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

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

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

Noninfectious manifestations-allergy, autoimmunity/inflammation, lymphoproliferation, and malignancies-are known to exist in many primary immunodeficiency diseases (PID) and to participate in prognosis.To obtain a global view on their occurrence, we retrieved data from a retrospective cohort of 1375 patients included in the French National Reference Center for Primary Immune Deficiencies (CEREDIH) for whom we had a 10-year follow-up since inclusion in the registry.These patients were followed for 10 years (2009-2018) by specialized centers in university hospitals. This study showed that 20.1% of patients without prior curative therapy (n = 1163) developed at least 1 manifestation (event) encompassing 277 events.Autoimmune/inflammatory events (n = 138) and malignancies (n = 85) affected all age classes and virtually all PID diagnostic groups. They were associated with a risk of death that occurred in 195 patients (14.2%) and were found to be causal in 43% of cases. Malignancies (odds ratio, 5.62; 95% confidence interval, 3.66-8.62) and autoimmunity (odds ratio, 1.9; 95% confidence interval, 1.27-2.84) were clearly identified as risk factors for lethality. Patients who underwent curative therapy (mostly allogeneic hematopoietic stem cell transplantation, with a few cases of gene therapy or thymus transplantation) before the 10-year study period (n = 212) had comparatively reduced but still detectable clinical manifestations (n = 16) leading to death in 9.4% of them.This study points to the frequency and severity of noninfectious manifestations in various PID groups across all age groups. These results warrant further prospective analysis to better assess their consequences and to adapt therapy, notably indication of curative therapy.

International audience; Dasatinib is a second-generation BCR-ABL1 tyrosine kinase inhibitor approved for patients with chronic myeloid leukaemia (CML). Dasatinib 100 mg per day is associated with an increased risk of pleural effusion (PlEff). We randomly evaluated whether therapeutic drug monitoring (TDM) may reduce dasatinib-associated significant adverse events (AEs) by 12 months (primary endpoint). Eligible patients started dasatinib at 100 mg per day followed by dasatinib (C)min assessment. Patients considered overdosed [(C)min ≥ 3 nmol/l) were randomised between a dose-reduction strategy (TDM arm) and standard of care (control arm). Out of 287 evaluable patients, 80 patients were randomised. The primary endpoint was not met due to early haematological AEs occurring before effective dose reduction. However, a major reduction in the cumulative incidence of PlEff was observed in the TDM arm compared to the control arm (4% vs. 15%; 11% vs. 35% and 12% vs. 39% at one, two and three years, respectively (P = 0·0094)). Molecular responses were superimposable in all arms. Dasatinib TDM during treatment initiation was feasible and resulted in a significant reduction of the incidence of PlEff in the long run, without impairing molecular responses. (NCT01916785; https://clinicaltrials.gov).

The effectiveness of tyrosine kinase inhibitors (TKIs) has made it possible to consider treatment discontinuation in chronic myeloid leukaemia (CML) patients that achieve an excellent response. However, a few of the patients included in the Europe Stop Tyrosine Kinase Inhibitors (EURO-SKI) trial reported musculoskeletal pain shortly after stopping TKIs, considered as a withdrawal syndrome (WS). To identify factors that may predispose to TKI WS, we analysed the pharmacovigilance declarations for the 6 months after stopping TKIs in a large cohort of CML (n = 427) that combined the French patients included in the STop IMatinib 2 (STIM2; n = 224) and EURO-SKI (n = 203) trials. Among these patients, 23% (99/427) developed TKI WS after stopping imatinib (77/373; 20·4%), nilotinib (12/29; 41·4%) or dasatinib (10/25; 40%). WS concerned mainly the upper body joints, and required multiple symptomatic treatments in 30% of patients. Univariate and multivariate analyses identified two risk factors: duration of TKI treatment [risk ratio (RR) = 1·68 (1·02-2·74)] with a 93-month cut-off time, and history of osteoarticular symptoms [RR = 1·84 (1·04-3·28)]. These findings confirm that WS is a TKI class effect. CML patients should be carefully screened before treatment initiation to identify pre-existent osteoarticular symptoms. Moreover, before TKI discontinuation, patients should be informed of the possibility of WS, particularly after a long treatment period.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

The STI571 prospective randomised trial (SPIRIT) French trial is a four-arm study comparing imatinib (IM) 400 mg versus IM 600 mg, IM 400 mg + cytarabine (AraC), and IM 400 mg + pegylated interferon alpha2a (PegIFN-α2a) for the front-line treatment of chronic-phase chronic myeloid leukaemia (CML). Long-term analyses included overall and progression-free survival, molecular responses to treatment, and severe adverse events. Starting in 2003, the trial included 787 evaluable patients. The median overall follow-up of the patients was 13.5 years (range 3 months to 16.7 years). Based on intention-to-treat analyses, at 15 years, overall and progression-free survival were similar across arms: 85%, 83%, 80%, and 82% and 84%, 87%, 79%, and 79% for the IM 400 mg (N = 223), IM 600 mg (N = 171), IM 400 mg + AraC (N = 172), and IM 400 mg + PegIFN-α2a (N = 221) arms, respectively. The rate of major molecular response at 12 months and deep molecular response (MR4) over time were significantly higher with the combination IM 400 mg + PegIFN-α2a than with IM 400 mg: p = 0.0001 and p = 0.0035, respectively. Progression to advanced phases and secondary malignancies were the most frequent causes of death. Toxicity was the main reason for stopping AraC or PegIFN-α2a treatment.

Background The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. Methods Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucemies Myeloides Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. Results Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. Conclusions This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.

BACKGROUND Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation. METHODS The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients. RESULTS The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others. CONCLUSIONS This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10. © 2017 American Cancer Society.

Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

International audience; To the Editor:Since the mid-1980s, continuous progress in genetics and genomics has accelerated the rapid identification of causative genetic variants leading to primary immunodeficiencies (PIDs; >300 genes),1 with the noticeable exception of B-cell disorders, such as common variable immunodeficiency (CVID). The identification of these mutations not only validates a clinical diagnosis but also is useful in several other respects (more accurate prognosis on phenotype/genotype correlation, targeted therapy, and genetic counseling). [...]

Tyrosine kinase inhibitors are considered as highly effective and relatively safe drugs for the treatment of chronic myeloid leukemia. If several side effects on short and long term are well known and described, their involvement in the development of carotid stenosis remains unclear. Here, we describe a case of carotid stenosis in a patient receiving tyrosine kinase inhibitors and discuss the current literature. Keywords: Case report, Chronic myeloid leukemia, Tyrosine kinase inhibitor, Carotid stenosis

