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We report a randomized prospective phase 3 study (CLL7), designed to evaluate the efficacy of fludarabine, cyclophosphamide, and rituximab (FCR) in patients with an early-stage high-risk chronic lymphocytic leukemia (CLL). Eight hundred patients with untreated-stage Binet A disease were enrolled as intent-to-treat population and assessed for four prognostic markers: lymphocyte doubling time 10 U/L, unmutated IGHV genes, and unfavorable cytogenetics (del(11q)/del(17p)/trisomy 12). Two hundred and one patients with ≥2 risk features were classified as high-risk CLL and 1:1 randomized to receive either immediate therapy with 6xFCR (Hi-FCR, 100 patients), or to be observed according to standard of care (Hi-W&W, 101 patients). The overall response rate after early FCR was 92.7%. Common adverse events were hematological toxicities and infections (61.0%/41.5% of patients, respectively). After median observation time of 55.6 (0–99.2) months, event-free survival was significantly prolonged in Hi-FCR compared with Hi-W&W patients (median not reached vs. 18.5 months, p p = 0.864). In conclusion, although FCR is efficient to induce remissions in the Binet A high-risk CLL, our data do not provide evidence that alters the current standard of care “watch and wait” for these patients.

Abstract Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC) and confers a high lifetime risk of CRC estimated to be up to 60%. Colonoscopy is recommended every 2 years in LS patients above the 20–25-year-old age bracket, and every year when colonic neoplasia has been detected. Efficient chemoprevention has the potential to represent a cost-effective intervention in these high-risk patients and could allow a delay in colonoscopy surveillance. Several epidemiological studies have shown that regular use of low dose aspirin is associated with a 20 to 30% reduction in the risk of sporadic colonic adenomas and colorectal cancer regardless of family risk. However, in recent large randomized trials in specific populations, aspirin use showed no protection for colorectal cancer. A prospective randomized CAPP-2 trial evaluated the effect of aspirin use in LS patients. The primary analysis of this trial showed no significant decrease in CRC in LS patients under daily aspirin. However, a preplanned secondary analysis after an extended follow-up showed a significant reduced risk of CRC in the aspirin group in the per-protocol analysis. The real effect and clinical benefit of aspirin are still to be consolidated in this population. The AAS-Lynch trial—a prospective, multicentric, double-blind, placebo-controlled, randomized clinical trial—was designed to investigate if daily aspirin therapy, at a dose of 100 or 300 mg, would decrease the occurrence or recurrence of colorectal adenomas in patients under 75 years of age, compared with placebo. Trial registration ClinicalTrials.gov NCT02813824. Registered on 27 June 2016. The trial was prospectively registered.

In total, 279 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 10 years. Data were collected up to June 2018. We analyzed responses to treatment, relapses, survival, and the occurrence of second malignancies during follow-up. The median age was 59 years. In total, 208 patients (75%) were treated with purine analogs (PNAs), either cladribine (159) or pentosatin (49), as the first-line therapy. After a median follow-up of 127 months, the median overall survival was 27 years, and the median relapse-free survival (RFS) was 11 years. The cumulative 10-year relapse incidence was 39%. In patients receiving second-line therapy, the median RFS was 7 years. For the second-line therapy, using the same or another PNA was equivalent. We identified 68 second malignancies in 59 patients: 49 solid cancers and 19 hematological malignancies. The 10-year cumulative incidences of cancers, solid tumors, and hematological malignancies were 15%, 11%, and 5.0%, respectively, and the standardized incidence ratios were 2.22, 1.81, and 6.67, respectively. In multivariate analysis, PNA was not a risk factor for second malignancies. HCL patients have a good long-term prognosis. PNAs are the first-line treatment. HCL patients require long-term follow-up because of their relatively increased risk of second malignancies.

Summary Background Most patients with chronic lymphocytic leukaemia relapse after initial therapy combining chemotherapy with rituximab. We assessed the efficacy and safety of rituximab maintenance treatment versus observation for elderly patients in remission after front-line abbreviated induction by fludarabine, cyclophosphamide, and rituximab (FCR). Methods This randomised, open-label, multicentre phase 3 trial at 89 centres in France enrolled treatment-naive and fit patients aged 65 years or older with chronic lymphocytic leukaemia without del(17p). Eligible patients had an Eastern Cooperative Oncology Group performance status of 0–1 and adequate renal and hepatic function. Patients in response to complete induction treatment with four monthly courses of full-dose FCR with two interim rituximab doses on day 14 of cycles 1 and 2 (oral fludarabine [40 mg/m 2 per day] and oral cyclophosphamide [250 mg/m 2 per day] for the first 3 days of each cycle, rituximab at 375 mg/m 2 intravenously on day 0 of cycle 1 and subsequently at 500 mg/m 2 on day 14 of cycle 1, days 1 and 14 of cycle 2, and day 1 of cycles 3 and 4) were eligible for randomisation. Recovery from FCR toxicity and patient willingness to continue the trial were mandatory. We randomly assigned (1:1) patients to either receive intravenous rituximab (500 mg/m 2 ) every 8 weeks for up to 2 years or undergo observation, with a central computer-generated randomisation list using randomly permuted blocks of variable sizes. Randomisation was stratified by IGHV mutational status, the presence or absence of del(11q), and response level to induction treatment. The primary endpoint was progression-free survival, with the objective to assess the superiority of rituximab maintenance relative to observation. The final analysis was done in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug in the rituximab group and in all patients in the observation group. This trial is closed to accrual whilst continuing patient follow-up. The study is registered with ClinicalTrials.gov, number NCT00645606. Findings Between Dec 14, 2007, and Feb 18, 2014, 542 patients were enrolled, of whom 525 started FCR induction. Between June 10, 2008, and Aug 14, 2014, 409 (78%) patients were randomly assigned to rituximab maintenance (n=202) or observation (n=207). Four (2%) patients in the rituximab group did not receive the allocated treatment (progressive disease [n=1], adverse events [n=3]). After a median follow-up of 47·7 months (IQR 30·4–65·8), median progression-free survival in the rituximab group (59·3 months, 95% CI 49·6–not estimable) was improved compared with the observation group (49·0 months, 39·9–60·5; hazard ratio 0·55, 95% CI 0·40–0·75; p=0·0002). Neutropenia and grade 3–4 infections were more common with rituximab maintenance (105 [53%] of 198 patients vs 74 [36%] of 207 patients and 38 [19%] vs 21 [10%], respectively) during the study. The most common grade 3–4 infection was lower respiratory tract infection (24 [12%] vs eight [4%]). The incidence of second cancers, except basal cell carcinoma, was similar in both groups (29 [15%] vs 23 [11%]). Deaths were related to adverse events for 23 (11%) patients in the rituximab group and 16 (8%) in the observation group. Interpretation 2-year maintenance rituximab in selected elderly patients improves progression-free survival and shows an acceptable safety profile. Immunotherapy maintenance strategy is a relevant option in front-line treatment of chronic lymphocytic leukaemia, even in the age of targeted therapy. Funding French National Cancer Institute (INCa), Roche, Chugai.

Introduction In previously untreated, medically fit patients with chronic lymphocytic leukaemia (CLL) and no 17p deletion, there is current research interest in improving survival outcomes and potentially sparing some patients from the standard 6 cycles of fludarabine, cyclophosphamide and rituximab (FCR). The phase II ICLL-07 (NCT02666898) trial, conducted by the French Innovative Leukemia Organization (FILO), aimed to explore the efficacy of obinutuzumab and ibrutinib treatment induction for 9 months, followed by a minimal residual disease (MRD)-driven strategy. Methods Following assessment at Month 9, patients in complete response (CR) with bone marrow (BM) MRD ResultsBetween 10/2015 and 05/2017, 135 patients were enrolled. At Month 9, only 8% of patients reached CR with BM MRD Conclusion These findings from the ICLL-07 trial demonstrated that, in previously untreated, medically fit patients with CLL and no 17p deletion, treatment induction with obinutuzumab and ibrutinib followed by an MRD-driven strategy yielded a high rate of CR with BM and PB MRD Disclosures Salles: Roche, Janssen, Gilead, Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Educational events; Amgen: Honoraria, Other: Educational events. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cartron:Roche, Celgene: Consultancy; Sanofi, Gilead, Janssen, Roche, Celgene: Honoraria. Cymbalista:Sunesis: Research Funding; Roche: Research Funding; Janssen: Honoraria; Abbvie: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria. Le Garff-Tavernier:Alexion: Consultancy, Honoraria. Letestu:Alexion: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Roche: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: speaker fee, expert contracts. Feugier:janssen: Honoraria, Research Funding, Speakers Bureau; gilead: Honoraria, Research Funding, Speakers Bureau; abbvie: Honoraria, Research Funding, Speakers Bureau; roche: Honoraria, Research Funding, Speakers Bureau.

In patients with chronic lymphocytic leukaemia, achievement of a complete response with minimal residual disease of less than 0·01% (ie,1 chronic lymphocytic leukaemia cell per 10 000 leukocytes) in bone marrow has been associated with improved progression-free survival. We aimed to explore the activity of induction therapy for 9 months with obinutuzumab and ibrutinib, followed up with a minimal residual disease-driven therapeutic strategy for 6 additional months, in previously untreated patients.We did a single-arm, phase 2 trial in 27 university hospitals, general hospitals, and specialist cancer centres in France. Eligible patients were at least 18 years old and previously untreated, and had immunophenotypically confirmed B-cell chronic lymphocytic leukaemia; an Eastern Cooperative Oncology Group (ECOG) performance status score of less than 2; a Binet stage C according to IWCLL 2008 criteria or Binet stage A and B with active disease; no 17p deletion or absence of p53 mutation; and were considered medically fit. In the first part of the study (induction phase), all participants received eight intravenous infusions of obinutuzumab 1000 mg over six 4-weekly cycles and oral ibrutinib 420 mg once per day for 9 months. In part 2, after assessment on day 1 of month 9, patients with a complete response and bone marrow minimal residual disease of less than 0·01% received only oral ibrutinib 420 mg once per day for 6 additional months. Patients with a partial response, or with a complete response and bone marrow minimal residual disease of 0·01% or more, received 6 months of four 4-weekly cycles of intravenous fludarabine, cyclophosphamide, and obinutuzumab 1000 mg, alongside continuing ibrutinib 420 mg once per day. The primary endpoint was the proportion of patients achieving a complete response with bone marrow minimal residual disease less than 0·01% on day 1 of month 16 assessed by intention to treat (ITT). This trial is registered with ClinicalTrials.gov (number NCT02666898) and is still open for follow-up.Between Oct 27, 2015, and May 16, 2017, 135 patients were enrolled. After induction treatment (day 1 of month 9), 130 patients were evaluable, of which ten (8%) achieved a complete response with bone marrow minimal residual disease of less than 0·01% and were assigned to ibrutinib, and 120 (92%) were assigned to ibrutinib plus fludarabine, cyclophosphamide, and obinutuzumab. After minimal residual disease-guided treatment (day 1 of month 16), 84 (62%, 90% CI 55-69) of 135 patients (ITT population) achieved a complete response with bone marrow minimal residual disease of less than 0·01%. The most common haematological adverse event was thrombocytopenia (in 45 [34%] of 133 patients at grade 1-2 in months 1-9 and in 43 [33%] of 130 patients at grade 1-2 in months 9-15). The most common non-haematological adverse events were infusion-related reactions (in 83 [62%] patients at grade 1-2 in months 1-9) and gastrointestinal disorders (in 62 [48%] patients at grades 1 and 2 in months 9-15). 49 serious adverse events occurred, most frequently infections (ten), cardiac events (eight), and haematological events (eight). No treatment-related deaths occurred.Obinutuzumab and ibrutinib induction therapy followed by a minimal residual disease driven strategy is safe and active in patients with previously untreated chronic lymphocytic leukaemia. With longer follow-up, including assessing the evolution of minimal residual disease, if response is maintained, this strategy could be an option in the first-line setting in patients with chronic lymphocytic leukaemia, although randomised evidence is needed.Roche, Janssen.

