 65 years with an indolent lymphoma, at diagnosis or in relapse, were treated in our institution by the RCM regimen. They received as “induction” an association of Chlorambucil (12 mg/D for 4 weeks D1 to D28), Rituximab (375 mg/sqm D 1 and D8) and Methylprednisolone (24 mg/D for D1 to D28). Responders (Cheson criteria 1999) completed this schedule by five monthly maintenance cycles associating Chlorambucil (12 mg/D for 10 days) and Rituximab (375 mg/sqm on D1). Results Between 2005 and 2009, twenty two patients, 12 males and 10 females were treated with the RCM regimen, 14 at diagnosis and 8 at relapse [median number of previous line = 1 (1-4)]. The median age was 77 years (66-89). The diagnosis of lymphoma was marginal zone for 10 patients (8 nodal forms and two Malt), follicular for 5, classic form of mantle-cell for 4, small lymphocytic for 3. Eighteen patients were at Ann Arbor stage III-IV (82%), 14/21 had high level LDH (65%), 9/22 had a PS of 2 or more (41%). Low, intermediate and high aaIPI scores were found in 8, 8 and 6 patients respectively. A high tumour burden was observed in 18/22 patients (82%). Among the 22 patients, 16 finished the entire treatment plan, 4 stopped early in one case because of progression and in 3 cases for grade 3 toxic events (2 skin rashes related to Chlorambucil and 1 neutropenia). Two patients are still under treatment. Grade 3 toxicities were uncommon, involving 2 patients with neutropenia, 2 with skin rashes and 2 with infection (one septicaemia and 2 pneumonias). The overall response rate (ORR) was 90% (20/22) with 14 patients in CR (64%) and 6 in PR (27%). Two patients progressed during treatment. The aaIPI appeared as the best prognostic factor of response:, 13/16 patients (81%) with score 1 or 2 reached CR versus only 2/6 patients (33%) with score 3. With a median follow-up of 9 months (4-49) all patients but one are alive and the 14 patients in CR have not relapsed after 6 to 49 months. Conclusion High intermittent dose of Chlorambucil associated with Rituximab offers a promising high ratio of efficacy/tolerance in elderly patients with indolent lymphoma. 1 Pegourié-Bandelier B, Cancer 1995, 75 (12), 2853-61 Disclosures: Gressin: celgene: Consultancy.

Description: Introduction: Hairy-cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder with a favorable outcome thanks to treatment with purine analogues (PNA) like cladribine and pentostatin. Here, we updated the French national retrospective cohort of HCL after 10 years of follow-up, in order to evaluate the risk of second cancers in these patients. Methods: Data were collected up to June 2018 through a questionnaire sent to the members of the Société Française d'Hématologie, and centralized in the cohort database. We described the second malignancies observed during the follow-up, distinguishing second 'solid' cancers from second hematological malignancies. Then, using a Fine and Gray model, we performed a multivariate analysis in order to identify second cancer risk factors. Finally, to evaluate the excess of cancers in our cohort in comparison with the French general population, we calculated the standardized incidence ratio (SIR). Results: 279 patients (pts) from 19 centers were included in our retrospective cohort. The median age was 59 years old (range 29-88). 21% had an infectious disease at diagnosis, 23% had a familial history of cancer and 11% a personal history of cancer before HCL diagnosis. The median number of lines of treatments was 1 (0-7). PNA (cladribine or pentostatin) were the first therapeutic choice in frontline (75% of pts) and at relapse (69%). With a median follow-up of 127 months (2-413), the median overall survival for the overall study population was 328 months (95% CI 299-357) and the median relapse-free survival (RFS) was 136 months (95% CI 109-163). Pts treated with cladribine or pentostatin in first line had a statistically significant better RFS than pts treated with 'other' treatments (log rank test, p 〈 0.001). The 10-year cumulative incidence of relapse was 39% (95% CI 33-46). Pts who received treatments other than PNA in first line had a higher risk of relapse (Gray's test, p 〈 0.001). For pts receiving PNA in first and second lines, there was no difference in outcomes between those who switched PNA and those who did not. In this cohort, we observed 68 second malignancies during the follow-up: 49 solid cancers (most prevalent: prostate and non-melanoma skin cancers) and 19 hematological malignancies (most prevalent: monoclonal gammopathy of undetermined significance (MGUS) and myelodysplastic syndromes (MDS)). The median onset of second cancer, second solid cancer and second hematological malignancy from HCL diagnosis was 81 months, 99 months and 78 months, respectively. The median age at diagnosis of cancer, solid cancer and hematological malignancy was 70, 69 and 77 years old, respectively. Considering death as a competing risk, the 10-year cumulative incidence of cancer, solid cancer and hematological malignancy was 15% (95% CI 11-19), 11% (95% CI 7.2-15), and 5.0% (95% CI 2.8-8.2), respectively. In multivariate analyses, IFN treatment was associated with a decreased risk for all cancers (Fine and Gray regression model, subdistribution Hazard Ratio (sdHR) 0.53 (95% CI 0.29-0.97); p = 0.038), a familial history of cancer was a risk factor for solid cancers (sdHR 2.12 (95% CI 1.15-3.91); p = 0.017), a personal history of cancer was a risk factor for hematological malignancies (sdHR 3.47 (95% CI 1.14-10.55); p = 0.028). Even after excluding non-melanoma skin cancers and MGUS, there was an excess of cancers (SIR = 2.22), solid cancers (SIR = 1.81) and hematological malignancies (SIR = 6.67). Conclusions: In this updated real-world retrospective cohort with a long follow-up and most pts treated with PNA, we highlighted the importance and the excess of second cancers in HCL patients, in particular hematological malignancies. Figure Disclosures Paillassa: Janssen: Other: Bibliography board with young hematologists. Thieblemont:Roche: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria; Kyte: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Cellectis: Membership on an entity's Board of Directors or advisory committees. Hermine:AB Science: Membership on an entity's Board of Directors or advisory committees. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau. Troussard:Innate Pharma: 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Research Support; Sysmex: Other: Research Support.

