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High-dose melphalan (HDM) and transplantation are recommended for eligible patients with multiple myeloma. No other conditioning regimen has proven to be more effective and/or safer. We previously reported in a phase 2 study that bortezomib can safely and effectively be combined with HDM (Bor-HDM), with a 32% complete response (CR) rate after transplantation. These data supported a randomized phase 3 trial. Randomization was stratified according to risk and response to induction: 300 patients were enrolled, and 154 were allocated to the experimental arm (ie, arm A) with bortezomib (1 mg/m2 intravenously [IV]) on days −6, –3, +1, and +4 and melphalan (200 mg/m2 IV) on day –2. The control arm (ie, arm B) consisted of HDM alone (200 mg/m2 IV). There were no differences in stringent CR + CR rates at day 60 posttransplant (primary end point): 22.1% in arm A vs 20.5% in arm B (P = .844). There were also no differences in undetectable minimum residual disease rates: 41.3% vs 39.4% (P = .864). Median progression-free survival was 34.0 months for arm A vs 29.6 months for arm B (adjusted HR, 0.82; 95% CI, 0.61-1.13; P = .244). The estimated 3-year overall survival was 89.5% in both arms (hazard ratio, 1.28; 95% CI, 0.62-2.64; P = .374). Sixty-nine serious adverse events occurred in 18.7% of Bor-HDM–treated patients (vs 13.1% in HDM-treated patients). The proportion of grade 3/4 AEs was similar within the 2 groups (72.0% vs 73.1%), mainly (as expected) blood and gastrointestinal disorders; 4% of patients reported grade 3/4 or painful peripheral neuropathy in arm A (vs 1.5% in arm B). In this randomized phase 3 study, a conditioning regimen with Bor-HDM did not improve efficacy end points or outcomes compared with HDM alone. The original trial was registered at www.clinicaltrials.gov as #NCT02197221.

PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

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.

Complete molecular response (CMR) after first-line immunochemotherapy reflects treatment efficacy and may predict prognosis in patients with follicular lymphoma (FL). RELEVANCE is the first phase 3 trial comparing the chemotherapy-free regimen lenalidomide/rituximab (R2) vs rituximab/chemotherapy (R-Chemo) in previously untreated FL patients (ClinicalTrials.gov identifier: NCT01650701). The objective of the minimal residual disease (MRD) analysis was to determine the ability of a chemotherapy-free regimen to induce CMR. Of 440 French patients participating in the Lymphoma Study Association (LYSA) RELEVANCE MRD study, all 222 patients with a BIOMED-2–detectable BCL2-JH translocation at diagnosis were analyzed. MRD was quantified by droplet digital polymerase chain reaction with a sensitivity ≤10−4. At week 24 (end of induction treatment), 98% and 78% of patients achieved CMR in peripheral blood (PB) and bone marrow (BM), respectively. Achievement of CMR (in PB and/or BM) had a significant impact on progression-free survival (PFS), with 3-year PFS of 84% and 55% for patients with CMR and detectable MRD, respectively (P = .015). CMR at week 24 was reached more frequently in the R2 arm (105/117; 90%) than in the R-Chemo arm (70/90; 77%) (P = .022). The poor prognostic value in terms of PFS for the persistence of molecular disease was observed irrespective of treatment arm (interaction test, P = .31). In agreement with the clinical results of the RELEVANCE trial, our results show that R2 immunomodulatory treatment in first-line FL can achieve high rates of CMR.