Waldenstrom's macroglobulinemia is generally treated with alkylating agents, purine analogs and monoclonal antibodies, alone or in combination. We report the outcomes of 82 patients (median age 61 years) treated with the RFC combination. Twenty-five patients were treatment-naive. RFC was administered every 4 weeks, for a median of five cycles. At treatment discontinuation, the overall response rate was 85.4%. The responses improved after treatment discontinuation in 25 patients, with a median time to best response achievement of 10.8 months, raising the major response rate (PR, VGPR and CR) from 64.6% to 76.8%. With a median follow-up of 47 months, the median progression-free survival time had not been reached (67% PFS at 48 months) and was influenced by age and treatment status before RFC. Likewise, the median time to next therapy had not been reached. Two cases of myelodysplastic syndrome/AML and 3 cases of transformation to aggressive lymphoma occurred. Thirteen patients died. The 3-year overall survival rate was 90%. Long-lasting cytopenias occurred in 19 patients. The RFC combination thus gave a high response rate and durable responses, even in heavily treatment-experienced patients. The high incidence of long-lasting cytopenia might be reduced by giving fewer courses and thereby minimizing myelotoxicity. Am. J. Hematol. 91:782-786, 2016. © 2016 Wiley Periodicals, Inc.

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response.

Purpose To assess the effect of serous retinal detachment (SRD) on functional and anatomical outcomes in ranibizumab-treated patients with diabetic macular edema (DME). Methods All consecutive ranibizumab-treated patients with SRD were included in this retrospective study. For each patient with SRD, a patient without SRD with the same baseline best-corrected visual acuity (BCVA) was randomly included for adjustment on their baseline BCVA. All patients with SRD were included in group 1 (G1) and those without SRD in G2. The primary endpoint was the mean change in BCVA between baseline and month 12 (M12). Secondary endpoints were the mean change in central retinal thickness (CRT) between baseline and M12, injection number, and proportion of patients who gained/lost ≥15 letters. Results Seventy-eight eyes were included, 39 in each group. Baseline BCVA was similar in both groups (45.2 and 45.3 letters). Mean change in BCVA between baseline and M12 was not statistically different: 11 ± 12 letters in G1 and 12 ± 13 letters in G2 (P = 0.78). Baseline CRT was 650 ± 130 μm in G1 and 480 ± 79 μm in G2. Mean change in CRT was -235 ± 170 μm in G1 and -130 ± 96 μm in G2 (P = 0.013). Patients received 5.2 and 5.5 injections in G1 and G2 (P = 0.46). In group 1, 38.5% and 2.6% of patients respectively gained and lost ≥15 letters versus 41% (P = 0.1) and 5.1% (P = 0.1) in G2. Conclusions Similar BCVA gains were observed regardless of the presence of SRD. The higher visual gain usually observed in DME with SRD could be associated with a lower baseline BCVA.

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.

Purpose: The aim of this study was to assess the efficacy and safety of ranibizumab in patients with diabetic macular edema (DME). Methods: We conducted a retrospective analysis of consecutive patients with vision loss due to DME who were treated with ranibizumab. All patients received a loading dose of 3 monthly injections followed by re-treatments on an as-needed basis. The primary endpoint was the change in best-corrected visual acuity (BCVA) at 12 months. Secondary endpoints were the change in central retinal thickness (CRT) and the number of intravitreal injections (IVI) at 12 months. Results: One hundred and six eyes of 78 patients were included. BCVA changed from 48.3 (20/100) letters at baseline to 59.0 letters (20/63) at 12 months (p < 0.0001; mean gain: +10.7 letters), and 38% of the patients had a final BCVA >70 letters. CRT decreased from 519 µm at baseline to 355 µm at 12 months (p < 0.0001). The threshold of the first quartile of the baseline VA was 40 letters. Patients with a baseline VA >40 letters had a higher final VA of 66 ± 14 letters (20/50) versus 43 ± 18 letters (20/125) for patients with a baseline VA ≤40 letters (p < 0.0001). A mean number of 5.4 (3-10) IVI were administered. Conclusion: This study conducted in a clinical setting confirms the results of previous randomized trials. The final BCVA was mainly influenced by the baseline BCVA, which supports the utility of early DME treatment before patients experience a severe vision loss.

International audience; Elderly patients with chronic lymphocytic leukemia (CLL) are underrepresented in trials evaluating fludarabine, cyclophosphamide, and rituximab (FCR). We assessed four cycles of FCR with two additional rituximab doses on day 14 of cycles 1 and 2 in 194 untreated CLL patients \textgreater 65 years (median age 71.2) without del17p. Four FCR cycles were administered to 90.7% (176/194), with (n = 74) or without (n = 102) dose-delay and/or dose-reduction. A total of 50% grade 3/4 neutropenia occurred after each cycle. Only 6.2% cycles were associated with severe infection. Complete remission (CR) was achieved in 19.7%, and partial remission (PR) in 73.9% of patients. Minimal residual disease (MRD) was negative in 36.7%. Overall survival at 36 months was estimated at 87.4%. Oral FC and dose-dense rituximab is feasible and active in fit elderly CLL patients. However, myelosuppression is significant and frequent dose adaptations are required implying that these results cannot be generalized to unfit or frail elderly CLL

To date, the majority of trials on chronic lymphocytic leukemia (CLL) have focused on patients considerably younger than the median age of onset for CLL. As a result, no definitive treatment exists for elderly patients, especially less medically fit patients. Even today, most physicians consider chlorambucil to be an appropriate option for elderly CLL patients. Practices, however, have subsequently changed following the results of several Phase III trials. Given the potential of these new immunotherapy regimens, selecting the right treatment for elderly CLL patients is still challenging.

Achievement of CR with undetectable minimal residual disease (uMRD) may be associated with a longer survival in CLL, but BCR signaling inhibitors alone seldom allow reaching uMRD. We conducted a multicenter phase II trial aiming at exploring the efficacy of an induction treatment associating obinutuzumab and ibrutinib, followed by immunochemotherapy for patients who do not reach CR with uMRD. Previously untreated fit patients with active Binet stage A and B or stage C CLL, no TP53 mutation/deletion, CIRS score < 7 and ECOG 0 or 1 were eligible. Induction treatment consisted of 6 courses of obinutuzumab (1000 mg D1, D8, D15 for cycle 1 and D1 for cycles 2 to 6) along with ibrutinib 420 mg/d for 9 months. Assessment of response to induction was performed at month 9, including CT-scan, bone marrow (BM) biopsy, peripheral blood (PB) and BM MRD testing. Patients in CR with BM MRD < 0.01% (by 8-color flow cytometry) received ibrutinib alone for 6 additional months whereas all the other patients received 4 courses of fludarabine (F) + cyclophosphamide (C) and obinutuzumab along with continuous ibrutinib until month 16. Patients with stable or progressive disease were taken off study. Final evaluation of response was performed at D1 Month 16. The primary endpoint of this study was the rate of CR (according to IWCLL 2008 guidelines) with uMRD in BM at month 16 and the assumption that at least 30% of patients would achieve this goal at the end of the overall strategy. Between November 2015 and May 2017, 135 patients (89 males/46 females) were enrolled; 7% were Binet stage A, 67% stage B and 26% stage C. Median age was 62 years (range, 35-80). Genetic alterations included 26% del(11q), 19% trisomy 12 and 56% del(13q); 15% had a complex karyotype and 56% patients had unmutated IGHV status. Median Beta 2 microglobulin was 3.6 mg/L (1.5-7.5) and median GFR (Cockroft) was 81 mL/min (42-173). At Month 9, 92% patients had received the 8 planned infusions of obinutuzumab. Ibrutinib dosage was reduced in 4 patients and definitively discontinued in 3 of them (3.9%) due to AE (atrial fibrillation, atrial flutter and neutropenia). Fifty seven percent of the patients presented at least a grade (G) 3 toxicity during the first 9 months of treatment (neutropenia 24%, anemia 6% and thrombocytopenia 31%). One hundred and thirty patients were evaluable for response at M9 and 5 not evaluable (2 deaths: one sudden at M7 and one accidental at M8; one acute coronary syndrome; one listeria meningitidis and one acute pulmonary edema at day 1 cycle 1). In intention to treat (ITT), ORR was 100% with 41% of patients reaching CR (42% for evaluable patients) but only 12% had BM MRD < 0.01%. Therefore 88% of the patients were planned to receive FC and obinutuzumab treatment while continuing ibrutinib. At month 16, 115 patients were evaluable for response. In ITT, the CR rate was 69% (78% for evaluable patients) and 79% of patients had BM MRD < 0.01% (90% of evaluable patients). Overall, 62% patients achieved CR with BM MRD < 0.01% (ITT) and 70% evaluable patients did so. The IGHV mutational status did not impact the quality of response. During the trial second period (M9 to M16), 38% patients presented at least a G3 toxicity: neutropenia 24%, thrombocytopenia 15%, anemia 1.5%, febrile neutropenia 3%, gastrointestinal disorders 9.5% and cardiac events 2.4%. A total of 41 serious AEs were observed throughout the entire treatment duration: 9 cardiac events including 1 atrial flutter and 3 atrial fibrillations, 4 hemorrhagic events, 7 infections, 3 second cancers (2 basocellular carcinoma, 1 renal adenocarcinoma) and 2 deaths. In conclusion, this MRD-driven strategy given for a definite period of time leads to a very high rate of uMRD CR in previously untreated CLL fit patients without TP53 aberration and displays an acceptable security profile. To our knowledge, these results are superior to standard FC + rituximab (FCR) or any chemo-free regimen. We hypothesize that this very high rate of bone marrow undetectable MRD will translate in a prolonged PFS while discontinuing treatment. Disclosures Laribi: Novartis: Other: Grant and personal fees; Takeda: Other: Grant and personal fees; Teva: Other: Grant; Gilead: Other: Personal fees; Sandoz: Other: Grant; Roche: Other: Grant; Amgen: Other: Personal fees; Hospira: Other: Grant. Salles:Novartis: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Abbvie: Honoraria; Acerta: Honoraria; Amgen: Honoraria; Epizyme: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Roche: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Sandoz: Honoraria; Amgen: Honoraria. Cartron:Celgene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Sanofi: Honoraria; Gilead Sciences: Honoraria; Janssen: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cymbalista:Gilead: Honoraria; AbbVie, Inc: Honoraria; Janssen: Honoraria; Sunesis: Research Funding. Feugier:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Background Autoimmune cytopenia (AIC) are well-known complications of chronic lymphocytic leukemia, occurring in approximately 4 to 10% of patients. The management of CLL-associated AIC is not consensual and patient with uncontrolled AIC are systematically excluded from clinical trials. Few data evaluating the efficacy of BCR inhibitors on CLL-related AIC are available. If some preliminary data focusing on patients included in clinical trials with controlled AIC suggested that ibrutinib was able to control AIC, the duration of responses were unknown. Moreover, no data regarding the ability of idelalisib to control AIC have been currently reported. The aim of this study was to retrospectively analyze the outcome of CLL patients suffering from autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), Evans syndrome or pure red cell anemia (PRCA) and treated with ibrutinib or idelalisib. Results Forty-four patients from 15 FILO centers were included in this study. First kinase inhibitor (KI) was ibrutinib for 25 patients and idelalisib for 19 patients. Among the ibrutinib treated patients, diagnosis of AIC was AIHA for 16 patients (64%), ITP for 5 patients (20%), Evans syndrome for 3 patients (12%) and PRCA for one patient (4%). In the idelalisib group, 12 patients were treated for AIHA (63%), 6 patients for ITP (32%) and one patient for an Evans syndrome (5%). Most patients presented with adverse prognostic factors such as 11q or 17p deletion by FISH and unmutated IgHV. Most patients had previously been treated either for CLL progression, autoimmune cytopenia or both and median number of prior therapies was 1 (0 to 6). Before starting ibrutinib or idelalisib, 34 patients (77%) had a history of AIC and had previously received corticosteroid monotherapy (N=15), rituximab monotherapy (N=15), a combination of rituximab, cyclophosphamide and dexamethasone (N=23) or rituximab and bendamustine (N=15). At the time of KI initiation, 66% of patients were receiving concomitant AIC therapy, consisting in corticosteroids in 26 patients (59%) or TPO (thrombopoietin) receptor agonists in 3 patients (7%). Overall response rates (ORRs) to ibrutinib and idelalisib on AIC were 92% and 95% respectively, and were not correlated to the AIC type. On ibrutinib therapy, 87.5% of patients with AIHA and 100% of patients with ITP or Evans syndrome achieved at least partial response (PR). In the idelalisib group, the ORR was 92% for AIHA patients and 100% for patients with ITP or PRCA. Considering CLL, Ibrutinib ORR and bone marrow unconfirmed complete response (CR) were 100% and 24% respectively. ORR and BM unconfirmed CR on CLL were 95% and 37% respectively the idelalisib group. KI therapy allowed discontinuing corticosteroids in 86% of ibrutinib patients and in 67% of idelalisib patients. Fifteen patients (34%) of the whole cohort experienced progression of CLL, CAI or both during the follow-up. Among them, nine (20%) experienced relapses of the CAI, and all of them were AIHA. In the ibrutinib arm, 1 patient withdrew ibrutinib shortly after initiation because of uncontrolled AIHA and 2 patients experienced relapse of AIHA while on therapy. In the idelalisib group, treatment failed to control AIHA in one case, but for responding patients, no AIHA relapse was described during idelalisib treatment. Five patients experienced relapse of AIHA after idelalisib discontinuation. With a median follow-up of the entire cohort of 26.8 months, the estimated two years overall survival (2y-OS) of the whole cohort was 88%, while the estimated two years progression free survival (2y-PFS) were 75.3% for CLL and 65.1% for AIC. In the ibrutinib cohort, 2y-OS was 95% and 2y-PFS were 81% for AIC and 94.4% for CLL. In the idelalisib arm, 2y-OS was 80%. Median PFS was 19 months for AIC and 25.7 months for CLL. Conclusion Our results demonstrate that kinase inhibitors are able to induce long-term control of both AIC and CLL and represent new therapeutics options for patients with AIC associated with CLL. Disclosures Quinquenel: Jansen Cilag: Honoraria, Research Funding; Abbvie: Honoraria. Ysebaert:Roche: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