Background: Tyrosine kinase inhibitors (TKIs) are able to induce, in some chronic myeloid leukemia (CML) patients in chronic phase (CP), long-term molecular response 4.5 (MR4.5) and several studies have now demonstrated that TKIs could be safely discontinued in those patients with a Treatment-Free Remission (TFR) rate reaching ~50%. The French CML group had recently demonstrated that a failure of the first TKI discontinuation attempt does not preclude a 2nd successful attempt (RE-STIM study, Legros et al. Cancer 2017). Methods: The RE-STIM study is a national observational multicentre study collecting all cases of 2nd TKI discontinuation attempt of regardless the type, the duration of TKI, the duration of MR4.5 and the reason of discontinuation. CP-CML Patients in failure of a 1st attempt, had to recover a 2nd sustained MR4.5 on TKI to be eligible for this new analysis of the enlarged database (n=106). Loss of MMR loss was the trigger for therapy re-introduction. Results: At the time of analysis (1st June 2019), 106 patients (median age: 55 years (range: 25-81 years)) were included with 41 months (2-131) of follow-up after 2nd discontinuation. Fifty males and 56 females were enrolled. The Sokal risk score was low in 45%, intermediate in 26.5%, high in 20% and unknown in 8.5% of patients. The majority of patients (95%) were treated with imatinib as first-line, and the others with a 2nd generation TKI. The median total time on TKI prior to a 2nd discontinuation was 104 months (range: 38-235) and the median duration of a 2nd MR4.5 prior to a 2nd discontinuation was 68 months (range: 20-176). After a 1st discontinuation attempt, the reason for TKI re-challenge was in majority a loss of MMR (66%), a loss of MR4.5 in 33% of patients (missing data in 1%). The TFR rates after a 2nd discontinuation attempt were 44.3% [95% CI 35.48-55.41] at 24 months, 38.5% [95% CI 29.65- 50.09] at 36 months and 33.2% [95% CI 24.31- 45.39] at 48 months. In univariate analysis, we failed to find any association between TFR and: age, gender, Sokal score, prior exposure to IFN, TKI in combination versus monotherapy, TKI type, TKI treatment duration and uMR4.5 duration before the 1st and 2nd discontinuation attempts, and type of molecular relapse after the 1st discontinuation attempt (MR4.5 versus MMR loss). However, the speed of molecular relapse after the 1st TKI discontinuation remains a factor significantly associated with outcome. In patients who remained in uMR4.5 at 3 months after the 1st discontinuation, the TFR rate at 48 months was 53% [95% CI: 35.32-79.31] and 26% [95% CI: 16.88-40.28] for others. Another factor significantly associated with outcome is the TKI-free duration after the 1st attempt (Figure). The TFR rate at 48 months was 45 % [95% CI: 28.64- 69.62] in patients who remained without treatment more than 6 months after their 1st attempt and 27% [95% CI: 17.57- 41.34] for others. All patients are alive at last follow-up except 2 who died from CML-unrelated reasons. One patient developed a sudden blast crisis at 4 years from 2nd discontinuation. The last previous molecular biology 3 months before transformation was MR4. In patients in TKI re-challenge (n=63), median TKI-free duration was 6 months (2-64), 55% of patients regained their MMR within 3 months (0-35) and 41% regained MR4.5 within 5 months (2-53). Conclusions: This larger cohort confirms that TKIs could safely and successfully be discontinued a 2nd time in CP CML patients despite a 1st failure. The speed of molecular relapse after the 1st TKI discontinuation and TKI-free duration remain major factors significantly associated with TFR outcome. Figure: TFR according TKI-free duration after the 1st attempt of discontinuation Figure Disclosures Legros: Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding; Novartis: Honoraria. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Etienne:BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Rea:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Incyte Biosciences: Honoraria. Guerci:INCYTE: Consultancy, Honoraria. Huguet:Incyte Biosciences: Honoraria; Novartis: Honoraria; Servier: Honoraria; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Coiteux:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

The combination of 2GTKI+pegylated IFN-α (Peg-IFN) is an attractive approach for first-line treatment of CP CML, inducing high rates of deep molecular responses in phase II trials. Thus, we evaluated nilotinib (NIL) alone versus NIL+Peg-IFN in newly diagnosed CP-CML patients (pts) in a randomised phase III trial (PETALs, EudraCT 2013-004974-82). Newly diagnosed CP CML pts ≤65 y, without prior history of arterial occlusion were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone for 30 days (M-1→M0) 30 μg/wk as priming, prior to NIL 300 mg BID + Peg-IFN 30 μg/wk 2 wks, upgraded to 45 μg/wk thereafter, for up to 2 y (M0 to M24, arm B) followed by NIL alone for 4 more years unless pts enter treatment-free remission (TFR). The primary endpoint is the rate of MR4.5 by 1 y. As a secondary endpoint, pts reaching MR4.5 ≥2 y are allowed to stop NIL and enter a TFR phase in both arms. The trigger for treatment resumption is loss of MMR. All molecular assessments are centralised, quantifications are expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Two hundred pts were randomized (99 in A, 101 in B), 130 M and 35 F in each arm, median age of 46 (18-66) y. Median follow-up is 43.8 (34.3-55.9) Mo. Results are analysed in intention-to-treat. Sokal and EUTOS LTS scores were H in 25% and 2.5%, Int. in 33% and 16.5% and L in 42% and 81% pts respectively equally balanced. Median age is 46 (18-66) y, 18 pts (9%) had ACAs, all pts have a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (in B) and 88% of pts in A and 90.4% of pts in B at M1. CCyR rates at M3 were 63% vs 75% in A and B (p=ns), and BCR-ABL1 ≤1% at M6 were 87% in A vs 93% in B (p=ns). By M12, the rates of MMR were 68.1% vs 70.1% (p=0.44), MR4 were 34% vs 47.5% (p=0.041), MR4.5 were 15.9% vs 21.5% (p=0.049), MR5 11.7% vs 23.71% (p=0.023), in A vs B respectively. By M36 the rates of MMR were 83% vs 86.6% (p=0.31), MR4 were 70.2% vs 71.13% (p=0.50), MR4.5 were 37.2% vs 49.5% (p=0.05), MR5 33% vs 42.3% (p=0.12), in A vs B respectively The overall cumulative incidence of MR4.5 is superior in B (54.6 [43.7-65.5]%) vs A (44 [31.5-54]%) close to significance (unilateral Fisher test, p=0.05, see Figure). Seven patients were mutated by Sanger in A (5 Y253, 1 E255K, 1 T315I) vs 2 in B (2 T315I). One pt (A) progressed toward AP and then myeloid BC with a Y253H mutation, is still alive in CMR on Ponatinib. Twenty nine (29%) pts were withdrawn from study in A (toxicity 9, cancer 3, resistance 14, investigator decision 2, lost for FU 1) vs 26 (26%) pts for B (toxicity 13, resistance 8, investigator decision 5), 1 pt died from cervix cancer (A). Median overall doses of NIL delivered by M36 were 600 mg/d in both arms (p=ns). The median overall dose of Peg-IFN delivered in B by M24 was 37.5 mg/wk. The overall rate of grade 3-4 hematologic toxicities was 22%; with 2% and 7% thrombocytopenia, 4% and 6% neutropenia, and 1% and 1% pancytopenia in A vs B respectively. Major grade 3-4 non-hematologic toxicities consisted in 9% of cardiac disorders in A (2 coronaropathies, 1 myocardial infarction, 2 thoracic pains, 2 atrial fibrillation, 1 bradycardia, 1 palpitations, 1 pericarditis) vs 8% in B (2 coronaropathies, 1 myocardial infarction, 3 atrial fibrillation, 1 palpitations, 1 pericarditis), 4% vascular disorders in A (1 thrombophlebitis + PE, 1 transient ischemic attack, 1 PAOD, 1 carotid stenosis) vs 3% in B (1 thrombophlebitis, 1 PAOD, 1 transient ischemic attack). Three % of gastro-intestinal disorders were observed in A (2 pancreatitis, 1 anal fissure) vs 6% in B (2 pancreatitis, 1 anal fissure, 1 abdominal pain, 2 cholecystectomies); 5% auto-immune disorders in B (1 recurrent pericarditis, 2 hemolytic anemia, 1 ITP, 1 thyroiditis); 5 and 8 pregnancies (2 pts + 3 partner Arm 1, 3 pts + 5 partner Arm B), despite recommended contraceptive methods. Secondary tumours were diagnosed in 4% (1 breast, 1 cervix, 1 thyroid, 1 neuroendocrine) in A vs 2% of pts (1 neuroendocrine and 1 testis) in B. Of note 8% psychiatric episodes were reported in B pts (2 unsuccessful suicide attempts), vs 2% in A. We observed 9% lipase elevations in A, 6% in B, 2% cholestatic episodes in A, 6% in B; 3% of transaminase elevations in A vs 2% in B. Infections were detected in 3% A vs 7% in B. The combination of NIL + Peg-IFN seems to provide somewhat higher MR4.5 rates by M36 in newly diagnosed CP CML pts without inducing significant higher toxicities than NIL alone. Whether this will translate in higher TFR rates is under evaluation. Final updated results at M36 will be presented Disclosures Nicolini: Sun Pharma Ltd: Consultancy; Novartis: Research Funding, Speakers Bureau; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Huguet:Servier: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Charbonnier:Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Legros:Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Incyte Biosciences: Honoraria, Research Funding; BMS: Honoraria. Coiteux:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cony-Makhoul:BMS: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Incyte Biosciences: Honoraria, Speakers Bureau; Novartis: Consultancy. Roy:Incyte Biosciences: Consultancy. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Quittet:Novartis: Honoraria, Speakers Bureau. Ame:Incyte Biosciences: Honoraria, Speakers Bureau. Rea:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Honoraria; BMS: Honoraria. Dulucq:Novartis: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Mahon:Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. OffLabel Disclosure: Pegylated Interferon alpha 2 a is not licensed in this setting