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 role of maintenance lenalidomide in myeloma, following autologous stem cell transplantation (ASCT) or not, is well established. However, 29% of patients discontinue the treatment with a median duration of less than 2 years with an increased rate of secondary primary malignancies (SPM). Pomalidomide could provide alternative maintenance therapy. Methods: This was a single arm phase II study of pomalidomide/dex (PD) maintenance therapy for MM patients (pts) in first relapse after treatment in the IFM 2009 trial. At first relapse, 100 pts received pomalidomide/cyclophosphamide/dex (PCD) for 4 cycles, after which half underwent ASCT (if no first line transplant) followed by 2 cycles of PCD consolidation (Arm A), or 5 cycles of PCD (if previously transplanted) (Arm B). All pts then received maintenance therapy consisting of 28-day cycles of pomalidomide 4 mg daily on days 1-21 and dex 20 mg once a week until progression (Blood 2018). The primary objective was to establish the safety and efficacy of PD as maintenance therapy. Results: A total of 75 pts were enrolled in the maintenance phase from January 2015 to November 2017 (Table 1) and the database was locked on 07/07/2021. The median age was 60 (range 39-70); 67% (50/75) were male. 53 pts had ISS stage I, 10 stage II and 3 stage III disease (9 missing). Infectious prophylaxis was antiviral in 94%, sulfamethoxazole/trimethoprim in 76%, penicillin in 69% and fluoroquinolone in 38%. A granulocyte colony stimulating factor was administered in 15 (20%) pts and immunoglobulins in 13 (17%). One quarter had thromboprophylaxis. The median follow-up was 73 months (95% CI: 68-75). Among the 75 pts, 63 (84%) left the study, 34 (54%) due to progressive disease, 19 (30%) due to AE/SAE, 7 (11%) on investigator (PI) discretion and 3 (5%) after consent withdrawal. 12 (16%) remained on therapy in July 2021.The median duration of maintenance was 23.7 months (IQR: 14.5-44). Pts received a median of 26 cycles (range 1-80) and 17 (23%) had 50 or more cycles. The reasons for pomalidomide discontinuation were progression or death in 54%, AE/SAE in 30%, PI decisions in 11% and patient decisions in 5%. 56 (75%) pts required a reduction in the dose of pomalidomide due to AE/SAE in 50%, omission in 19%, resumption of treatment in 11%, PI decisions in 16% and patient decisions in 2.7%. The reasons for dex discontinuation were progression or death in 30%, AE/SAE in 43%, PI decisions in 22% and patient decisions in 3%. 57 (76%) pts required a reduction in the dose of dex due to AE/SAE in 54%, omission in 3.4%, resumption of treatment in 0.3%, PI decisions in 38.7% and patient decisions in 3.1%. 31 SAE were reported in 22 pts: 13 (42%) infections, 5 tumors, 1 case of thrombosis, 1 diabetic ketoacidosis and 12 others. Grade 3/4 hematologic AE included neutropenia (51%), lymphopenia (35%), anemia and thrombocytopenia (0%). G3/4 drug-related non-hematologic AE (>5%) comprised 13% infections (5% pneumonia). G1/2 AE included 69% infections (49% bronchitis), 49.3% gastrointestinal disorders (20% diarrhea, 20% constipation), 48% fatigue, 31% skin disorders, 25% muscle spasms, 24% insomnia and 14.7% eye disorders (6.7% cataracts, 4% dry eyes). Concerning peripheral neuropathy, one patient had G3/4 and 45% G1/2. Eight pts developed SPM: 4 basocellular carcinoma, 1 epidermoid carcinoma, 1 melanoma, 1 colon carcinoma and 1 non small cell bronchial carcinoma. We observed an improvement in the response from the initiation of treatment: PR: 32.4 to 17.4%, VGPR: 56.8 to 49.3%, CR: 9.5 to 28%, sCR: 0 to 5.3% (at initiation to best response, respectively). A total of 33.4% of pts improved their response. The median PFS was 33.2 months (95% CI: 25.6-53.3). 41 pts died and the median OS was not reached (95% CI: 70.7-NR). All deaths were related to myeloma progression except 2 due to pulmonary infection, 1 lung carcinoma and 1 colorectal cancer. Conclusions: In the first relapse PCD trial, 75% initiated maintenance therapy. Long term administration of pomalidomide/dexamethasone as maintenance therapy is feasible. Thirty percent stopped pomalidomide because of SAE/AE, mostly related to hematologic AE, but this could be managed with dose reductions. There was generally G1/2 neuropathy, rare SPM and no other unexpected toxicity. One third of the pts improved their depth of response. The combination is safe, feasible and well tolerated and experience to date supports its further exploration with monoclonal antibodies. Figure 1 Figure 1. Disclosures Garderet: Amgen: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy. Roussel: Amgen: Consultancy; BMS: Honoraria; GSK: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy. Leleu: Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Oncopeptides: Honoraria; Pierre Fabre: Honoraria; Roche: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support. Karlin: Takeda: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Sanofi: Honoraria; Abbvie: Honoraria; oncopeptide: Honoraria; GSK: Honoraria, Other: member of advisory board; Janssen: Honoraria, Other: member of advisory board, travel support; Celgene-BMS: Honoraria, Other: member of advisory board. Perrot: Abbvie: Honoraria; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: 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. Moreau: Abbvie: Honoraria; Oncopeptides: Honoraria; Celgene BMS: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Janssen: Honoraria. Macro: abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; takeda: Honoraria; janssen: Honoraria. Jourdan: Novartis: Consultancy; Abbvie: Consultancy; bms/celgene: Consultancy. Jaccard: Pfizer: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria. Mohty: Celgene: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Astellas: Honoraria; Amgen: Honoraria; Sanofi: Honoraria, Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Takeda: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Adaptive Biotechnologies: Honoraria. Hulin: Celgene/BMS: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; abbvie: Honoraria. OffLabel Disclosure: pomalidomide as maintenance treatment