Everolimus displays antiproliferative effects on cancer cells, yields antiangiogenic activity in established tumours, and shows synergistic activity with paclitaxel in preclinical models. This study assessed the safety and the pharmacokinetic interactions of everolimus and paclitaxel in patients with advanced malignancies. Everolimus was dose escalated from 15 to 30 mg and administered with paclitaxel 80 mg m(-2) on days 1, 8, and 15 every 28 days. Safety was assessed weekly, and dose-limiting toxicity (DLT) was evaluated in cycle 1. A total of 16 patients (median age 54.5 years, range 33-69) were entered; 11 had prior taxane therapy for breast (n=5), ovarian (n=3), and vaginal cancer (n=1) or angiosarcoma (n=2). Grade 3 neutropenia in six patients met the criteria for DLT in two patients receiving everolimus 30 mg weekly. Other drug-related grade 3 toxicities were leucopenia, anaemia, thrombocytopenia, stomatitis, asthenia, and increased liver enzymes. Tumour stabilisation reported in 11 patients exceeded 6 months in 2 patients with breast cancer. Everolimus showed an acceptable safety profile at the dose of 30 mg when combined with weekly paclitaxel 80 mg m(-2), warranting further clinical investigation.

Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia and are increasingly used for other indications. Fluid retention, however, including pleural effusions, are a significant side effect of imatinib, the first-line treatment for chronic myeloid leukemia. We investigated pleural and pulmonary complications in patients treated with dasatinib, a novel multitargeted tyrosine kinase inhibitor, as part of clinical trial protocols. Of 40 patients who received dasatinib (70 mg twice daily) for imatinib resistance or intolerance, 9 (22.5%) developed dyspnea, cough, and chest pain. Of these nine patients, six had pleural effusions (all were exudates) and seven had lung parenchyma changes with either ground-glass or alveolar opacities and septal thickening (four patients had both pleural effusions and lung parenchyma changes). Lymphocytic accumulations were detected in pleural and bronchoalveolar lavage fluids in all patients except for one who presented with neutrophilic alveolitis. Pleural biopsies revealed lymphocytic infiltration in one patient and myeloid infiltration in another. After dasatinib interruption, lung manifestations resolved in all cases and did not recur in three of four patients when dasatinib was reintroduced at a lower dose (40 mg twice daily). Thus, lung physicians should be aware that lung manifestations, presumably related to an immune-mediated mechanism rather than fluid retention, may occur with dasatinib treatment.

Fludarabine (FDR) therapy gives a response rate of about 30% in previously treated patients with Waldenström's macroglobulinemia (WM). The combination of FDR and cyclophosphamide (Cy) has been shown to be effective in chronic lymphoproliferative disorders. We administered the combination of FDR (30 mg/m2 i.v. D1-D3) and Cy (300 mg/m2 i.v. D1-D3) to 49 patients. Median age was 64 years. The median hemoglobin, albumin, beta 2 microglobulin and immunoglobulin M (IgM) levels were 9.9 g/100 ml, 39.6 g/l, 3 mg/l and 24.7 g/l, respectively. In all, 14 patients (29%) had not previously been treated. FDR/Cy was administered every 4 weeks for a median of four cycles. In all, 38 patients (77.6%) had partial responses, nine had stable disease and two had progressive disease. After a median of follow-up of 25 months, six patients relapsed and two patients developed large-cell lymphoma. The median time to treatment failure was 27 months. The main toxicity was hematological. In all, 12 patients died, four from progression, one from large-cell lymphoma, three from infection and four from a second malignancy. Two factors negatively influenced overall and event-free survival, age65 years and IgM40 g/l. The FDR/Cy combination, therefore, gives a high response rate in WM, even in previously treated patients with factors of poor prognosis.

To decrease red blood cell (RBC) transfusion requirements during high-dose therapy (HDT) for hematological malignancies, we conducted a pilot study to assess the effect of recombinant human erythropoietin (rHuEpo) given during chemotherapy before HDT and autologous peripheral stem-cell transplantation (APSCT). The transfusion histories of 15 HDT and APSCT for hematological disease performed in 11 consecutive patients who received rHuEpo (10 000 U subcutaneously three times/week) were compared to those of 22 HDT and ASCT performed in 17 consecutive historical controls matched for hematological parameters. rHuEpo increased the hemoglobin (Hb) level from 10.3+/-2.3 g/dl at diagnosis to 12.9+/-2.2 g/dl at the time of HDT in 11 patients; no major adverse effects occurred. Compared to historical controls (95%, 21/22), RBC transfusion requirements were significantly lower for rHuEpo recipients (26%, 4/15) (P=0.00001) and rHuEpo responders (15%, 2/13) (P=0.000002). After HDT and APSCT, fewer RBC transfusions were needed: 3.3, 1.2 and 0.3 RBC units for controls, rHuEpo recipients and rHuEpo responders, respectively (P=0.006 and 0.00002). Therefore, rHuEpo should be administered before, and not after HDT and APSCT, to lower RBC transfusion requirements after HDT and APSCT.

Mantle cell lymphoma (MCL) is a distinct clinico-pathological entity with a poor prognosis. We have conducted a prospective study in patients with MCL to evaluate a therapeutic strategy in which CHOP polychemotherapy was followed by DHAP if CHOP failed to induce complete remission. Responding patients then proceeded to an intensification therapy with autologous peripheral blood stem cell transplantation (APBSCT). Twenty-eight consecutive patients with newly diagnosed aggressive MCL were included. After four cycles of CHOP regimen, two complete responses (CR) were obtained (7%) and 14 (50%), five (18%) and seven (25%) patients achieved partial (PR), minor (MR) and no response, respectively (one patient died from septic complications during CHOP induction). The two patients in CR after CHOP underwent intensification with TBI, high-dose cyclophosphamide-etoposide and APBSCT. The other twenty-five patients received DHAP and in this group a response rate of 92% (21 CR (84%), two PR (8%)) was observed. Two patients had progressive disease. The twenty-three responding patients received high-dose therapy (TAM8 regimen: TBI-cytarabine-melphalan) followed by APBSCT. One of the two partial responding patients achieved CR after TAM8. After a median follow-up of 47.6 months (range, 14-70), seven patients have relapsed. Our data confirm that: (1) CHOP regimen induces a low CR rate in MCL; (2) CHOP plus DHAP appears to be much more efficient and allows a large proportion of patients to proceed to high-dose therapy in CR; (3) consolidation therapy including TBI and high-dose Arac-C followed by APBSCT may improve event-free survival.

TPS9596 Background: Treatment options are limited for patients (pts) with locally advanced or metastatic cSCCs. Cisplatin-based combinations have some efficacy but their toxicity often prohibits their use, particularly for the elderly. New therapeutic options are needed. Tumors divert the programmed death receptor 1 (PD-1) pathway suppressing immune control. Pembrolizumab (MK-3475) is a high-affinity humanized monoclonal anti-PD-1 antibody. It leads to dual PD-1 ligand (PD-L1 and PD-L2) blockade that may reactivate the immune surveillance and elicit anti-tumor response. It has antitumor activity in several tumors including head and neck SCCs. Moreover, an efficacy of pembrolizumab in cSCCs has been reported recently in a series of 6 cases. Methods: CARSKIN (ClinicalTrials.gov, NCT02883556) is a French multicenter, open-label, nonrandomized phase 2 trial, designed to evaluate the efficacy and safety of pembrolizumab in 39 pts with unresectable and/or metastatic cSCCs, naive of chemotherapy and of EGFR inhibitors. Pembrolizumab is administered (200 mg IV Q3W) for up to 24 months or until disease progression or unacceptable toxicity. Eligible pts must undergo a baseline biopsy of the tumor prior to treatment for PD-L1 evaluation. Response is to be assessed at baseline, wk 9, 15 and 24, and thereafter Q12W by central radiology review per RECIST 1.1 and per modified RECIST v1.1. The primary objective is response rate (RR) at wk 15 per RECIST 1.1. Secondary efficacy objectives are to assess whether patients with PD-L1+ tumors have a better RR than the whole sample at wk 15 and to assess in the whole sample and in PD-L1+ pts, disease control rate (DCR) at wk15, RR at wk 24, best RR, overall survival (OS), progression free survival (PFS), duration of response / control and time to disease progression. A Simon optimal two-stage design will be used. Four responders among 19 pts will be needed in the 1st step to continue the trial. Overall 9 responses will be needed to conclude the effectiveness. Kaplan-Meier statistics will assess PFS and OS. Adverse events (AEs) will be assessed throughout the study and for 30 d thereafter (6 m for serious AEs) and graded per NCI CTCAE v4.0. Clinical trial information: NCT02883556.