Background : Providing achievement and sustainability of deep molecular responses (DMR), patients (pts) taking tyrosine kinase inhibitors (TKI) against CML may discontinue therapy. The STOP 2G-TKI observational study showed that dasatinib and nilotinib could be safely stopped and prior suboptimal response or resistance to imatinib was an adverse prognostic factor for treatment-free remission (TFR). We present updated results with a specific focus on the risk of relapse using post-baseline information during follow-up. Methods : Adult CML pts treated with dasatinib or nilotinib without a history of allogeneic stem cell transplantation (ASCT) or progression to advanced phase stopped TKI provided that: (1) BCR-ABL transcripts were of the major type, (2) total TKI treatment duration was ≥36 months, (3) uMR4.5 had been achieved and maintained for ≥24 months (undetectable BCR-ABL with ≥32000 copies of ABL). Relapse was defined by loss of major molecular response (MMR: BCR-ABL IS >0.1%) on a single occasion and triggered TKI reintroduction. The primary objective was TFR at 12 months. After TKI discontinuation, BCR-ABL transcripts were monitored monthly during the first 6-12 months, every 3 months during the 2nd year and then every 3-6 months. Data as of July 1, 2019 are reported in 104 pts (median follow-up 55 months (range: 6-70)). Results: Median age at inclusion was 56 years (range: 21-82) and 65.4% of pts were female. Sokal risk score was low in 49%, intermediate in 31%, high in 16% and unknown in 4%. 2G-TKIs were given after imatinib intolerance in 47% of pts, suboptimal response or resistance to imatinib in 22%, lack of DMR on imatinib in 3% and as 1st line treatment in 28%. Median duration of TKI, 2G-TKI and uMR4.5 was 74 months (range: 36-163), 49 months (range: 19-112) and 31 months (range: 24-72), respectively. Overall, 43 pts (41%) lost MMR within a median time of 5 months (range: 1-59). Overall 60-month TFR was 56% (95% CI, 45.8-66.3) but TFR probabilities increased up to 64% (95% CI: 53.3-74.8), 76.7% (95% CI, 65.9-87.5), 86.2% (95% CI; 76.3-96.2), and 92.1% (95% CI: 83.4-100) for pts still in MMR at 3, 6, 12 and 18 months, respectively (Figure 1). Prior suboptimal response or resistance to TKI was confirmed as the strongest adverse baseline prognostic factor with a 60-month TFR rate of 29.8% (95% CI; 10.8-48.7) (median TFR 12 months) versus 63.6% (95% CI; 52.1-75.2) (median not reached) in pts without such history (logrank p=0.0012). This was explained by significantly higher risk of early relapses (within 6 months but not later) in pts with prior suboptimal response or resistance to TKI (cumulative incidence of relapses by 6 months 47.8% (95% CI; 31.2-73.2) versus 20.9 (95% CI; 13.7-32) in other pts (p=0.00879)). Landmark analyses at specific time points were performed to study the prognostic value of molecular responses categories after TKI discontinuation. All pts in MMR but not deeper at 3 months relapsed by month 9 (median time to relapse 4 months) while pts in ≥MR4 (BCR-ABL IS ≤0.01%) had 12- and 60-months probabilities of 86.8% (95% CI; 79.1-94.4) and 74.9% (95% CI: 64-85.7), respectively (logrank p Forty three pts restarted treatment including 1 who lost MR4.5 but not MMR and 42 who lost MMR. When treatment was reintroduced, 42 pts were in CHR and all regained MMR after a median time of 3 months (range: 1-11). The remaining pt lost MMR but not CHR 5 month after 1st line nilotinib cessation and was found in sudden myeloid blast crisis at the month 6 TKI reintroduction visit. No BCR-ABL mutation was found but an inversion of chromosome 3 at karyotyping analysis. The pt underwent ASCT after chemotherapy + ponatinib and is alive in remission 29 months later. Conclusion: 2G-TKI may be successfully stopped in CML pts with long-lasting MR4.5. Those without a history of suboptimal response or resistance have greatest chances of success. Sudden blast crisis is rare but unpredictable. Post-TKI discontinuation estimates of TFR change overtime. Together with that of molecular response type at specific time points, they represent important dynamic prognostic measures of outcome. They may also help individualizing molecular monitoring programs after TKI cessation. Disclosures Rea: Incyte Biosciences: Honoraria; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nicolini:Sun Pharma Ltd: Consultancy; Incyte Biosciences: Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Rousselot:Pfizer: Research Funding; Incyte: Research Funding. Etienne:Pfizer: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Guerci:INCYTE: Consultancy, Honoraria. Legros:Pfizer: Honoraria, Research Funding; BMS: Honoraria; Novartis: Honoraria; Incyte Biosciences: Honoraria, Research Funding. Coiteux:Pfizer: Honoraria; BMS: Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mahon:Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau.