It is important to have an effective therapy for patients with multiple myeloma (MM) at first relapse, particularly if an autologous stem cell transplant (ASCT) is considered at this stage. This multicenter, phase 2 trial evaluated the efficacy and safety of weekly oral pomalidomide-cyclophosphamide-dexamethasone (PCD) in patients with MM in first relapse after treatment with lenalidomide-bortezomib-dexamethasone (RVD). All patients had received RVD as induction and consolidation therapy, plus lenalidomide maintenance for 1 year (arm A). Half had also received an ASCT after induction (arm B). At MM relapse, all patients received 4 oral cycles of pomalidomide 4 mg (days 1-21), cyclophosphamide 300 mg (days 1, 8, 15, and 22), and dexamethasone 40 mg (days 1-4 and days 15-18 of a 28-day cycle; PCD). Responding patients in arm A underwent ASCT and received 2 additional cycles of PCD, whereas those in arm B received 5 cycles of PCD. All patients received pomalidomide-dexamethasone maintenance until disease progression. Primary end point was partial remission or better after the initial 4 cycles of PCD. Responses were obtained in 82/97 (85%) patients evaluated: complete remission (n = 1; 1%), very good partial remission (n = 32; 33%), and partial remission (n = 49; 51%). Three patients (3%) had stable disease, and 6 (6%) had disease progression (6 response failures). Forty-five (94%) of the 48 patients in arm A underwent planned ASCT. PCD was effective therapy after first relapse with RVD. After 4 cycles, the rate of partial remission or better was 85%, and 94% of planned ASCTs were performed. Toxicity was mostly hematologic and manageable. This trial was registered at www.clinicaltrials.gov as #NCT02244125.

Evolution d’une relationDepuis le diagnostic jusqu’a la phase la plus avancee de la maladie, la relation medecin-patient connait de nombreuses evolutions. Les positionnements de chacun changent, evoluent, et dans cette relation polymorphe et mouvante, on voit emerger a grand traits quelques constantes.Au diagnostic, souvent le medecin se positionne dans un role actif, il dispose alors d’une position de savoir absolu face a l’autre souffrant, ebranle par l’annonce, en rupture [...]