Acquired methemoglobinemia is a rare but severe condition associated with oxidizing stressors, most notably medications. Although the symptoms can be life threatening, they usually respond promptly to exposure cessation and methylene blue injection. We describe the first case of methemoglobinemia associated with tetracaine lozenge use. A previously healthy 33-year-old man was admitted with fever, respiratory distress, cyanosis, and acute hemolysis. Physical findings and chest radiograph were normal. Low pulse oximetry readings contrasted with normal partial pressure of oxygen and calculated oxygen saturation. The methemoglobin level was 10.8%. The patient recovered with methylene blue injection and blood transfusions. He reported recent self-medication with tetracaine lozenges for a sore throat during a flu-like illness. No other cause of methemoglobinemia was found.

International audience; BACKGROUND:Although recent studies have demonstrated an improvement in the prognosis of critically ill cancer patients, little is known regarding the prognosis of patients with non-aggressive underlying malignancies. The aims of this study were to assess the prognosis of critically ill patients with chronic lymphocytic leukemia (CLL) and to evaluate risk factors for hospital mortality.METHODS:In retrospective mono-center cohort study, consecutive adult patients with CLL requiring ICU admission from 1997 to 2008 were included.RESULTS:Sixty-two patients of 67 years (62-75) were included. Median time interval between CLL diagnosis and ICU admission was 6.7 years (2.6-10.8). Nine patients (15 %) had stage C disease at the time of ICU admission, and seven patients (11 %) had Richter syndrome. Most ICU admissions were related to bacterial or fungal pulmonary infections (n = 47; 76 %). ICU, in-hospital, and 90-day mortality were 35 % (n = 22), 42 % (n = 26), and 58 % (n = 36), respectively. Only three factors were independently associated with in-hospital mortality: oxygen saturation lower than 95 % when breathing room air (odds ratio (OR) 5.80; 95 % confidence interval (CI) 1.23-27.33), need for vasopressors (OR 27.94; 95 % CI 5.37-145.4), and past history of infection (OR 6.62; 95 % CI 1.34-32.68). The final model did not change when disease-related variables (Binet classification, Richter syndrome, long-term steroids) or treatment-related variables (fludarabine, rituximab, or alemtuzumab) were included.CONCLUSION:Acute pulmonary infections remain the leading cause of ICU admission in patients with CLL. The severity at ICU admission and past history of infection were the only factors associated with hospital mortality. Neither disease characteristics nor previous cancer treatments were associated with outcome.

Introduction Patients with residual disease following initial treatment of chronic lymphocyticleukemia(CLL) withfludarabine, cyclophosphamide and rituximab (FCR) chemotherapy have reduced progression free (PFS) and overall survival (OS). The CLL6 RESIDUUM trial is a joint trial of the Australasian Leukaemia and Lymphoma Group (ALLG) and the French CLL branch of the French InnovativeLeukemiaOrganization (FILO) thatanalyzesthe role oflenalidomide(LEN) as consolidation therapy in patients following front-line treatment for CLL who do not enter minimal residual disease (MRD) negative complete remission. Methods CLL patients with CIRS score Results As of end of July 2016, data from 79 patients randomized on the study were analyzedfor the effects of consolidation treatment on blood and marrow MRD. Median duration from randomization was 488 days. There were 63 males and 16 females. Median age was 62 years (range 29 to 81). 37 patients were randomized to receive LEN, 42 to OBS .On the LEN arm 13, 3 and 21 patientsvs 12, 9 and 21 on the OBS arm were in CR, nodular PR and PR respectively at the time of randomization. There were 26 serious adverse events (SAEs) reported in 22 patients. 12 SAEs in 11 patients were attributed to LEN including pneumonia/chest infection (n=4), pulmonary infiltrate (1), prostatitis (1) second primary malignancy (SPM) (1), vomiting (1), neutropenia (1), tumorflare (1), acute kidney injury (1) and anal warts (1). There were 5 SAEs in the OBS arm comprising SPM (2), neutropenia (1), gout (1) and GuillainBarre syndrome(1). Peripheral blood samples were analyzedprior to consolidation and at 3, 6 and 12 months and every 6 months thereafter. MRD levels during consolidation were compared with pre-consolidation levels and categorized as increasing, decreasing, stable detectable or stable undetectable (Fig 1). MRD increased over the period of observation in 38% of patient on the LEN arm and in 62% of patients on the OBS arm (p = 0.032, Χ2). 10 patients (27%) in the LEN arm and 2 patients (5%) in the control arm had decreasing levels of MRD in the blood (p = 0.006, Χ2). There was no difference between consolidation treatments in the percentage of patients with stable blood MRD measurements, whether in the detectable or the undetectable range. The effect of LEN was most apparent in patients in PR at randomization where 5 patients (24%) taking LEN had increasing MRD in the blood compared to 15 patients (71%) on the OBS arm (p = 0.002, Χ2). Bone marrow MRD levels were assessed prior to consolidation and after 12 months in 9 patients in each arm of the study (LEN arm 2 CR, 1 nPR, 6 PR; OBS arm 4 CR, 1 nPR, 4 PR at randomization). Eight patients in the LEN arm and 2 patients in the OBS arm were observed to have a reduction in marrow MRD. There was a significant reduction between the 2 time points in the LEN arm (p=0.022 paired Wilcoxon test) but not in the OBS arm. Four of 9 patients in the LEN arm and 1 patient in the OBS arm achieved marrow MRD values below 10-4 after 1 year on trial. Conclusion LEN consolidation therapy for residual disease after FCR front-line therapy for CLL is associated with improved control of MRD in both blood and bone marrow. A large group of recently randomized patients will provide more data to determine whether these encouraging results will translate into improved progression free and overall survival. Figure 1 Percentage of patients on LEN and OBS arms with increasing, decreasing, stable detectable or stable undetectable MRD. Figure 1. Percentage of patients on LEN and OBS arms with increasing, decreasing, stable detectable or stable undetectable MRD. Disclosures Gottlieb: Indee: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees. Aurran:Janssen: Honoraria. Tam:Gilead: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Janssen: Honoraria. Letestu:Roche: Honoraria; Alexion: Honoraria. Levy:Roche: Honoraria; Gilead: Honoraria; Abbive: Honoraria; Janssen: Honoraria. Leblond:Roche: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Abbvie: Honoraria. Mulligan:GSK: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau. Cymbalista:Abbvie: Honoraria; Roche: Honoraria; Janssen: Consultancy, Research Funding; Gilead: Consultancy, Honoraria.

7505Background: A promising concept to improve outcome in CLL is maintenance with immunotherapy after induction with FCR to improve quality and duration of response. Methods: Treatment-naive, ≥ 65 ...

BACKGROUND: In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg. METHODS: A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n = 101) or high-dose imatinib 800 mg (400 mg twice daily; n = 49). RESULTS: At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P = .034), major cytogenetic response (MCyR) (53% vs 33%; P = .017), and complete cytogenetic response (44% vs 18%; P = .0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P = .028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P = .0012). CONCLUSIONS: After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib. Cancer 2009. © 2009 American Cancer Society.

We recently reported an increased incidence of cirrhosis in hepatitis C virus (HCV)-infected stem cell transplant (SCT) recipients. Here, we describe our experience in the treatment of these patients, which has been, to date, poorly reported in the literature. Among 99 HCV-infected HCT recipients, 36 had HCV-related liver lesions on biopsy requiring therapy. Owing to HCV treatment contraindications, only 61% of patients (22/36) could be treated. In all, 12 patients received more than one course of anti-HCV treatment if they had HCV RNA still detectable after the first course of treatment and no treatment contraindications. Combined therapy (pegylated interferon (IFN): n=9, or standard IFN: n=9, in combination with ribavirin) led to sustained virological response in 4/18 (20%) patients as compared to 2/20 (10%) in patients who received IFN alone. Hematological toxicity was more frequent with combined therapy. While anemia responded to erythropoietin and/or dose modification, thrombocytopenia usually led to treatment interruption (n=3). This study thus highlights the efficacy of combined therapy and emphasizes the fact that the undue safety concerns are not a problem when treating this particular population.

The WM1 study is a prospective randomized open-label study that includes patients with previously untreated Waldenstrom's macroglobulinemia (WM), splenic lymphoma with villous lymphocytes (SLVL), and non–immunoglobulin (Ig) M lymphoplasmacytic lymphoma (LPL) who have an indication for treatment. At registration, patients are categorized as having WM, SLVL, or LPL, and these cohorts are to be analyzed separately. The aim of the study is to compare the efficacy of oral chlorambucil at a dose of 8 mg/m 2 (6 mg/m 2 for those > 75 years of age) for 10 days every 28 days to a maximum of 12 cycles with oral or intravenous (I.V.) fludarabine at a dose of 40 mg/m 2 orally or 25 mg/m 2 I.V. (30 mg/m 2 orally or 20 mg/m 2 I.V. for those > 75 years of age) for 5 days every 28 days to a maximum of 6 cycles. Primary endpoints are response to therapy and duration of response; secondary endpoints are improvement in hematologic parameters, toxicity of therapy, quality of life, and survival. To detect a difference in response rate of patients with WM of 15%, assuming that the overall response rates will be 50% to chlorambucil and 65% to fludarabine, with a power of 80%, requires the sample size of each group to be 183, indicating the need for collaboration among a number of national investigator groups. As of February 2005, accrual to the study stands at 143. Registration, randomization, and data collection are entirely Internet-based (www.waldenstroms.org), and the study is organized by an international collaboration, with a planned interim analysis and an external data monitoring committee.

Peripheral cytopenias are common in patients with agnogenic myeloid metaplasia (AMM). They are an important cause of morbidity and mortality, and their treatment is difficult. We report on 4 patients with AMM and severe cytopenia treated with danazol (400-600 mg/ day). Three of them became independent of red blood cell (RBC) transfusion, while the other had a slight reduction in RBC requirement. In addition, correction of thrombocytopenia and disappearance of splenomegaly were observed in 1 and 2 patients, respectively. No side effects were observed. In our experience, danazol appears effective and safe in the subset of patients with AMM whose disease is mainly characterized by bone-marrow failure. These data warrant further studies to evaluate this treatment and explore its mechanism of action.

Summary A 49 year old man was medically treated, first in 1986 and then in 1988, for atypical primary pulmonary infection caused by Mycobacterium malmoense. Since no clinical or bacteriological improvement of both smear and culture was observed, upper right bilobectomy was performed in december 1988. Oral treatment with rifabutin, clofazimine, ethambutol and isoniazid was clinically and bacteriologically successful in May 1989. In 1990, Aspergillus flavus infection developed in a sequeleae cavity located in the posterior segment of the upper left lobe. To our knowledge the Mycobacterium malmoense-Aspergillus flavus association has not yet been described.