Introduction Le Nilotinib est un inhibiteur de tyrosine kinase (ITK) de seconde generation et constitue un des traitements majeurs de la leucemie myeloide chronique (LMC). Ses effets indesirables a court terme ont ete bien etudies mais de nombreuses interrogations persistent sur le long terme. Suite a differentes etudes montrant le role de ce traitement dans le developpement d’une arteriopathie des membres inferieurs et la constatation recurrente du developpement de stenoses carotidiennes chez ces patients, nous nous sommes interroges sur l’existence d’un lien entre ce traitement et l’apparition d’une atteinte carotidienne. Le but de cette communication est de vous presenter le cas d’un patient ayant developpe une stenose de l’artere carotide interne, rapidement progressive, quatre ans apres l’introduction d’un traitement par Nilotinib et d’effectuer une revue de la litterature. Observation A 61 ans, notre patient presentait comme comorbidite principale une LMC traitee par differents ITK et notamment par du Nilotinib de 2010 a 2015. A noter, que concernant ses facteurs de risque cardiovasculaires, il presentait un surpoids et une hypercholesterolemie avec un SCORE calcule a 3 %. Devant ce tableau, un echodoppler des troncs supra-aortiques etait realise en 2014 et retrouvait une plaque hypoechogene reguliere de la carotide interne droite. Des echodopplers successifs etaient realises et faisaient apparaitre une progression importante et rapide de cette plaque hypoechogene, nous amenant a proposer une chirurgie carotidienne, qui etait realisee en fevrier 2018. Discussion Tout d’abord, Naif et al ont demontre que le Nilotinib activait l’endothelium et potentialisait la formation et la croissance de thrombus, effet qui n’etait pas retrouve avec les autres ITK. De plus, il semblerait que cette propriete ne survienne que sur un terrain predisposant et soit dose-dependante. Ce cas est un avant-propos, necessitant une etude dediee a la recherche de l’impact du Nilotinib dans le developpement d’une atteinte carotidienne. A terme, cela permettrait de mieux comprendre les effets indesirables au long cours de ce traitement, de definir l’implication potentielle de l’existence anterieure d’un terrain a risque et de pouvoir etablir une surveillance, qui reste jusqu’a present mal definie, les seules recommandations emanant des societes savantes etant peu specifiques.

The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice.Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucémies Myéloïdes Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice.Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction.This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. © 2018 American Cancer Society.

This prospective, observational study enrolled 150 adult patients with chronic myeloid leukaemia (CML) in chronic phase (CP) treated with nilotinib as second-line after imatinib, in a real life setting in France. Two-thirds of patients switched to nilotinib treatment due to lack of imatinib efficacy. Of 146 evaluable patients, 16 (11·0%) (95% confidence interval: 6·4-17·2%) achieved uMR4 , defined as undetectable molecular disease in cDNA with MR4 sensitivity (≥10 000 ABL1 transcripts) at 18 months and confirmed at 24 months (primary endpoint). Among patients without major molecular response (MMR) or deep molecular response (DMR) at study entry, 66·3% achieved MMR and 44·2% DMR within a median of 5·7 and 6·24 months, respectively. Fifty-three patients (36·3%) have prematurely terminated the study before 24 months of follow-up, primarily due to nilotinib treatment discontinuation (n = 43; 29·5%), mainly motivated by treatment intolerance (n = 27; 18·5%) and inefficacy (n = 10; 6·8%). The most frequent extra-haematological adverse events (AEs) reported as related to treatment with nilotinib were pruritus (16·4%), asthenia (13·7%) and dry skin (13·0%). Ischaemic cardiovascular AEs were reported in 18 patients (12·3%). This French nationwide large cohort adds valuable information to the body of evidence on the efficiency and safety of nilotinib in the treatment of patients with CP-CML.

Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID. The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed. Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0–1400]*106/L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P

Several studies have demonstrated that approximately one-half of patients with chronic myeloid leukemia (CML) who receive treatment with tyrosine kinase inhibitors (TKIs) and achieve and maintain a deep molecular response (DMR) are able to successfully discontinue therapy. In patients who have a molecular relapse, a DMR is rapidly regained upon treatment re-initiation.The authors report the results from RE-STIM, a French observational, multicenter study that evaluated treatment-free remission (TFR) in 70 patients who re-attempted TKI discontinuation after a first unsuccessful attempt. After the second TKI discontinuation attempt, the trigger for treatment re-introduction was the loss of a major molecular response in all patients.The median follow-up was 38.3 months (range, 4.7-117 months), and 45 patients (64.3%) lost a major molecular response after a median time off therapy of 5.3 months (range, 2-42 months). TFR rates at 12, 24, and 36 months were 48% (95% confidence interval [CI], 37.6%-61.5%), 42% (95% CI, 31.5%-55.4%), and 35% (95% CI, 24.4%-49.4%), respectively. No progression toward advanced-phase CML occurred, and no efficacy issue was observed upon TKI re-introduction. In univariate analysis, the speed of molecular relapse after the first TKI discontinuation attempt was the only factor significantly associated with outcome. The TFR rate at 24 months was 72% (95% CI, 48.8%-100%) in patients who remained in DMR within the first 3 months after the first TKI discontinuation and 36% (95% CI, 25.8%-51.3%) for others.This study is the first to demonstrate that a second TKI discontinuation attempt is safe and that a first failed attempt at discontinuing TKI does not preclude a second successful attempt. Cancer 2017;123:4403-10. © 2017 American Cancer Society.

Despite persistence of leukemic stem cells, patients with chronic myeloid leukemia who achieve and maintain deep molecular responses may successfully stop the tyrosine kinase inhibitor imatinib. However, questions remain unanswered regarding the biological basis of molecular relapse after imatinib cessation. In IMMUNOSTIM, we monitored 51 patients from the French Stop IMatinib trial for peripheral blood T cells and natural killer cells. Molecular relapse-free survival at 24 months was 45.1% (95% CI: 31.44%-58.75%). At the time of imatinib discontinuation, non-relapsing patients had significantly higher numbers of natural killer cells of the cytotoxic CD56dim subset than had relapsing patients, while CD56bright natural killer cells, T cells and their subsets did not differ significantly. Furthermore, the CD56dim natural killer-cell count was an independent prognostic factor of molecular-relapse free survival in a multivariate analysis. However, expression of natural killer-cell activating receptors, BCR-ABL1+ leukemia cell line K562-specific degranulation and cytokine-induced interferon-gamma secretion were decreased in non-relapsing and relapsing patients as compared with healthy individuals. After imatinib cessation, the natural killer-cell count increased significantly and stayed higher in non-relapsing patients than in relapsing patients, while receptor expression and functional properties remained unchanged. Altogether, our results suggest that natural killer cells may play a role in controlling leukemia-initiating cells at the origin of relapse after imatinib cessation, provided that these cells are numerous enough to compensate for their functional defects. Further research will decipher mechanisms underlying functional differences between natural killer cells from patients and healthy individuals and evaluate the potential interest of immunostimulatory approaches in tyrosine kinase inhibitor discontinuation strategies. (ClinicalTrial.gov Identifier NCT00478985).

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

Purpose More than half of patients with chronic-phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and Methods A multicenter observational study (A-STIM [According to Stop Imatinib]) evaluating MMR persistence was conducted in 80 patients with CP-CML who had stopped imatinib after prolonged CMR. Results Median time from imatinib initiation to discontinuation was 79 months (range, 30 to 145 months);median duration of CMR before imatinib discontinuation was 41 months (range, 24 to 96 months); median follow-up after discontinuation was 31 months (range, 8 to 92 months). Twenty-nine patients (36%) lost MMR after a median of 4 months off therapy (range, 2 to 17 months). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25% to 46%) at 12 months and 36% (95% CI, 26% to 47%) at 24 months, whereas probability of losing CMR was higher. Fluctuation of BCR-ABL transcript levels below the MMR threshold (≥ two consecutive positive values) was observed in 31% of patients after imatinib discontinuation. Treatment-free remission was estimated as 64% (95% CI, 54% to 75%) at 12 and 24 months and 61% (95% CI, 51% to 73%) at 36 months. Median to time to second CMR was estimated as 7.3 months in re-treated patients. Conclusion Loss of MMR is a practical and safe criterion for restarting therapy in patients with CML with prolonged CMR.