International audience; Prognosis of Philadelphia-positive (Ph(+)) acute lymphoblastic leukemia (ALL) in the elderly has improved during the imatinib era. We investigated dasatinib, another potent tyrosine kinase inhibitor, in combination with low-intensity chemotherapy. Patients older than age 55 years were included in the European Working Group on Adult ALL (EWALL) study number 01 for Ph(+) ALL (EWALL-PH-01 international study) and were treated with dasatinib 140 mg/day (100 mg/day over 70 years) with intrathecal chemotherapy, vincristine, and dexamethasone during induction. Patients in complete remission continued consolidation with dasatinib, sequentially with cytarabine, asparaginase, and methotrexate for 6 months. Maintenance therapy was dasatinib and vincristine/dexamethasone reinductions for 18 months followed by dasatinib until relapse or death. Seventy-one patients with a median age of 69 years were enrolled; 77% had a high comorbidity score. Complete remission rate was 96% and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation. Only 7 patients underwent allogeneic hematopoietic stem cell transplantation. At 5 years, overall survival was 36% and up to 45% taking into account deaths unrelated to disease or treatment as competitors. Thirty-six patients relapsed, 24 were tested for mutation by Sanger sequencing, and 75% were T315I-positive. BCR-ABL1(T315I) was tested by allele-specific oligonucleotide reverse transcription-quantitative polymerase chain reaction in 43 patients and detection was associated with short-term relapses. Ten patients (23%) were positive before any therapy and 8 relapsed, all with this mutation. In conclusion, dasatinib combined with low-intensity chemotherapy was well-tolerated and gave long-term survival in 36% of elderly patients with Ph(+) ALL. Monitoring of BCR-ABL1(T315I) from diagnosis identified patients with at high risk of early relapse and may help to personalize therapy

Introduction We aimed to confirm the diagnostic value and to evaluate the pre- and post-therapeutic prognostic value of cerebrospinal fluid (CSF) concentrations of interleukin (IL)-10 and IL-6 in patients with diffuse large B-cell primary central nervous system lymphoma (PCNSL). Patients and methods IL-10 and IL-6 concentrations were measured in 79 patients with PCNSL at diagnosis and in 40 control individuals. Fifty-four PCNSL patients underwent repeat assessments starting at diagnosis. Results The IL-10 concentration distinguished PCNSL from other neurologic diseases with a sensitivity of 88.6% and a specificity of 88.9% with a cutoff of 4 pg/ml. In a multivariate analysis of PCNSL patients, CSF involvement was associated with a higher IL-10 concentration (mean log (IL-10) of 4.4 versus 2.5 pg/ml, respectively, p = 0.0004). The pre-therapeutic IL-10 concentration had no prognostic impact on outcome. The IL-10 concentration decreased after treatment for most patients tested. Among patients with complete remission or partial remission, as evaluated by magnetic resonance imaging (MRI), a persistent detectable IL-10 level in the CSF at the end of treatment was associated with a negative impact on progression-free survival (PFS) (1-year PFS: 15%, 95% confidence interval [CI]: 2.5–38% versus 59%, 95% CI: 32–78%, respectively, p = 0.0004). Conclusion Our study confirmed that IL-10 is a useful biomarker for the diagnosis of PCNSL. We highlight new findings showing that the IL-10 level in the CSF could be used as a surrogate marker for CSF involvement and that the post-treatment IL-10 concentration could complement standard MRI for therapeutic response assessment in PCNSL.

The Intergroupe Francophone du Myelome conducted a randomized trial to compare bortezomib-thalidomide-dexamethasone (VTD) with bortezomib-cyclophosphamide-dexamethasone (VCD) as induction before high-dose therapy and autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma. Overall, a total of 340 patients were centrally randomly assigned to receive VTD or VCD. After 4 cycles, on an intent-to-treat basis, 66.3% of the patients in the VTD arm achieved at least a very good partial response (primary end point) vs 56.2% in the VCD arm (P = .05). In addition, the overall response rate was significantly higher in the VTD arm (92.3% vs 83.4% in the VCD arm; P = .01). Hematologic toxicity was higher in the VCD arm, with significantly increased rates of grade 3 and 4 anemia, thrombocytopenia, and neutropenia. On the other hand, the rate of peripheral neuropathy (PN) was significantly higher in the VTD arm. With the exception of hematologic adverse events and PN, other grade 3 or 4 toxicities were rare, with no significant differences between the VTD and VCD arms. Our data support the preferential use of VTD rather than VCD in preparation for ASCT. This trial was registered at www.clinicaltrials.gov as #NCT01564537 and at EudraCT as #2013-003174-27.