Evaluation of MRD after treatment has an increasing importance in CLL treatment. Recent studies have demonstrated that patients achieving MRD below 10-4 have significantly longer OS and/or PFS compared to subjects with positive MRD (Böttcher, JCO 2012). Additionally, in CLL patients treated by FC(R)-based regimen, 4-color flow MRD was found as effective as ASO RQ PCR for MRD evaluation down to the level of 10-4, but below that level, PCR was more sensitive (Böttcher, Leukemia 2009). The aim of our study was to investigate the sensitivity of 8-color Flow-MRD and compare it to ASO RQPCR for disease evaluation at post-treatment time-point. 140 patients with active disease were recruited in a randomized first-line phase II trial evaluating the benefit of the addition of a high-dose rituximab pre-phase to standard FCR (R-dense arm) as compared to standard FCR. Clinical response and MRD were monitored at 3 months after last cycle, Flow-MRD was performed in peripheral blood (PB) and bone marrow (BM), and RQPCR in blood only. IGH ASO RQPCR was performed in an EU-MRD laboratory according to EU-MRD guidelines. Results were expressed as 10-8, corresponding to undetectable MRD, when no specific signal was detected, 10-6 when positivity was detected below quantitative range for the patient, and specific number when residual disease was within the quantitative range. For Flow-MRD we have developed an 8-color 9-antibody panel, the analyses were performed in four centers using harmonization procedures. Flow-MRD was considered undetectable (u-MRD) when less than 10 CLL events were detected or if the percentage of CLL events was below the absolute limit of detection (LOD) of the technique established at 0.5x10-6on normal blood samples. Quantitative range was reached when at least 50 CLL events were detected (Rawstron, Leukemia 2012). 137 patients were randomized and analyzed for clinical response. Approximately 87% had MRD evaluation by Flow, ASO RQPCR or both. U-MRD was observed in 81 patients out of 121 tested by flow in blood (67%) and in 49/109 (45%) in marrow. Samples with u-MRD reached good median LOD of 0.7x10-5 and 10-5in PB and BM respectively. MRD results were concordant in PB and BM (undetectable or positive in both samples) in 84/109 patients. The discordant cases were all positive in BM and negative in PB suggesting a better sensitivity and/or informativity in marrow. Therefore, when considering as Flow-MRD positive the cases with positive MRD in PB and/or BM and as undetectable those with u-MRD in BM, Flow-CR rate was 43%. The 66 cases that were analyzed in PB using ASO RQPCR showed a global PCR-CR rate of 76.5%. Sixty patients were analyzed by both flow cytometry and ASO RQPCR in PB. Results were concordant in 49 patients (82%), either both positive (n=9) or undetectable (n=40), resulting in a good global agreement between the two techniques (Kappa coefficient: 0.50 [0.20-0.73]). The 11 cases with discrepant results are of interest as they highlight the importance of the limit of detection for interpretation of MRD results. Among the 7 patients with u-MRD by ASO RQPCR and positive Flow-MRD, 4 showed a median sensitivity of 5.10-5 by ASO RQPCR and a very low median positivity by Flow 0.0024%. Moreover, all these 7 patients had a positive Flow-MRD in BM. The last 4 discordant cases had negative Flow-MRD and positive ASO RQPCR. In 2 of them a poor LOD in Flow-MRD contrasted with a 10-5sensitivity of ASO RQPCR and positive Flow-MRD was found in BM for 2 of these patients. Finally, clinical response was evaluable in 123 patients with MRD results. Among 65 patients in CR or CRi, 16 (24.6%) were MRD positive and among 55 patients in PR or nPR, 29 (52.7%) were MRD negative. Our 8-color panel for MRD detection by flow cytometry in CLL is applicable for treatment evaluation. This work shows that lowering the limit of detection by one log renders the 8 color flow-MRD as sensitive as ASO RQPCR and that the exploration of bone marrow improves the performances of MRD detection. As previously observed using less sensitive techniques, MRD results do not superimpose clinical response. Finally, a longer follow-up will validate the clinical interest of a one-log gain of sensitivity in MRD detection for prediction of PFS and OS. Disclosures Cartron: Roche: Consultancy, Honoraria. Cymbalista:Roche: Honoraria.

Few reports are available on the treatment of patients with Waldenström macroglobulinemia (WM) and primary or secondary resistance to alkylating-agent-based regimens. From December 1993 through December 1997, 92 patients with WM resistant to first-line therapy (42) or with first relapse (50) after alkylating-agent therapy were randomly assigned to receive fludarabine (25 mg/m(2) of body-surface area on days 1-5) or cyclophosphamide, doxorubicin (Adriamycin), and prednisone (CAP; 750 mg/m(2) cyclophosphamide and 25 mg/m(2) doxorubicin on day 1 and 40 mg/m(2) prednisone on days 1-5). The first end point evaluated was the response rate after 6 treatment courses. Forty-five patients received CAP and 45 received fludarabine. Two patients died before the first course of chemotherapy. No statistical differences were observed between the 2 treatment arms with respect to hematologic toxicity or infections. Mucositis and alopecia occurred significantly more often in patients treated with CAP. Partial responses were obtained in 14 patients (30%) treated with fludarabine and 5 patients (11%) treated with CAP (P =.019). Responses were more durable in patients treated with fludarabine (19 months versus 3 months), and the event-free survival rate was significantly higher in this group (P.01). Forty-four patients died, 22 in the fludarabine group and 22 in the CAP group. There was no statistical difference in the median overall survival time in the 2 study arms. Fludarabine was thus more active than CAP in salvage therapy of WM and should be tested as first-line therapy in a randomized comparison with alkylating agents.

A randomized phase II multicenter clinical trial comparing the efficacy of fludarabine (FAMP) to that of the association of cyclophosphamide, doxorubicin and prednisone (CAP) in 92 patients with Waldenstrom's macroglobulinemia in first relapse or with primarily resistant disease, was conducted on the behalf of the 'Groupe Cooperatif Macroglobulinemie'. The main analysis of this study failed to demonstrate a clear cut benefit of FAMP in terms of overall survival (OS), although a significant benefit in terms of time to disease progression and event-free survival (EFS) was noted. In this rare disorder, where few randomized trials have been conducted, we took advantage of this trial to assess treatment differences while integrating quality of life considerations. We thus performed a quality-adjusted survival analysis, using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach. Four health states differing in terms of quality of life (QoL) were defined, namely treatment-related toxicity, treatment free of toxicity, no treatment or symptoms, and relapse. The average time spent in these health states (TOX, CT, TWiST and REL, respectively) were then weighted by utility coefficients reflecting relative QoL value according to that of TWiST and summed up giving the so-called Q-TWiST. No difference was found between randomized groups in terms of mean CT. Mean TOX in the two groups were similarly close except when considering alopecia as a relevant toxic event. By contrast, mean TWiST was 5.9 months longer in the FAMP group than in the CAP group (P = 0.006). Unsurprisingly, given the absence of difference in OS but the difference in EFS in favor of the FAMP group, mean REL was increased by 6.8 months in the CAP group (P = 0.047). As a result, benefit of FAMP in terms of average Q-TWiST only relied on the value of the utility coefficient attributed to REL (U(REL)), with a significant benefit when UREL ranged from 0 to 0.28, ie in patients undergoing poor QoL after relapse, which is likely.

A 23-year-old man, intensively treated for acute lymphoblastic leukaemia in relapse and with documented pulmonary aspergillosis, was admitted to the intensive care unit for acute respiratory failure. The diagnosis of invasive tracheal aspergillosis was made by bronchoscopy and biopsy. The lesions consisted of extensive necrotizing bronchitis with transmural and peribronchial extension associated with tracheal and bronchial obstruction due to the presence of pseudomembranes almost entirely composed of fungal hyphae. Despite treatment with amphotericin B and itraconazole, mechanical ventilation and bronchoscopy, the patient died 3 weeks later of massive bleeding.

Two successive studies comparing tazocilline (12 g piperacillin + 1.5 g tazobactam/ day) + aminoside (15 mg/k/day amikacin in the first trial, 3 mg/kg/d tobramycin in the second) to ceftazidime (3 g/day) + aminoside included 466 febrile episodes in profoundly neutropenic patients after chemotherapy (or chemo-radiotherapy) for hematological malignancies. Patients were treated for acute leukemia (72%), or autografted for non-Hodgkin lymphoma or myeloma (25%), few patients for solid tumors. The mean duration of neutropenia was 21 days ± 11 (92% > 7 days); 466 febrile episodes were analysed for intention-to-treat, and were attributed to bacteremia in 119 cases, to local infection in 178 cases, and were of unknown origin (FUO) in 169 cases. A majority of Gram positive strains (55.5%) was isolated at day 0. The 72 h apyrexia was obtained more often (51.6% of the cases) with Tazocillin + aminoside than with ceftazidime + aminoside (33.6%, p < 0.0001). This results was due to a better control of bacteremia (p = 0.03) and local infection (p = 0.006) with tazocillin + aminoside, but not FUO (p = 0.19). Identical results of both antibiotic associations were observed during the first course of antitumoral chemotherapy, but tazocillin was significantly superior for 72 h apyrexia when fever occurred during consolidation therapy (p < 0.0001) or relapse treatment (p = 0.006). Superinfections due to Gram positive strains and major infectious events (infectious deaths and retardations of underlying disease treatment due to infection) were less frequent when patients received tazocillin + aminoside (respectively p = 0.002 and p = 0.02). The initial empirical antibiotic association remained unchanged and lead to a persisting apyrexia in only 20.3% of the cases treated with tazocillin + aminoside, but this was significantly better than with the other association (9.5%, p = 0.02).

Introduction Patients with asymptomatic early Rai or Binet stage chronic lymphocytic leukemia (CLL) do not benefit from mono-chemotherapy. Therefore, clinical observation without treatment (watch&wait; W&W) has been the gold standard for the management of these patients. Chemoimmunotherapy with FCR improves the outcome of patients with advanced CLL, but its efficacy in early stage disease has not been investigated. Several clinical and biological variables identify those patients who have a high risk of an aggressive disease course and who might benefit from early interventions. Consequently, this trial was conducted to test the value of FCR treatment in patients with early stage, high-risk CLL. Methods This report represents the endpoint and safety analysis of a randomized German-French cooperative phase III trial comparing the efficacy of early versus deferred FCR therapy in treatment-naïve Binet stage A CLL patients with a high risk of disease progression. Risk assessment was performed using 4 prognostic markers: Lymphocyte doubling time 10 U/L, an unmutated immunoglobulin heavy chain variable region gene (IGHV) status, and presence of unfavorable cytogenetics (del11q, del17p, trisomy 12) by fluorescence-in-situ hybridization. Presence of at least 2 versus less than 2 of these factors defined “high-risk” versus “low-risk” CLL. High-risk CLL patients were further randomized to receive either 6 cycles FCR (HR-FCR) or to be followed by a W&W strategy (HR-W&W). Patients with low-risk CLL were observed only (LR-W&W). Results Between 2005 and 2010, a total of 824 patients was enrolled, 423 patients in 69 centers of the German CLL Study Group and 401 patients in 25 centers of the French Cooperative Group on CLL. The diagnosis of CLL needed to be established no longer than 12 months prior to enrollment and patients were required to present with previously untreated stage Binet A CLL at the time of inclusion. Overall, 800 patients (97.1%) were stratified, 201 of them categorized as high-risk CLL (25.1%). There was no significant difference between high-risk patients from the two study groups regarding common baseline characteristics (e.g., age, sex, comorbidity, immunophenotype) and the distribution of risk factors used for stratification. 100 out of 201 high-risk patients were randomized to receive FCR therapy (HR-FCR), while 101 patients were allocated to the HR-W&W arm. 18 out of 100 patients (18%) withdrew consent for FCR therapy before treatment was started. 71 (86.6%) of 82 treated patients completed ≥4 cycles. The most common of 228 CTC grade III/IV adverse events reported within 12 months after treatment initiation were hematotoxicity (73.2% of patients) and infections (19.5% of patients). Three patients (3.7%) developed fatal CTC grade V infections (2 septic bacteremias, 1 of them with pulmonary aspergillosis; 1 encephalitis). Out of 79 patients available for response assessment until month 12 after treatment start, 76 showed a complete or partial remission (ORR 96.2%), 2 patients had stable disease (2.5%) and 1 patient had progressed (1.3%). After a median follow up of 46 months (range 0-88 months), HR-FCR patients demonstrated a significantly improved event-free survival (EFS) compared to HR-W&W patients (median EFS not reached versus 24.5 months, respectively, P Conclusion This is the first randomized phase III trial investigating the efficacy of FCR chemoimmunotherapy in early stage CLL. So far, the study has revealed two major results: 1. A combination of clinical and biological factors can be used to identify early stage CLL patients who experience a rapid disease progression with unfavorable outcome, 2. FCR chemoimmunotherapy substantially improves event-free survival in early stage high-risk CLL. Disclosures: Langerbeins: Roche: travel grants Other. Cazin:roche: meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees; GSK: meeting invitation, meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees. Fischer:Mundipharma: Travel grants, Travel grants Other; Roche: Travel grants Other. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