Introduction Up to 10% of patients (pts) with chronic myeloid leukemia (CML) are already in accelerated phase (AP) at diagnosis and despite treatment advances in the field of tyrosine kinase inhibitors (TKIs), management of these pts is challenging. This study aims to examine the benefit of second generation BCR-ABL tyrosine kinase inhibitors (TKI2) as first-line treatment for newly diagnosed AP-CML. Methods Pts meeting criteria for AP-CML at diagnosis and treated with first-line TKI2 (i. e. Nilotinib or Dasatinib) were included in this retrospective multicenter observational national study. AP-CML were defined according to the ELN (Baccarani, Blood 2013) as hematological acceleration (HEM-AP, any of the following features: blasts in PB or marrow 15-29%, or blasts+promyelocytes in PB or marrow >30% with blasts Results Sixty-six pts were analysed: 45 males (68%) and 21 females (32%) with a median age at diagnosis of 49 (15-78.5) years. The median follow-up of the cohort was 43.5 (1.7-117) months. We segregated the pts in HEM-AP (n=33) and ACA-AP (n=33) for further analyses. Nine pts with HEM-AP harboured ACA and were analysed in the HEM-AP group. Fusion transcripts were of the Major BCR in 57 pts, 6 pts had atypical BCR-ABL transcripts (2 e19a2, and 1 e1a2 in the HEM-AP group and 2 e19a2 and 1 Ma3 in the ACA-AP group), and 3 transcripts unknown. Not surprisingly, spleen enlargement was significantly greater in the HEM-AP group [10 (5-14.75) vs. 3 (0-10)cm, p=0.014]. PB basophils [median 10 (6-16) vs. 3 (2-5)%, p Treatment responses did not significantly differ between ACA-AP and HEM-AP group, regardless of the TKI2 administered, with 33/33 (100%) vs 31/33 (94%) pts achieving a CHR, 2/33 (6%) pts vs 0/33 (0%) pts achieving a MCyR, 5/33 (15%) pts vs 5/33 (15%) pts achieving CCyR, 9/33 (27%) pts vs 4/33 (12%) pts achieving a MMR respectively. However, 11/33 (33%) HEM-AP vs 22/33 (66%) ACA-AP pts achieved a deep molecular response (p=0.013, Fisher test). Median times to CHR and MMR were not significantly different between ACA-AP group and HEM-AP group with 1.05 vs 1.25 months (p=0.088) for CHR and 6 vs 7 months (p=0.156) for MMR, respectively. Overall, the estimated 7-yr FFS rate was 56.92% (95%CI: 40-81), 7-yr PFS was 83.42% (95% CI: 69.6-100%) and 7-yr OS was 87.14% (95%CI: 73.5-100%) (Figure 1.) with no significant differences between ACA-AP vs HEM-AP pts [7-yr FFS: 57.7 vs. 62%, p=0.739; 7-yr PFS: 84.7% vs. 84%, p=0.185; 7-yr OS: 88.9% vs 86.6%, p=0.132] respectively. There was also no difference in FFS, PFS and OS according to the type of TKI2. The only factors influencing negatively OS were the % of BM blasts (HR=1.17, 95%CI: 1.1-1.28, p Conclusion The initiation of a TKI2 in newly diagnosed AP-CML pts induces excellent response and survival rates, probably superior to that of Imatinib first-line, and counterbalances the negative impact of this advanced disease, particularly in HEM AP subgroup. Disclosures Etienne: Pfizer: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Patents & Royalties, Speakers Bureau. Berger:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mahon:Incyte: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; BMS: Speakers Bureau. Rea:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Pfizer: Honoraria. Nicolini:BMS: Consultancy, Speakers Bureau; Incyte Biosciences: Consultancy, Speakers Bureau; Sun Pharma Ltd: Consultancy.

STOP second generation (2G)-tyrosine kinase inhibitor (TKI) is a multicenter observational study designed to evaluate 2G-TKI discontinuation in chronic myeloid leukemia (CML). Patients receiving first-line or subsequent dasatinib or nilotinib who stopped therapy after at least 3 years of TKI treatment and in molecular response 4.5 (MR4.5) with undetectable BCR-ABL1 transcripts for the 2 preceding years at least were eligible for inclusion. This interim analysis reports outcomes of 60 patients with a minimum follow-up of 12 months (median 47, range: 12-65). Twenty-six patients (43.3%) experienced a molecular relapse defined as the loss of a major molecular response (MMR). Relapses occurred after a median time of 4 months (range: 1-38). Cumulative incidences of molecular relapse by 12 and 48 months were 35% (95% confidence interval [CI], 24.79% to 49.41%) and 44.76% (95% CI, 33.35% to 59.91%), respectively. Treatment-free remission (TFR) rates at 12 and 48 months were 63.33% (95% CI, 51.14% to 75.53%) and 53.57% (95% CI, 40.49% to 66.65%), respectively. In univariate analysis, prior suboptimal response or TKI resistance was the only baseline factor associated with significantly worse outcome. A landmark analysis demonstrated that loss of MR4.5 3 months after stopping TKI was predictive of failure to maintain MMR later on. During the treatment-free phase, no progression toward advanced phase CML occurred, and all relapsing patients regained MMR and MR4.5 after restarting therapy. In conclusion, discontinuation of first-line or subsequent 2G-TKI yields promising TFR rates without safety concerns. Further research is encouraged to better define conditions that will offer patients the highest chance to remain free from 2G-TKI therapy.

Thirty-nine children under two years of age with newly diagnosed Acute Myeloid Leukemia (AML) were consecutively admitted to the Hopital Saint-Louis (Paris) over a ten-year period (1978-1987). Nineteen were under one year of age at diagnosis and 3 had congenital leukemia. Comparison of FAB sub-classes among the different age categories showed that AML with a monocytic component (M4 and M5) (44%), and AML with megakaryocytic elements (M7) (21%), were much more frequent in children before the age of two years. This comparison was made on a series of 1409 AML and 859 ALL diagnosed in the same hospital during a twelve years period of time. During this period of observation, the compared incidence of ALL and AML showed 50% for each category for children under 2 years, 73% ALL versus 27% AML for children under 15 years, and 18% ALL versus 82% AML for adults. Of the 29 cases subjected to cytogenetic study, 62% had clonal chromosomal abnormalities, the most frequent being a translocation involving the long arm of chromosome 11. With a 72 months median follow-up for patients who are still alive, the 6-year actuarial survival was 23%, while the event free interval for Complete Remission (CR) patients was 35%. For the M4-M5 subgroup, these results were 37% and 50% respectively with a plateau reached at 27 months. M4-M5 FAB types represented the most common leukemia at this age, and these usually correlated with translocation of the long arm of chromosome 11. We obtained an unexpectedly high rate of survival, with acceptable sequellae, for children treated with intensive chemotherapy.