Background: Acute Myeloid Leukemia (AML) is a heterogeneous disease carrying a dismal prognosis. This outcome is the consequence of patient factors (age, comorbidity) and intrinsic biologic abnormalities. Cytogenetic and mutational data are already used to define treatment strategy, but many cellular signaling pathways are deregulated in AML, including targetable PI3K/mTOR pathway. Activation of the PI3K/mTOR pathway promotes cell growth, survival and resistance to chemotherapy and is detected in virtually all AML samples. mTOR, a serine/threonine kinase downstream of PI3K, may be activated independently of PI3K. Gedatolisib is a small molecule in development of solid tumors. It inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of leukemic cells. We explored the clinical activity and tolerance of Gedatolisib in the particularly underserved group of relapse/refractory and adverse prognosis AML. Methods: We conducted an open, prospective, single-arm, multicentric phase 2 trial in 4 academic French hematology centers. Enrollment took place between September 2015 and August 2016. Inclusion criteria were relapse/refractory AML and therapy-related AML. Experimental drug dosage was derived from phase 1 studies in solid tumors. Treatment protocol consisted in 4 cycles, each cycle containing 4 weekly injections of Gedatolisib 150 mg delivered IV. Monitoring included weekly blood counts and bone marrow (BM) aspiration after 2 and 4 cycles. Primary objective was Overall Response Rate and secondary objectives were Progression-Free Survival (PFS) and Overall Survival (OS). An ancillary biologic study focused on RNA sequencing (RNAseq) of AML-infiltrated BM samples (>30% blasts at diagnosis) before and after drug exposure to explore its molecular impact. This trial was funded by French National Cancer Institute (INCa) and registered as NCT02438761. Results: 12 patients were included but only 10 patients were retained in the final analysis. 6 patients (pts) were males (60%) and the median age was 59.6 years (range: 33-74). All pts had relapsed AML (5 pts in 1st relapse, 5 pts in 2nd relapse) and symptomatic uncontrolled AML. 1 patient (pt) had therapy-related AML (prostate adenocarcinoma). Cytogenetic risk: 4 pts had intermediate and 6 pts had adverse risk. Only 1 pt completed the treatment including 4 cycles of Gedatolisib. 1 pt received 3 cycles, 3 pts received 2 cycles and 5 pts received 1 cycle (i.e. 4 injections). Reasons for early patient withdrawal were: objective disease progression for 5 pts (including uncontrolled hyperleukocytosis for 4 pts), global deterioration of health status for 2 pts, treatment-related adverse event for 1 pt (anal ulcer), treatment-unrelated adverse event for 1 patient (pneumonia). No objective response was detected for any of the 10 pts according to the IWG AML criteria (Cheson, 2003). Serious adverse events included mouth ulcers (2 pts) and anal ulcer (1 pt). Median follow-up was 4.4 months (mo) (range: 1.7-16.3). OS was 3.5 mo (IC95%=2 mo). PFS was 2.3 mo (IC95%=2 mo). The biologic study used 6 paired BM samples (at inclusion and after drug exposure) which could be analyzed by RNAseq: 1 pair after 4 cycles, 3 pairs after 2 cycles, 2 pairs after more than 1 cycle (6 and 7 drug injections). Transcriptomic principal component analysis showed that each pair clustered together and apart of the other samples, reflecting the heterogeneity of the cohort. The drug impacts weakly gene expression pattern as only 38 genes were significantly differentially-expressed. Among up-regulated genes, 4 were associated with NK cell immunity. Gedatolisib might affect immune cells as already described for other PI3K inhibitors. We detected 23 pathogenic variants and 58 variants of unknown pathogenicity (median=6 variants/sample [1-22]) without obvious correlation with drug resistance. Ongoing research focuses on genes and pathways previously associated with PI3K inhibitor resistance in solid tumors. Conclusion: Gedatolisib, a dual PI3K/mTOR inhibitor used as a single therapy had no clinical benefit in adverse prognosis and relapsed/refractory AML patients. Combination of Gedatolisib with chemotherapy was not explored, yet this could be a potential therapeutic development, as it was recently shown for Midostaurin and FLT3-mutated AML. Disclosures No relevant conflicts of interest to declare.