Abstract 434 Introduction: The German CLL8 trial has demonstrated that addition of R to FC improves quality and durability of response in CLL (Hallek et al, 2010), which has led to the recommendation of FCR as first line therapy for fit patients. Although elderly patients were included in the CLL8 trial (up to 81 y-old), the median age of the cohort was 61 y, thus at least 10 y younger than median age at CLL diagnosis. The elderly population is underrepresented in clinical trials and it is still not clear how FCR should be applied in this subgroup. In December 2007, the French intergroup launched the LLC 2007 SA trial (NCT00645606) in which CLL patients aged > 65 y receive an induction with abbreviated FCR followed by randomization between observation or maintenance with rituximab. We now report the safety and efficacy of the induction part in the first 200 patients enrolled in this study. Patients and methods: Stage B or C previously untreated fit (CIRS ≤ 6, CCR ≥ 60 ml/min, PS ≤ 1) CLL patients aged > 65 y needing treatment (NCI criteria) were included. Patients with del17p and/or Matutes scoring < 4 were excluded. From these 200 first patients included, 6 were removed because of incorrect inclusion (n=4) or consent withdrawal (n=2). In total, 194 patients (included between Dec/07 and Feb/10) were analyzed. FCR consisted of four monthly cycles of oral FC (F 40 mg/msq/d and C 250 mg/msq/d, × 3d) and iv R (375 mg/msq d1 cycle 1, 500 mg/msq d14 cycle 1, d1 and 14 of cycle 2, and d1 of cycles 3 and 4). Response was assessed by NCI criteria. MRD analysis was done using 6-color FCM in PB and BM. No later than 90 d after the last FCR, patients were further randomized as per protocol. Disease outcome after randomization remains completely blinded to date. Results: The median age was 71 y (range 65–85) and 65% were males. 83% had CIRS between 0 and 3. Binet stage was B in 127 (65.5%) and C in 67 (34.5%). Median (n=143) Beta-2-microglobulin was 4 mg/L (range 2–8). Fifty-six % had unmutated IgVH and FISH revealed 18% with del11q, 15% with trisomy 12, and 57% with del13q. Karyotype (ODN+IL2-stimulated) was abnormal in 67%. Balanced and unbalanced translocations were seen in 16% and 17%, respectively. Complex (>2 abn) karyotype occurred in 14% of the patients. Toxicity: 167 (86%) received all four cycles of FCR. Only 4.6% and 3.2% of patients did not receive d14 rituximab at cycle 1 and 2, respectively. 158 patients (81%) could proceed to the randomization (the main reason for failure was insufficient marrow recovery). Dose delay (by ≥ 1 w) and dose reduction (by ≥ 25% of F and C) for cycles 2, 3, and 4 were 12% and 7%, 14% and 8%, 15% and 11%, respectively. Neutropenia g3/4 occurred after cycle 1, 2, 3 and 4, in 46% (19% g4), 50% (21% g4), 53% (29% g4), and 46% (26% g4) of the patients. G-CSF was given in 32%, 46%, 48%, and 52% of them after cycles 1, 2, 3, and 4. G4 thrombocytopenia occurred in less than 2% of the cycles. G3/4 anemia was seen in 11%, 7%, 6%, and 3% of the patients after cycle 1, 2, 3, and 4, respectively. G 3/4 infectious events occurred in 6.2%, 4.8%, 7.6%, and 6.2% of the patients after each of the 4 cycles. Seventy SAE (including 46 febrile neutropenia and/or documented infection) were declared in 53 patients during the induction and the period of recovery prior to randomization. In total, 6.3% of the 732 cycles were followed by febrile neutropenia or infection qualified as SAE. Six deaths (all infections) occurred during induction, corresponding to a 3.1% (6/194) death rate from immediate toxicity. Efficacy: Among 188 evaluable patients, complete responses (CR) were observed in 19.7%, nodular partial response (PR) in 2.7%, and PR in 73.9%, for an ORR of 96.3%, using stringent criteria. According to the updated guidelines of 2008 (Hallek), CR, CRi, and PR rates were 19.7%, 13.3%, and 63.3%, respectively. Conclusion: Four cycles of oral FC combined with 6 doses of R appear feasible in elderly patients with CLL; only 14% cannot receive the 4 courses and only 19% cannot proceed to randomization planned at day 90 post FCR4. Dose reduction and treatment interruption are unusual despite strict stopping criteria. Grade 3/4 neutropenia is frequent but rarely translates into serious infection. The response rate is high, and further analysis of MRD eradication is ongoing and will be presented. In conclusion, this approach could enable the safe administration of FCR to elderly fit CLL patients in first line. Long-term toxicity, occurring after randomization, will be scrutinized. Disclosures: Dartigeas: Roche: Consultancy. Van Den Neste:Roche: Consultancy. Leblond:Mundipharma: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria.

Abstract 1797 Introduction: The FCGCLL/MW and GOELAMS intergroup have conducted a multicenter phase III trial, CLL2007FMP, to evaluate the efficacy of FCCam versus FCR in previously untreated medically fit CLL patients. This trial was discontinued after randomisation of 165 patients for unacceptable toxicity in the FCCam arm. A sensitive 6-color flow cytometry technique was used to evaluate the response at month 9 (M9) in blood and bone marrow and to subsequently monitor minimal residual disease (MRD). Methods and patients: 178 medically fit patients (CIRS< 6 and creatinin clearance ≥ 60 ml/min), younger than 65 years old, were enrolled. 165 patients were subsequently randomized to receive six oral courses of FC (F: 40mg/m2 d1-3 and C: 250 mg/m2 d1-3; q 28 days) in combination with either R (n=83; 375 mg/m2 i.v. d 0 at first cycle and 500 mg/m2 d1 all subsequent cycles; q 28 days) or Cam (n=82; 30 mg s/c d1-3; q 28 days). Patients were stratified according to IGHV mutational status and presence of 11q deletion. Cases with 17p deletion were excluded. Clinical response was evaluated based on iwCLL classical criteria. We established a sensitive and specific approach for the evaluation of MRD, using a 6-color flow cytometry technique with 3 combinations, including characteristic markers and light chain expression. We determined the limit of detection (LOD) of the assay by studying normal blood samples, and LOD varied from 0.5 to 0.7×10−5, depending on the combination considered. Results: The overall response rate was 87.8% in the FCR arm compared to 85.5% in the FCCam arm (p: NS). CR rates were not significantly different between the two arms with 64.6% in FCR arm and 50.6% in FCCam arm (p=.08). At M9, the rate of undetectable MRD was significantly lower in bone marrow as compared to blood but neither in blood nor bone marrow did reach a significant difference between FCR and FCCam arms. MRD was undetectable in blood in 60.2% of patients (53% of patients in the FCCAm arm and 66.7% in the FCR arm (NS)). In bone marrow samples, MRD was undetectable in 33.7% of patients (25% of patients in the FCCam arm and 41.7% in the FCR arm (NS)). The results were similar when considering exclusively the patients who reached CR. Moreover, MRD was never found detectable in blood when undetectable in bone marrow at the same time point. Therefore, irrespective of treatment arm, the bone marrow sample appeared more efficient than the blood sample for the detection of a persistent residual disease. We next combined blood and bone marrow results to define immunophenotypic remission, we considered MRD at M9 as undetectable when undetectable in bone marrow and MRD as positive when detectable either in blood or bone marrow. The rate of immunophenotypic remission was significantly lower in the FCCam arm as compared to the FCR arm (p=0.03) with our sensitive technique but, interestingly, was no longer significant when using the classical threshold of 10−4 to assess MRD status. The number of best responders, identified by MRD negativity and clinical complete response was significantly higher with FCR than with FCCam (p= 0.029). MRD was again assessed in blood at month 12 and was undetectable in 36.8% of patients in the FCCAm and 41.7% in the FCR arm (NS). All cases with positive blood MRD at M9 remained positive at M12. Among the 21 cases with positive bone marrow MRD and undetectable blood MRD at M9, only 10 explorations in blood at M12 are available at the moment but 4 cases remained undetectable. Conversely, when MRD was undetectable at M9 in both blood and bone marrow, 16/18 remained undetectable at M12, corresponding to a positive switch rate of only 11%. Conclusion: In the era of combined immuno-chemotherapy with the goal of achieving the best response, the most sensitive MRD technique is warranted. The sensitivity of 6-color flow cytometry has proved useful to uncover the differences between the two treatment arms. In this study, the evaluation of MRD in bone marrow by 6-color flow cytometry is the most sensitive technique for the early evaluation of persisting residual disease. It may not be supplanted by MRD determination in blood at M12 for the precise assessment of the immunophenotypic remission rate. Studies including sequential determinations and MRD kinetics are ongoing to determine which interpretation threshold and time-points are the best predictors of progression-free survival. Disclosures: Leblond: Roche, Genzyme: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding.