International audience; Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucemies Myeloides Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients

We appreciate the correspondence from Richter et al reporting for the first time a so-called tyrosine kinase inhibitor withdrawal syndrome consisting of musculoskeletal pain after imatinib discontinuation in patients with chronic myelogenous leukemia (CML). All patients (15 of 50; 30%) were graded as 1 to 2 on the Common Terminology Criteria for Adverse Events scale (version 4.0), and 11 patients (22%) did not experience any musculoskeletal pain before discontinuation. Richter et al ask whether such events were observed in the According to Stop Imatinib (A-STIM) study. The A-STIM study was not designed to collect data on low-grade events, either before discontinuation or after discontinuation. We thus tried to retrospectively collect this information and asked the A-STIM investigators to check their patients’ files. As a result, we estimated that four of 80 patients presented similar symptoms after discontinuation. Because of the retrospective collection of the data, we believe that this proportion may be underestimated. French investigators have pioneered the field of tyrosine kinase discontinuation from the first pilot study in 2007 to the multicentric Stop Imatinib 1 (STIM1) study. In none of these studies was the collection of data on low-grade adverse events planned. We are currently conducting the Stop Imatinib 2 (STIM2) study for patients treated only with imatinib and are prospectively recording events of all grades at the time of discontinuation and after discontinuation. We calculated that 400 patients were enrolled in discontinuation studies in France from 2007 to 2013. Few grade 3 or grade 4 events were reported as being possibly related to the discontinuation of tyrosine kinase inhibitors. Such events were mainly related to exacerbation of preexisting inflammatory diseases such as Crohn’s disease or rheumatoid arthritis, as reported. In a recently published study, thermal pain thresholds were significantly increased in 39 patients with CML who were treated with imatinib or nilotinib as compared with ageand sex-matched healthy controls. The authors suggested that c-Kit inhibition may modulate nociceptive sensitivity in humans, as reported in mice. Sudden discontinuation of imatinib may reverse this phenomenon. Prolonged inhibition of c-Kit signaling by imatinib may also suppress mast cell function and activation over the long term, as suggested by the observation that imatinib may improve asthma in asthmatic patients with CML. Taken together, these observations favor the hypothesis that c-Kit signaling may contribute to the symptoms that were observed by Richter et al after imatinib discontinuation.

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent infections and defective immunoglobulin production.The DEFI French national prospective study investigated peripheral T-cell and B-cell compartments in 313 CVID patients grouped according to their clinical phenotype, using flow cytometry.In patients developing infection only (IO), the main B-cell or T-cell abnormalities were a defect in switched memory B cells and a decrease in naive CD4(+) T cells associated with an increase in CD4(+)CD95(+) cells. These abnormalities were more pronounced in patients developing lymphoproliferation (LP), autoimmune cytopenia (AC), or chronic enteropathy (CE). Moreover, LP and AC patients presented an increase in CD21(low) B cells and CD4(+)HLA-DR(+) T cells and a decrease in regulatory T cells.In these large series of CVID patients, the major abnormalities of the B-cell and T-cell compartments, although a hallmark of CVID, were only observed in half of the IO patients and were more frequent and severe in patients with additional lymphoproliferative, autoimmune, and digestive complications.

Background We previously demonstrated that the combination of Nilotinib (NIL) + Pegylated IFN-a2a (Peg-IFN) is able to induce high deep molecular response rates in chronic phase CML (CP CML) patients, as first-line therapy (Nicolini FE et al., Lancet Haematol. 2015). Aims Assessment of the molecular responses obtained with the same combination vs NIL alone prospectively, in newly diagnosed CP-CML. (EudraCT 2013-004974-82). Methods Patients (pts) ≤65 years with no history of arterial damage were randomized 1:1 to get NIL 300 mg BID alone (M0 to M48, arm A) vs Peg-IFN alone (± HU) for 30 days (M-1 to M0) 30 mg/wk as a priming, prior to a combination of NIL 300 mg BID + Peg-IFN 30 mg/wk 2 weeks, upgraded to 45 mg/wk thereafter if proper tolerance for up to 2 years (M0 to M24, arm B) followed by NIL alone for 2 more years. The primary endpoint was the rate of molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised, quantifications were expressed as BCR-ABL/ABL1 (IS) in % with ≥32,000 copies of ABL1 as control. Results Two hundred and one pts were randomized (100 in arm A, 101 in arm B), 65 males in both arms, 35 females in arm A, 36 in arm B. The median follow-up is 20.6 (9.1-34.7) months. Results are analysed in intention-to-treat. Sokal scores were high in 25%, intermediate in 36% and low in 39% of pts; Euro scores were high in 13%, intermediate in 44% and low in 43% of pts; Eutos LTS scores were high in 2%, intermediate in 17%, and 81% low; equally balanced in the 2 arms The median age was 46 (18-66) years, equally balanced. Eight (4%) pts had a cryptic Philadelphia chromosome, 12 (6%) a variant form, and 15 (7.5%) had ACAs, all pts had a "Major" BCR transcript. CHR was obtained in 9.6% of pts at M0 (arm B) and in 88% of pts in arm A and 90.4% of pts in arm B at M1. The rates of CCyR at M3 were 63% vs 65% in arms A and B, and BCR-ABL1≤1% at M6 were 83% in arm A vs 86% and arm B, on evaluable samples. The incidence of molecular responses are shown in Fig. 1. Of note, 90% of the pts had a BCR-ABL1 ≤10% at M3 in arm A vs 84% in arm B (p=ns). By M12, the rates of MMR were 69.9% vs 72.4% (p=0.079), MR4 were 34.65% vs 47.9% (p=0.094), MR4.5 were 17.9% vs 24.11% (p=0.272), MR5 12.1% vs 22.31% (p=0.075), in arm A and arm B respectively. Data from 11 pts in arm A and 16 in arm B at M12 are still pending. Definitive results at 1 year will be presented. One pt progressed toward accelerated phase in arm A with a Y253H mutation. Fifteen pts were withdrawn from study in arm A (toxicity 5, other cancer 2, failure 8) and 12 patients from arm B (toxicity 6, failure 6), no pt died. Interestingly, 5 mutated (ie. failure) pts were found in arm A (3 Y253H, 1 E225K, 1 F317L), vs only 1 pt (T315I) in arm B. The median dose of Peg-IFN delivered in arm B during the first month is 30 (0-30) mg/wk, 30 (0-45) mg/wk at M2, 45 (0-45) mg/wk at M3, 37.5 (0-45) mg/wk at M6, 30 (0-45) mg/wk at M9 and 12. The median doses of NIL delivered were 600 mg daily at M2, 3, 6, 9, 12 as initially planned in both arms. The rate of grade 4 hematologic toxicities overall was 15%, with no anemias, 1% and 4% thrombocytopenias, 3% and 4% neutropenias, 0% and 1% leucopenias, and 0 and 1% pancytopenias in arms A and B respectively. Grade ¾ non-hematologic toxicities consisted in 4% of cardiac disorders in arm A (1 coronaropathy, 2 thoracic pains and 1 atrial fibrillation) vs 1% in arm B (palpitation), 2% vascular disorders in arm A (1 pulmonary embolism, 1 transient ischemic attack) and 1% in arm B (PAOD). Three % of gastro-intestinal disorders in arm A (resolutive pancreatitis) vs 1% in arm B (anal fissure); 1% of skin disorders in arm A; 2% auto-immune disorders in arm B (1 recurrent pericarditis, 1 hemolytic anemia); 2 and 5 pregnancies (of the partner except 1) were observed in arm A and B respectively, despite recommended contraceptive methods. We observed 10% lipase elevations in arm A, 3 in arm B, 2% cholestatic episodes in arm A, 1% in arm B; 1% of transaminase elevations in each arm. There were 2% depressive episodes in arm B, 1% in arm A; infections were detected in 1% arm 1 and 3% in arm B. Finally 3 intercurrent cancers were detected in arm A (cervix, breast, thyroid). Conclusion The combination of NIL + Peg-IFN seems to provide slightly deeper molecular responses rates (especially MR5) by M12, but so far not significantly, in newly diagnosed CP CML pts without increasing the rate of more frequent early SAEs in such a setting. Definitive results at M12 will be updated for the meeting. Disclosures Nicolini: BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ARIAD: Honoraria, Speakers Bureau; Incyte Biosciences: Honoraria, Speakers Bureau. Etienne: Incyte: Speakers Bureau; BMS: Speakers Bureau; Novartis: Consultancy, Research Funding. Guerci-Bresler: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Charbonnier: Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau. Legros: BMS: Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau. Coiteux: Incyte: Speakers Bureau; BMS: Speakers Bureau. Cony-Makhoul: BMS: Speakers Bureau. Rousselot: Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sunesis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Pfizer: Research Funding. Guyotat: BMS: Speakers Bureau. Ianotto: Novartis: Other: Grant. Rea: BMS: Consultancy, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Mahon: Pfizer: Speakers Bureau; Incyte: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