Introduction ASCT is a cornerstone in lymphoma therapeutics, especially in the relapse setting. BEAM (carmustine, etoposide, cytarabine, and melphalan) is the most widely used conditioning regimen with a low rate of transplant mortality. Bendamustine has occasionally been used in France as a substitute for carmustine during a period of shortage ("BendaEAM"). SOS is a potentially life-threatening complication, rarely observed in ASCT. In an EBMT study of 1010 ASCT, SOS occurred in less than 1% after BEAM in patients who had a normal level of AST before conditioning1. After having observed 5 cases of SOS in our institution during a 3 year period and numerous cases in other centers, we did perform a retrospective study in order to try to understand the apparent increase in incidence of this complication. Methods After a national alert spread through our cooperative group (LYSA) and the French health agency (ANSM), we collected history of lymphoma, hepatic disease, chemotherapy, SOS risks factor, conditioning of ASCT, diagnostic criteria for SOS (based on the EBMT classification2 or liver biopsy), treatment and outcomes. We did determine the incidence in 2 centers (Henri Mondor University Hospital and Curie Institute) where the total number of ASCT was available. Results We observed 6 cases of SOS after ASCT in Henri Mondor University Hospital during the last 10 years (incidence 4.1% on 145 ASCT for lymphoma) among which the 5 most recent cases had oxaliplatin exposure before ASCT. Oxaliplatin exposition tended to be associated with SOS (p=0.09). In Curie Institute, a SOS incidence of 3/46 (6.5%) was reported during a 6 year-period, and all three patients had received oxaliplatin before ASCT. A national query permitted to find 22 cases of SOS in 10 centers during the last 6 years. Twenty had a history of oxaliplatine exposure before ASCT. Principal characteristics are presented in table 1. No patient had a history of cirrhosis or significant hepatic pathology. Two patients had liver infiltration due to the lymphoma before treatment by oxaliplatin. The majority of patients didn't present with any of the known risk factors for SOS. One patient had liver anomalies (AST > 2 ULN and cholestasis) after 4 cycles of an oxaliplatin-containing regimen for relapsing diffuse large B-cell lymphoma. Biopsy of liver showed early sinusoidal lesions. Despite these results, he proceeded to ASCT with BEAM conditioning and experimented a moderate form of SOS. Five patients received fluconazole and aprepitant during conditioning. Discussion During the last decade, cisplatin was often substituted by oxaliplatin inside the DHAP protocol in order to avoid renal impairment. Pre-operative oxaliplatin in hepatic metastases of colorectal cancer leads to asymptomatic damage of sinusoidal endothelial cells (SEC) in half of the patients3. Our principal hypothesis is that oxaliplatin provokes a frailty of liver and conditioning of ASCT and co-factors (peg-filgrastim and cytochromes inhibitors- fluconazole and aprepitant) lead to SOS. SEC had a receptor for G-CSF and activation of this receptor lead to inflammatory state4. Peg-filgrastim administered at a fixed dose in the early time of ASCT (Day+1 or +3) with low concurrence increases the inflammatory state of SEC. Fluconazole and aprepitant are inhibitors of cytochromes 3A4 which metabolize etoposide. Each inhibitor could increase exposition to etoposide. Five patients received both inhibitors during conditioning which might have increased liver toxicity which led to SOS. Conclusion We want to warn about the probable association of oxaliplatin before ASCT and SOS. In some French centers, this led to switch oxaliplatin by carboplatin for patients eligible to ASCT. BibliographyCarreras E et al. Incidence and outcome of hepatic VOD after blood or marrow transplantation: a prospective cohort study of the EBMT. Blood. 1998;92(10):3599-3604.Mohty M et al. Revised diagnosis and severity criteria for SOS/VOD in adult patients: a new classification from the EBMT. Bone Marrow Transplant. 2016;51(7):906-912.Rubbia-Brandt L et al. Severe SOS associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol. 2004;15(3):460-466.Fusté B et al. GSF factor increases expression of adhesion receptors on endothelial cells through activation of p38 MAPK. Haematologica, 2004;8. Table 1. Table 1. Disclosures Tilly: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria. Haioun:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sciences: Consultancy, Honoraria.