Abstract 3900 Current treatment approaches in CLL aim at achieving the best clinical response without detectable minimal residual disease (MRD) in order to prolong the duration of response and potentially overall survival. Such a goal could be achieved by combining chemotherapy and monoclonal antibodies. This phase II trial was designed to evaluate the safety and the efficacy of alemtuzumab given as consolidation therapy after 3 courses of oral FC (F 40 mg/m2 and C 250 mg/m2 D1 to D3 every 4 weeks) in patients (pts) aged 65 to 70 years with previously untreated Binet stage B or C CLL. Pts who had achieved either complete response (CR) or partial response (PR) after FC were eligible for consolidation with alemtuzumab. Alemtuzumab was administered subcutaneously (SC) at the dose of 10 mg thrice a week for 8 consecutive weeks. CMV antigenemia was monitored every week and alemtuzumab should be discontinued in pts with more than 3 positive nuclei. Such stringent stopping rules for CMV reactivation, as well as the limitation of FC regimen to 3 courses and of the duration of alemtuzumab treatment to 8 weeks, were adopted in this trial targeting elderly patients in their first line treatment because of the severe infectious toxicities reported by others with similar strategies. MRD was evaluated by 6 color flow cytometry before, during and after alemtuzumab treatment and all samples were centralized in one center (RL & FC). From June 2004 to January 2008, 55 patients with advanced (stage B or C) fully annotated CLL have been recruited in 14 french centers. Response to induction is evaluable in 51 of them (suicide before FC 1 pt and missing data 3 pts). A CR was achieved in 18 pts (34.6%) and a PR in 22 pts (42.3%) for an overall response rate (ORR) of 77% after 3 courses of FC. FC regimen was discontinued in 6 pts (progression 1 pt, renal carcinoma 1 pt, neutropenia 2 pts, PRCA 1 pt, myocardial infarction 1 pt) and a stable disease was observed in 5 pts. All the responding pts except two of them (onset of breast cancer in one CR pt and of lung carcinoma in one PR pt) proceeded to alemtuzumab consolidation after a planned 2 month period of rest (median 63 days, range 33 to 152). Alemtuzumab treatment was fully completed in 29/38 pts (76%) while it has been stopped prematurely (mainly between the 6th and 8th weeks) in 9 pts (24%). CMV reactivation occurred in 8 pts (21%) but it was associated with systemic symptoms in only one case (febrile pneumonia). A grade 3–4 neutropenia was observed in 9 pts at some point during alemtuzumab treatment. Eleven of the 21 PR pts (52%) converted from PR to CR after alemtuzumab consolidation while 2 patients went down from CR to PR. Overall, 26 pts were in CR after the whole treatment strategy (FC followed by alemtuzumab) accounting for 51% of the entire cohort. Blood MRD could be assessed sequentially in roughly two thirds of pts. While all patients but one (33/34 pts) were MRD positive after chemotherapy and before alemtuzumab treatment, only 8/22 pts (36%) had detectable MRD at the sensitivity level of 10-4 after the end of alemtuzumab consolidation, and 12 out of the 25 assessed pts (48%) still had undetectable MRD at 6 months after the end of treatment. With a median follow up of 34 months (range 2 to 58), only 6 out of the 38 pts (16%) who received FC followed by alemtuzumab consolidation, had CLL disease progression. Five patients have died but only one from CLL (solid tumors 3 pts, stroke 1 pt). No serious delayed infectious complication was observed and two patients developed auto-immune cytopenia (AIHA 1 pt and ITP 1 pt). Because of the few number of events (disease progression) observed so far, no correlation between the duration of response and the MRD data could be done by now. In conclusion, three courses of FC only yielded a rather high response rate in previously untreated elderly CLL patients and a short (8 weeks) alemtuzumab consolidation course could thereafter be administered safely, leading to a high rate of PR to CR switches, a high proportion of patients with undetectable blood MRD after the end of treatment and durable responses. Disclosures: Cazin: LFB Biotechnologies: Honoraria. Cymbalista:Roche (d) Mundipharma (e) Genzyme (e): Honoraria, Research Funding.

Abstract 3951 Background: Polyneuropathy is the most frequent neurological complication in Waldenstrom macroglobulinemia (WM). Most patients have an insidiously progressive distal symmetric sensorimotor and ataxic neuropathy due to a monoclonal immunoglobulin M anti-myelin-associated glycoprotein (MAG). There is still no treatment reference today. Recent studies underline the interest of Rituximab (RTX) but its efficacy is not yet proven. In order to identify the interest of immunotherapy, we performed a retrospective study in 61 patients with anti-MAG over a period of 12 years. Methods: All patients underwent neurological, biological (anti-MAG antibodies, IgM serum) and electrophysiological examination before and after each treatment. Clinically, patients were considered to be improved if they had a decrease of at least two points on the INCAT sensory sum score and/or a decrease of 20 mm on the visual analogue scale and/or motor strength improvement by at least two MRC points in the ankle dorsiflexor. Biologically, response anti-MAG antibodies and IgM serum were considered to be improved if their level was diminished by half. Electrophysiological studies were performed using standard procedures. Results: A total of 61 patients were analyzed. The median age at onset was 64 years (range 33–84), median serum IgM concentration 4.6 g/L (0-17), median anti-MAG antibodies 49900 BTU (23000>70000), RANKIN score 1 (35 patients), 2(20 patients), 3(6 patients). Twenty-five patients had WM with lymphoplasmacytic cells bone marrow infiltration. None of the patients had criteria for therapy initiation according to the 2th international workshop except symptomatic or evolving neuropathy. In first line, 45 patients were treated with Chlorambucil (CBL) (8 improved, 28 were stabilised, 9 worsened), 16 patients were treated with RTX alone (9) or in combination (7) (11 improved, 2 were stabilised, 3 worsened). RTX gave a significant higher response rate compared with CBL (p=2×10-4). With a median follow up of 96 months, 15 patients treated with CBL relapsed. Only one patient treated with RTX relapsed but the median follow up was not reached (60 months follow up). In the CBL group, 15 patients were treated at relapse with RTX and 11 improved, 3 were stabilised, 1 worsened. The average time follow up of the 2nd response was 48 months. Twelve patients in failure were treated with RTX: 8 improved, 1 was stabilised, 3 failed with an average follow up of 48 months. There was no significant difference between anti-MAG antibodies level before and after treatment (p=0.64) in patients in response but a low IgM level was associated with response to treatment (p Conclusion: In first line, RTX alone or in combination is associated with a higher response rate than CBL. For patients who relapsed after CHL, patients favourably responded to RTX with an average time follow up of 48 months. IgM level is a prognosis factor (p Disclosures: Choquet: Roche: Consultancy. Leblond:ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees.

Abstract 2547 Introduction. Minimal residual disease (MRD) eradication in patients with chronic lymphocytic leukemia (CLL) treated by standard chemo-immunotherapy regimens correlates with improved outcome. However, there is limited information about the interest of negative MRD after allogeneic stem cell transplantation (allo-SCT). In this study we investigated whether blood phenotypic remission could impact post-transplant outcome in patients with CLL. Methods. We retrospectively included patients who underwent allo-SCT for CLL and with post-transplant MRD monitored by four or six-colour flow cytofluorometry in blood samples (sensitivity≥10−4). Prognostic impact was evaluated on overall survival (OS) and progression-free survival (PFS). Each of these parameters was evaluated according to the best response and to the 12 month-MRD status, using log-rank test. Results. Thirty-three patients from 4 hematology departments were included. Median age at transplant was 54 years (range, 41 to 66 years). The median number of prior chemotherapy regimens was 3 (range, 1 to 6) including autologous stem cell transplantation in 48% of the patients. Status at transplant was available in 27 patients and 11% of them had negative MRD, 26% haematological complete response (CR), 59.% partial response (PR) and 4% had refractory disease. Twenty-two patients (67%) received a reduced intensity conditionning regimen. Conditioning regimen included serotherapy (antithymoglobulin n = 10, alemtuzumab n = 1, rituximab n = 1) in 12 patients. Twenty-two patients (67%) were transplanted with HLA identical sibling donor. The median number of MRD evaluations after transplant was 5 (range, 1 to 23). Response to transplant: After transplant, 16 patients achieved negative MRD, 15 patients achieved haematological CR, 1 PR and 1 did not respond to transplant. Among the 16 patients with phenotypic remission, negativation of MDR was obtained before the cessation of immunosuppressive therapy for 15 of them (94%) and median time to negativation was 7 months (range, 2 to 20 months). In patients achieving phenotypic remission chronic GVHD rate was 75% versus 44% in patients with post-transplant detectable MRD. Post-transplant outcomes: With a median follow-up of 27 months, the 2-y OS and the 2-y PFS were respectively 84% and 53%. Cause of death (n = 8) was progression in 4 cases and transplant related mortality in 4 cases. Impact of phenotypic remission: The achievement of phenotypic remission (whatever the time of evaluation) correlates with better PFS: 2-y PFS was 85% in these patients versus 27% in the other patients (p = 0.012). Considering the 19 patients with MRD evaluation available at 12 months after transplant, 2-y PFS was 100% in 12-month-negative-MRD patients (n = 10) versus 17% in positive-MRD patients at that date (p = 0.003) No relapse was observed in the group of patients who achieved phenotypic remission at 12 months post-transplant (figure). Conclusion. These data suggest that achievement of post transplant negative MRD in patients with CLL is associated with a long-term control of the disease and better PFS. In our series, no relapse occurred in patients with negative MRD at 12 months post transplant. These results could lead to decrease immunotherapy and to administrate donor lymphocytes to patients with post-transplant persistent positive MRD. Disclosures: Leblond: ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Abstract 4625 CLL - Therapy, excluding Transplantation Acadesine induces cell death in B-cell chronic lymphocytic leukemia (CLL) cells in a dose-dependent manner. Acadesine enters B-cells where it is phosphorylated to ZMP, which induces apoptosis independently of ATM or p53. It is active in vitro against CLL cells from patients who have not responded to prior treatment with fludarabine and/or chlorambucil. A phase I/II open-labeled clinical study was designed to determine the safety and tolerability of acadesine given intravenously as a 4-hour infusion to patients with CLL. Part I is the dose escalation part of the study where patients receive a single dose of acadesine on Day 1 and are followed up to Day 22. In Part II, patients will receive up to 5 doses of acadesine at the maximum tolerated dose (MTD) identified in Part I over a period of up to 20 days. Patient population includes CLL patients with relapsed/refractory disease who have received one or more prior lines of treatment including either a fludarabine or an alkylator-based regimen. A patient is defined as having refractory disease if they fail to achieve less than a partial response (PR) according to the NCI working group guidelines, or relapse within the first 6 months after treatment after achieving at least partial response. Primary endpoints of the study evaluate the safety and tolerability of acadesine. Secondary endpoints evaluate the pharmacokinetics of acadesine and ZMP, and B and T-cell counts in peripheral blood as efficacy biomarkers. Twenty-one patients have been included to date, eighteen in Part I at doses of 50, 83.5, 139.5, 210 or 315 mg/kg, and three in Part II, with two doses at 210 mg/kg at days 1 and 4. Pharmacokinetic data showed acadesine is rapidly converted into ZMP inside blood cells. In part I, at single acadesine dose, the Cmax levels for ZMP in whole blood obtained at 315 mg/kg were similar to the ones obtained at the previous dose (210 mg/kg), suggesting that the saturation plateau was reached, which was confirmed by the PK modeling. In 5 patients treated with acadesine at 210 mg/kg and 315 mg/kg a decrease in absolute B cell count was observed, ranging from 6% to 54% with respect to the B cell count prior to acadesine administration. Reversible asymptomatic hyperuricaemia was observed in four patients in cohorts 1 to 3, probably due the metabolism of acadesine to ZMP and uric acid. Prophylactic allopurinol was used in cohorts 4 and 5 and it has significantly reduced the incidence of hyperuricaemia. Acadesine 315 mg/kg was the dose limiting toxicity (DLT) dose with 2 of 3 patients having DLTs-Tumour Lysis Syndrome (TLS) and clinically significant acute renal failure (CTCAE V3.0 Grade 3-chronic dialysis not indicated). We started Part II of the study, with two consecutive doses at 210 mg/kg (Optimal Biological Dose). Three patients have been included to date. No DLT nor grade 3 or 4 Adverse Events related to acadesine were observed, and in all of treated patients a decrease in absolute B cell count was observed ranging from 6% to 35% with respect to the B cell count prior to acadesine administration. In the following cohort, we will administer 5 consecutive doses of acadesine at 210 mg/kg, at days 1, 4, 8, 11 and 15. In conclusion, a MTD was found at one single acadesine dose. Two consecutive doses have already been tested without safety concerns and 5 consecutive doses are currently planned in part II of this ongoing study. Results for this cohort and additional safety, pharmacokinetics and efficacy data will be presented at the meeting. Disclosures: Saunders: Advancell: Consultancy. de Frias:Advancell: Employment. Campàs:Advancell: Employment.