Description: Abstract 890 Background: While, with the combination of ATRA and anthracycline-based chemotherapy, 90–95% of APL pts included in APL clinical trials achieve complete remission (CR), it has been suggested that the actual early death (ED) rate may be as high as 15–17%, many pts being unable to enter clinical trials (Park JH, Blood 2011, Lehmann S, Leukemia. 2011 ). In some cases, an important delay in starting ATRA was also incriminated in ED (Altman, Blood 2011). We assessed the early outcome of newly diagnosed APL pts diagnosed in 16 large French centers during a period of 5 years, included or not in a clinical trial. Methods: 16 French University hospitals retrospectively provided data on all their APL pts diagnosed between Dec 2006 and Dec 2011, included or not in APL 2006 trial, the only active French APL trial during that period, which randomly assessed the role of ATO and ATRA during consolidation treatment, after ATRA – anthracycline based chemotherapy induction, and which had no upper age limit for inclusions. Every effort was made to collect all cases, by checking all APL diagnoses made in the lab and including pts admitted directly to ICU or to departments other than that of hematology, to avoid any bias. Intervals between first blood count, hospital admission and ATRA onset were particularly analyzed. ED was defined as death within 30 days of admission, irrespective of its cause. Results: 355 cases of newly diagnosed APL were seen during that period: 52% men, median age 52 years (range 16 –87). 26% of the pts had WBC 〉10 G/L. 65.6% pts were included in APL 2006 trial and 34.4% not included. Reasons for non-inclusion in APL 2006 trial were: 32 patients refusing or unable to give consent (9%), 20 initial admissions in ICU (5.6%), 20 older age and/or comorbidities (5.6%), 8 previous cancer (2.3%), 11 contraindications to anthracyclines (3.1%), 5 other exclusion criteria (pregnancy, HIV, poor socioeconomic conditions) (1.4%), 2 deaths before ATRA onset (0.6%), 2 CNS bleeding at admission (0.6%) and 22 unknown reasons (6.2%). Pts not included were characterized by older age (median 62 vs 48 y, p 〈 0.0001) but a similar proportion of pts with high WBC (31% vs 24%,p=0.16). 20/33 (61%) pts aged ≥ 75 and 19/26 (73%) pts initially admitted in ICU were not included in APL 2006 trial. Median interval from first abnormal blood count to hospitalization was 〈 1 day (1 d and 〉 1 d in 20% and 22% pts, respectively), from hospitalization to ATRA onset 〈 1 day (1 d and 〉 1 d in 24.5% and 25% pts respectively) and from bone marrow aspirate to ATRA onset 〈 1 day ( 1d in 66%, 19%, 15% pts respectively), without significant difference between pts included and not included in APL 2006. 316 (89.8%) pts reached CR, 1 had resistant leukemia and 35 pts (9.9%) had ED. 8 of the 35 ED (2.2% of the whole population) occurred before ATRA onset. Causes of ED in pts who received ATRA were: differentiation syndrome (DS) (n=5), CNS bleeding (n=4), sepsis (n=7), myocardial infarction (n=2), multiple organ failure (n=4), uncertain (n=5). No significant differences in the incidence of ED were seen based on the various intervals analyzed (from first blood count to hospital admission, admission to ATRA onset, BM aspirate to ATRA onset). In particular, ATRA onset within 1 day of hospitalization was associated with ED rates of 9.4%, 7% and 8%, respectively (p=0.961). ED was seen in 3% (7/233) of pts included in APL 2006 trial and 23% (28/122) of non protocol pts (p 〈 0.0001), and the CR rate was 97% and 77% in APL trial and non protocol pts (p 〈 0.0001). In particular, in pts aged ≥ 75, the ED rate was 0% and 30% in protocol and non protocol pts, respectively (p=0.06). Still, overall, 16/26 (61.5%) of the pts admitted directly in ICU, 27/33 (82%) of the pts aged ≥ 75, and 77/92 (83.7%) of the pts with WBC 〉 10G/L achieved CR. Conclusions: (1) A large majority of APL pts are rapidly admitted to hospital and rapidly treated with ATRA in France, with an overall CR rate of 89.8%. (2) One third of the pts are not included in clinical trials, especially due to their age or critical condition, and their outcome is less favorable than that of protocol patients (77% versus 97% CR). On the other hand, 61.5% of the pts directly admitted to ICU and 82% of those aged ≥ 75 y achieved CR. (3) Our overall early death rate (9.9%) appears inferior to those published in several recent studies. Disclosures: No relevant conflicts of interest to declare.

Description: Background: High dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in multiple myeloma (MM) patients as upfront and salvage therapy. However, the safety and efficacy of ASCT in patients with renal insufficiency (RI) is controversial, which have led to an inconsistent arbitrary cut-off for creatinine clearance (CrCl) for performing ASCT. Here we analyzed prospectively the outcomes of MM patients with severe RI who underwent ASCT. Methods: We enrolled prospectively 50 newly diagnosed MM patients who had a serum CrCl of