To assess real-life treatment practices with imatinib for chronic-phase chronic myeloid leukaemia (CP-CML) in France.In the observational 'Unmet Needs in CML' (UNIC) study of CML management in Europe, case report forms were completed retrospectively for eligible patients (or =18 years of age, currently treated for CML) during enrolment (September 2006-March 2007). Results from the subset of patients from France are presented.Primary objectives were to estimate from the collected data the proportions of patients ever treated with imatinib and those experiencing imatinib resistance and/or intolerance as determined by physicians' diagnoses of resistance/intolerance leading to a change in imatinib use. Collected data were analysed descriptively. Secondary descriptive measures included imatinib dose modifications and methods for treatment response monitoring.Of the 654 French CP-CML patients, 95.9% had received imatinib. Of these, 15% were judged by physicians as imatinib-resistant and 31% as imatinib-intolerant (not mutually exclusive) during treatment, 44% required dose modification and 23% discontinued imatinib. In the 12 months preceding the last observation, 65% had a cytogenetic features analysis and 93% had a polymerase chain reaction (PCR) assessment of molecular response. Importantly, and contrasting with European recommendations, 46% of imatinib-resistant patients had never been assessed for BCR-ABL mutations.The observational study design limits data collection and interpretation. The findings are specific to the French healthcare system and may not apply to other countries.This observational study of CP-CML management in France confirmed that most patients are treated with imatinib, a treatment widely recognised as efficacious. The study highlights opportunities for optimising CML management, as a proportion of patients may require alternative treatment strategies due to imatinib resistance/intolerance. Response monitoring rates differ from recommendations, representing another opportunity for improving care for CP-CML patients through early identification of patients failing current therapy.

Deferoxamine (DFO) is an iron chelator used to treat iron overload in patients receiving chronic blood transfusions, and is usually administered as overnight subcutaneous infusions. ISOSFER was a prospective, observational, cross-sectional study conducted in metropolitan France that evaluated patient characteristics, quality of life (QoL), compliance and patient satisfaction with DFO monotherapy. Of 70 patients with either thalassemia, sickle cell disease or myelodysplastic syndromes, 30% were 'satisfied' or 'very satisfied' with DFO. Patients' SF-36 scores were lower than those of the general French population, and lower among patients with comorbidities and those dissatisfied with treatment. Although 72% of patients had good compliance to DFO, 57% reported missing at least one infusion in the previous month, and 82% of patients expressed a preference for oral therapy. These results suggest that QoL is severely compromised in patients receiving DFO, and that compliance is not optimal.

International audience; BACKGROUND:Primary immunodeficiencies (PIDs) are inherited diseases associated with a considerable increase in susceptibility to infections. It is known that PIDs can also predispose to cancer and immune diseases, including allergy, autoimmunity, and inflammation.OBJECTIVE:We aimed at determining the incidence of autoimmunity and inflammation in patients with PIDs.METHODS:We have retrospectively screened 2183 consecutive cases of PID in the Centre de Référence Déficits Immunitaires Héréditaires registry (CEREDIH; the French national PID registry) for the occurrence of autoimmunity and inflammation.RESULTS:One or more autoimmune and inflammatory complications were noted in 26.2% of patients, with a risk of onset throughout the patient's lifetime. The risk of autoimmune cytopenia was at least 120 times higher than in the general population, the risk of inflammatory bowel disease in children was 80 times higher, and the risk of other autoimmune manifestations was approximately 10 times higher. Remarkably, all types of PIDs were associated with a risk of autoimmune and inflammatory complications, although the greatest risk was associated with T-cell PIDs and common variable immunodeficiency. The occurrence of autoimmune disease is a negative prognostic factor for survival.CONCLUSIONS:Our results provide the basis for a detailed prospective evaluation of autoimmunity and inflammation in the context of PIDs, with a view to accurately assessing these risks and describing the possible effect of medical intervention.

The JAK2V617F mutation does not elucidate the phenotypic variability observed in myeloproliferative neoplasm (MPN) families. A putative tumor suppressor gene, TET2, was recently implicated in MPN and myelodysplastic syndromes through the identification of acquired mutations affecting hematopoietic stem cells. The present study analyzed the TET2 gene in 61 MPN cases from 42 families. Fifteen distinct mutations were identified in 12 (20%) JAK2V617F-positive or -negative patients. In a patient with 2 TET2 mutations, the analysis of 5 blood samples at different phases of her disease showed the sequential occurrence of JAK2V617F and TET2 mutations concomitantly to the disease evolution. Analysis of familial segregation confirmed that TET2 mutations were not inherited but somatically acquired. TET2 mutations were mainly observed (10 of 12) in patients with primary myelofibrosis or patients with polycythemia vera or essential thrombocythemia who secondarily evolved toward myelofibrosis or acute myeloid leukemia.

Erythropoiesis-stimulating agents (ESAs) remain the first-line treatment of anemia in lower risk myelodysplastic syndromes (MDS) without 5q deletion. A preliminary report suggested that adding all-trans retinoic acid (ATRA) to ESAs may improve their erythroid response, particularly in patients with high endogenous erythropoietin (EPO) level, and may improve other cytopenias. We conducted a prospective multicenter study of EPO-beta and ATRA in anemic MDS patients with marrow blasts10% and either previous ESA failure or relapse, endogenous EPO500 U/l or other cytopenia(s) (absolute neutrophilic count1.0 G/l or platelets50 G/l). A total of 59 patients were evaluable after 12 weeks of treatment. The erythroid response rates according to IWG 2000 and 2006 criteria, respectively, were as follows: overall: 49 and 36%; patients with previous ESA failure (n=28): 43 and 32%; patients with endogenous EPO500 U/l (n=18): 11 and 19%; patients transfused2 red blood cells units/month (n=28) 43 and 39%. Only one neutrophil, but no platelet response, and no major side effect were observed. EPO-beta-ATRA combination appears a possible therapeutic option in anemia of MDS having failed an ESA alone, but not in patients with high endogenous EPO level, and does not improve neutropenia and thrombocytopenia.

Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucémies Myéloïdes Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients.

Summary Patients (n = 47) with low-risk myelodysplastic syndrome were treated with thalidomide [200 mg/d, increased by 200 mg/d/4 weeks up to week 16]. Responses were evaluated according to the International Working Group criteria at week 16 for 39 patients who received at least 8 weeks of treatment. Twenty-three (59%) patients showed haematological improvement (HI): four major erythroid response (HI-EM), 15 minor erythroid response, six major neutrophil response, two major platelet response. Side effects caused 22/39 to stop thalidomide before week 16. Nine of 23 responders continued thalidomide after week 16 [19% of trial patients] with sustained response in eight of nine. Six reached week 56, including the four HI-EM patients [13% of trial patients]. Nineteen of 36 red blood cell transfusion-dependent patients (53%) showed erythroid response, but only four became transfusion-independent. Among the 23 responders, the median duration of response was 260 d (range 30–650). Responses were sustained in all patients except one, and were observed between week 4 and week 8 in 85% of patients, at doses ranging from 200 to 400 mg. Only two patients responded at 600 mg/d and none at 800 mg/d. No clinical characteristics of responding versus non-responding patients were identified. The erythroid response rate was identical in all cytogenetic subgroups, including 5q31.1 deletions. Pretreatment vascular endothelial growth factor levels were lower in responders compared with non-responders (P = 0·004). Microvessel density (MVD) increased and apoptosis decreased in four of six and in all six responders studied respectively whereas MVD and apoptosis were unchanged in three non-responders.

In chronic myelogenous leukemia (CML) imatinib mesylate has been shown to selectively inhibit the tyrosine kinase domain of the oncogenic bcr-abl fusion protein. Using this agent alone high rates of cytogenetic responses were recorded. However, several mechanisms of resistance have been described. In vitro studies examining the effects of imatinib mesylate plus cytarabine have shown synergistic antiproliferative effects of this combination. Thus, the CML French Group decided to perform a phase 2 trial testing a combination of imatinib mesylate and low-dose cytarabine in 30 previously untreated patients in chronic phase. Treatment was administered on 28-day cycles. Patients were treated continuously with imatinib mesylate orally at a dose of 400 mg daily. Cytarabine was given on days 15 to 28 of each cycle at an initial dose of 20 mg/m2/d via subcutaneous injection. Adverse events were frequently observed with grade 3 or 4 hematologic toxicities and nonhematologic toxicities in 53% (n = 16) and 23% (n = 7) of patients, respectively. The cumulative incidence of complete cytogenetic response (CCR) at 12 months was 83% and at 6 months 100% of the patients achieved complete hematologic response (CHR). We concluded that the combination was safe and promising given the rates of response. (Blood. 2003;102:4298-4305)

Myeloid neoplasms and eosinophilia with rearrangements of PDGFRB are uncommon Philadelphia-negative myeloproliferative neoplasms. Patients are typically male, with morphologic features of a Philadelphia-negative chronic myeloproliferative syndrome or chronic myelomonocytic leukemia with eosinophilia. Reciprocal translocations involving PDGFRB result in fusion genes with constitutively activated receptor tyrosine kinase sensitive to inhibition with imatinib. We present an updated and expanded analysis of a cohort of 26 such patients treated with imatinib. After a median follow-up of 10.2 years (range, 1.8-17 years), the 10-year overall survival rate was 90% (95% confidence interval, 64%-97%); after median imatinib duration of 6.6 years (range, 0.1-12 years), the 6-year progression-free survival rate was 88% (95% confidence interval, 65%-96%). Of the patients, 96% responded; no patients who achieved a complete cytogenetic (n = 13) or molecular (n = 8) remission lost their response or progressed to blast crisis. Imatinib is well-tolerated and achieves excellent long-term responses in patients with PDGFRB rearrangements.

Treatment of primary central nervous system lymphoma (PCNSL) in elderly patients remains unsatisfactory. To develop a new high-dose methotrexate (HD-MTX)-based regimen including idarubicin, a phase 1 multicenter dose escalation study was conducted to determine the maximum-tolerated dose (MTD) of idarubicin. Thirty-five immunocompetent patients with PCNSL were enrolled. The median age was 65 years (range, 60-70 years). MTX and vindesine (VDS) were given at the fixed dose of 3 g/m(2) (6-hr intravenous [IV]) and 3 mg/m(2) IV on day 1, respectively. Prednisolone (PRED) was given at the fixed dose of 60 mg/m(2) (IV or orally) on days 1-5. Idarubicin was escalated in increments of 2 mg/m(2) with doses ranging from 12-18 mg/m(2) IV on day 1. Treatment was repeated three times every 3 weeks. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia for more than 7 days, thrombocytopenia grade 4 or nonhaematological toxicity more than grade 2. The MTD of idarubicin was reached at 16 mg/m(2) . At this level, the main haematological toxicities were thrombocytopenia grade 4: 5% and neutropenia grade 3 or 4 (52%); the main nonhaematological toxicities were grade 3 or 4 infectious disease (5%) and grade 2 renal failure (9%). For the study population, median overall and progression-free survival were 19 and 13 months, respectively. Our study suggests that the MTD of idarubicin in combination with HD-MTX, VDS, and PRED, should be 16 mg/m(2) . Further studies will be necessary to challenge a standard treatment in elderly patients with PCNSL.

International audience

In the present study, we address the issue of the discontinuation of imatinib mesylate (Gleevec) in chronic myelogenous leukemia with undetectable residual disease for more than 2 years. Twelve patients were included. The median duration of real-time quantitative–polymerase chain reaction (RTQ-PCR) negativity and imatinib therapy were, respectively, 32 months (range, 24-46 months) and 45 months (range, 32-56 months) before imatinib interruption. Six patients displayed a molecular relapse with a detectable BCR-ABL transcript at 1, 1, 2, 3, 4, and 5 months. Imatinib was then reintroduced and led to a novel molecular response in most patients. Six other patients (50%) still have an undetectable level of BCR-ABL transcript after a median follow-up of 18 months (range, 9-24 months). We hypothesize that relapses observed within 6 months reflect the kinetics of undetectable dividing chronic myelogenous leukemia (CML) cells. Those cells may be eradicated or controlled in long-term nonrelapsing patients, as described in our study.

We conducted a randomized multicenter study to compare the efficacy and safety of two antibiotic regimens (cefepime [2 g b.i.d.] plus amikacin or ceftazidime [2 g t.i.d.] plus amikacin) as first-line therapy for fever in patients with hematologic malignancies and neutropenia. A total of 353 patients were randomized according to a 2:1 (cefepime:ceftazidime) ratio. Two hundred-twelve patients in the cefepime group and 107 in the ceftazidime group (90% of all patients) were evaluable for efficacy. The polymorphonuclear neutrophil count was