Abstract 1757 Treatment of Waldenström's Macroglobulinemia relies on alkylator agents, nucleoside analogs and/or monoclonal antibody based therapies. We showed previously that combination of fludarabine and cyclophosphamide yields a 78% response rate (RR). We performed a retrospective study in 55 WM patients (pts) treated with RFC regimen in 10 French centers. The median age was 65 years (range: 34–79), the median IgM level measured by electrophoresis was 27.3 g/L (range: 6.5–64), the median haemoglobin level was 9.7g/dl (range: 3.7–14), the median platelet count was 174 × 109/L (range: 22–500), the median beta 2 microglobulin level was 3.4 mg/l (range: 1.7–9). In all, 40/55 pts had previously been treated with a median of 2 lines of therapy (range: 1–4), including 24 patients with relapsed disease and 16 patients with refractory disease. RFC regimen was given every 4 weeks and consisted in: Rituximab 375 mg/m2 IV Day 1, Fludarabine 40 mg/m2 per os Day 1 to Day 3, Cyclophosphamide 250 mg/m2 per os Day 1 to Day 3. 55 pts received the first cycle of RFC, and 52 received two or more cycles (median of 4 cycles, range 2–6). Main toxicity was hematological. No toxic death was observed.Response was assessed 3 months after the last RFC cycle according to response criteria agreed by the 3rd International Workshop on WM (Kimby, 2006), but delayed responses with improvement of the response occurring more than 3 months after treatment discontinuation were observed in 15 patients. The best response was evaluated in 51 pts (3 early discontinuation treatments, one progressive disease), including 26 partial responses (PR), 5 minor responses (MR), and 2 stable diseases (SD). Of note 18 very good PR/ near RC (VGPR) were observed (> 90% decrease in M-protein) . The overall response rate was 89%. Long lasting cytopenia was observed in 10 patients. In the untreated group one pt in failure had a Burkitt-like lymphoma, the other 14 pts are alive in response. In the previously treated group, 6 pts relapsed, one developed a large B-cell lymphoma. Three ASCT and 4 allogeneic SCT were performed in six patients. With a median follow-up time of 28 months, median time to treatment failure (TTF) was not reached, even in previously treated patients. There was not significant difference in the TTF duration in patients in VGPR compared with those in PR + MR.The median progression free survival time was not reached. Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) was observed in two heavily treated patients and 3 pts had a secondary solid cancer. In all, 48 pts are alive, 7 patients died (4 from progressive disease, 2 from secondary cancer, and 1 from Burkitt-like transformation). Conclusion: RFC combination even in heavily treated patients with poor prognostic factors gives a very high response rate (89%) with 33% of patients achieving at least a very good partial response with acceptable toxicity. The toxicity on the hematopoietic stem cell reservoir is a major concern. This combination could be offered to relapsed/refractory patients. In first line, the choice of this combination must be discuss, increased incidence of MDS/ AML after purine analogs, and impairment of stem cell mobilization having previously been reported by us and others. Because frequent delayed responses, a long follow-up with periodic electrophoresis is needed to assess the best response after RFC. Disclosures: Leblond: ROCHE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JANSSEN: Membership on an entity's Board of Directors or advisory committees. Tournilhac:MUNDIPHARMA: Membership on an entity's Board of Directors or advisory committees; GENZYME: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees. Choquet:ROCHE : Consultancy.

Abstract 3408 Poster Board III-296 The t(4;14)(p16.3;q32), leading to the ectopic expression of two potential oncogenes, the Multiple Myeloma Set Gene (MMSET) and the Fibroblast Growth Factor 3 (FGFR3), is found in 15% of patients with multiple myeloma (MM) and is associated with a very poor prognosis. We previously shown in patients under 65 years of age that High Dose Therapy followed by Peripheral Blood Stem Cell Transplantation (HDT-PBSCT) provides a high response rate (RR) but a very short median relapse-free survival of only 11 months. In addition, relapses are often aggressive and chemoresistant. Thus, more effective regimen is urgently needed. We prospectively studied 23 t(4;14) MM patients treated with 3 or 4 cycles of a combination of Bortezomib and Dexamethasone (VD) (n=4) or of Bortezomib, Adriamycine and Dexamethasone (PAD) (n=19) as induction treatment before HDT-PBSCT (Melphalan 200 mg/m2). T(4;14) was detected using real time quantitative PCR searching for IGH/MMSET and FGFR3 transcripts. RR, event-free survival (EFS) and overall survival (OS) were evaluated. Median age at diagnosis was 51 years (range, 33-64). Isotype was IgA in 12 (52%) patients. All patients had stage II or III MM. An elevated serum β2m level (>3.5 mg/L) was found in 14 (61%) patients, and a low haemoglobin (Hb) level ( Disclosures: No relevant conflicts of interest to declare.

Abstract 4549 Introduction Chronic lymphocytic leukemia (CLL) is the most common adult haematological malignancy in the Western world. It remains incurable and follows an extremely variable clinical course with survival ranging from months to decades. In those who become refractory to fludarabine based therapy, median survival is less than 1 year. Methods To identify data related to the clinical and economic sequelae of patients in routine clinical care diagnosed with refractory CLL, a systematic literature search of MEDLINE and EMBASE was conducted for the period January 1999-July 2009. The search terms used included incidence, prevalence, natural history, characteristics, clinical management, clinical outcomes, use of health care resources and was focused on patients with fludarabine refractory CLL also refractory to alemtuzumab (fludarabine and alemtuzumab refractory) or less suitable for alemtuzumab due to bulky lymph nodes (bulky fludarabine refractory). Supplementary checks were made of reference lists, particularly in review articles. Relevant conference proceedings for the period January 2006-July 2009 were also examined. Results The search of MEDLINE and EMBASE identified 102 articles of which 26 reported on the more general populations of patients with haematological malignancies, 61 on CLL and 15 on refractory CLL. Of those articles reporting data in relation to CLL (n=61), 49 described patient characteristics and outcomes, prognostic factors, diagnostic and treatment options, natural history of the disease, epidemiology, patient management and specific treatment outcomes and 12 review articles addressed areas such as prognostic factors and treatment options. Of those reporting on refractory CLL (n=15), one was a review article of novel agents and 14 were studies evaluating outcomes following salvage treatment with various pharmaceutical agents and other therapeutic interventions but mainly in patients refractory to fludarabine. Only one US study had evaluated patients who were refractory to both fludarabine and alemtuzumab or were bulky fludarabine refractory, examining response and survival following a variety of salvage treatments (Tam et al. Leukemia and Lymphoma 2007;48:1931-9). The search of conference proceedings identified 27 abstracts, 19 of which evaluated patients with CLL reporting on a range of topics including natural history and survival, prognostic factors and outcomes achieved with existing and experimental pharmaceutical interventions. Only two abstracts specifically reported on patients who were refractory to both fludarabine and alemtuzumab or were bulky fludarabine refractory, examining response rates following administration of a novel pharmaceutical agent (European Haematology Association Meeting 2009, abstracts 0494 and 0919). Conclusions There is very little data from clinical practice on clinical outcomes and none on economic sequelae for patients with double refractory or bulky nodal refractory disease. The lack of such data is likely to hinder the achievement of better outcomes for patients and the evaluation of cost effectiveness for newer agents. This lack of data to inform clinical practice and decision making has prompted the initiation of an observational study in five European countries with the objectives of characterising the current patterns of care, survival outcomes and resource utilization in double refractory and bulky nodal refractory CLL patients in Europe. The study, based on a retrospective chart review of approximately 250 patients, is currently underway in France, Germany, Italy, Spain and the UK. It is anticipated that the results, planned to be available by the end of 2009, will help to identify unmet clinical needs, quantify the clinical and economic burden in this particular population and contribute to the development of new treatment guidelines. Disclosures: Lévy: GlaxoSmithKline: Consultancy. Payne:GlaxoSmithKline: Consultancy. Wasiak:GlaxoSmithKline: Consultancy. Lis:GlaxoSmithKline: Consultancy.

Nucleoside analogs (NA) are used alone or in combination in low grade B-cell lymphoproliferative disorders for 20 years. The incidence of disease transformation (Richter syndrome: RS) and development of MDS/AML among patients (pts) with indolent B-cell malignancies receiving NA are still controversial. We have reviewed the crude incidence of RS and MDS/AML in 165 WM patients treated with 3 F-based regimens. Results: Retrospective Study 1 (Leblond J Clin Oncol 1998): F (25mg/m2 iv D1–5) in 71 WM pts in relapse/refractory treated with alkylator, median time from diagnosis (dg) to tt: 5.9yrs, median prior tt: 2 (1–4). Randomized prospective study 2 (Leblond Blood 2001) in 92pts in first relapse after alkylator: Arm 1: F (25mg/m2 ivD1–D5) (45pts) vs Arm 2: CAP (doxorubicine 25mg/m2 IV D1, cyclophosphamide 750mg/m2 IV D1, Prednisone 40mg/m2 D1–5) (45pts), median time from dg to tt: 3.9yrs. Retrospective study N°3 (Tamburini Leukemia 2005) in first-line WM (14pts) or relapse WM (35pts): F 30mg/m2 D1–3 by oral route + Cyclophosphamide (C) 300mg/m2 D1–3 by oral route, median time from dg to tt: 2.1 yrs. The incidences of MDS/AML and RS are shown in Table 1 Discussion: the crude incidence of RS varied from 6,6% to 8% and was not statistically different in the randomized prospective study N°2 between the two groups. However, the incidence reported in pts treated with only alkylating-based regimens was lower: 3/167(1.8%) (Facon J Clin Oncol1993) and 3/217 (1.4%) (Garcia Sanz Br J Hematol 2001) and could be explained by a F use as salvage treatment in the CAP arm. The impact of fludarabine on RS needs to be confirmed in larger prospective studies. The crude incidence of MDS/AML varied from 1.4 to 8.9% in pts treated with fludarabine alone and was 6% in pts treated with F+C. The incidence reported in pts treated with alkylating based regimens varied from 1% (2/167, Facon 1993, 3/217 Garcia-Sanz 2001) to 6% (3/46, Kyle Br J Hematol 2000,) and was not different. In other low grade B-cell malignancies, a higher incidence of MDS/AML has been reported in pts treated with analog-alkylator combination compared to F or alkylator alone (Morrison J Clin Oncol 2002, Bowcock Br J Hematol 2006, Tam Hematologica 2006). In our study, the rate was the same in the two populations. The impact of late effects, particularly second malignancies, need to be better evaluated in prospective studies, especially in young patients and clinicians should discuss the risk when recommending such therapy to pts. MDS/AML and RS incidences in the three studies Study N°, pts Median survival time from study Median follow-up time from study MDS/AML (N,%) RS (N,%) N°1 71 pts 23 mo 34 mo 1/71 (1.4%) 5/71 (7%) N°2- 92 pts 41mo( arm1), 45 mo (arm2) 34mo 4/45 (8.9%, arm1), 2/45( 4.5%, arm2) 3/45 (6.6% arm1), 2/45 (4.5%, arm2) N°3-49pts 64% at 60 mo 42 mo 3/49 (6%) 4/49 (8%)