Background This multicentre, single-arm, open-label phase 2 trial investigated the efficacy and safety of lenalidomide monotherapy in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL). Methods Patients received oral lenalidomide 25mg once daily on days 1–21 of each 28-day cycle for a maximum of 24months, until disease progression or development of unacceptable adverse events (AEs). The primary end-point was efficacy; safety was evaluated as a secondary end-point. This study was registered with ClinicalTrials.gov, number NCT00655668. Findings A total of 54 patients with PTCL were treated. The overall response rate was 22% (12 of 54), including complete response (CR) or unconfirmed CR (CRu) in 11% of patients; 31% of patients with angioimmunoblastic T-cell lymphoma (AITL) responded (CR/CRu in 15% of patients). The median progression-free survival and median response duration were 2.5 and 3.6months, respectively, in the intent-to-treat population, and 4.6 and 3.5months, respectively, in patients with AITL. Thrombocytopenia and neutropenia were the most common grade 3 or 4 haematological AEs, in 11 (20%) and 8 (15%) patients, respectively. Overall, 19 patients (35%) experienced at least 1AE leading to study dose interruption or reduction (commonly neutropenia or thrombocytopenia). Serious AEs were observed in 54% of patients and 12 patients died during the study; lymphoma progression ( n =6); and acute respiratory distress syndrome, dyspnea, lung infiltration, neutropenic sepsis, pneumonia and cerebral ischaemia ( n =1 each). Interpretation Lenalidomide exhibited single-agent activity in heavily pretreated patients with PTCL, particularly in patients with AITL. Future development is warranted in specific histologies, such as AITL, and in combination with chemotherapy or other agents considered active in PTCL. Funding Celgene Corporation.

The aim of this study was to evaluate the efficacy and toxicity of two chemotherapy regimens based on platinum and cytarabine in association with etoposide and methylprednisolone (ESHAP) or with dexamethasone (DHAP) with or without Rituximab (± R) in patients with refractory or a relapsed Primary Central Nervous System Lymphoma (PCNSL). All consecutive patients from two French centers with refractory or relapsed PCNSL treated with ESHAP/DHAP ± R were included. We analyzed the overall response rate (ORR), toxicity and overall survival (OS) after salvage chemotherapy. Intensive chemotherapy and hematopoietic stem cell rescue (IC + HCR) was offered to patients less than 65 years of age and consisted of high-dose thiotepa, busulfan and cyclophosphamide. These results were compared with two previously reported series of PCNSL patients treated with the CYVE (high-dose cytarabine and etoposide) regimen at relapse. Twenty-two patients received a total of 60 DHAP/ESHAP cycles (median 3; range 1–5). The median age was 59 years. The ORR after salvage chemotherapy was 59%. Toxicity was mainly hematological, 18% of patients showing febrile neutropenia. There was no treatment-related death. ESHAP or DHAP regimens led to similar ORRs compared to the CYVE regimen in relapsed or refractory PCNSL, although they seemed less toxic. The therapeutic results of the ESHAP/DHAP regimens in relapsed or refractory PCNSL were also similar to those for relapsed systemic non-Hodgkin’s lymphomas (sNHL). Both chemotherapies, CYVE regimen and ESHAP/DHAP are treatment options to be considered in relapsed or refractory PCNSL, especially when IC + HCR is planned as a consolidation treatment. More efforts are still needed to improve the ORR at relapse.

Background Induction therapy followed by autologous stem cell transplantation (ASCT) is the standard of care for patients with symptomatic multiple myeloma less than 66 years old. The quality of response to the induction treatment is an important prognostic factor and is predictive of progression free survival (PFS) following ASCT. The triplet combinations bortezomib-thalidomide-dexamethasone (VTD) and bortezomib-cyclophosphamide-dexamethasone (VCD) have demonstrated high response rates in prospective phase 2 and phase 3 clinical trials, they are 2 of the most commonly used induction regimens prior to ASCT, and are both recommended in the International guidelines. To date, no comparative data from prospective randomized trials of the safety and efficacy of VTD vs VCD are available. This provided the rationale for the phase 3 investigation of VTD vs VCD prior to ASCT in patients with de novo MM in this randomized multicenter study (NCT01564537). Methods Patients with de novo symptomatic MM less than 66 years old were prospectively randomized to receive either 4 cycles of VTD (arm A) or 4 cycles of VCD (arm B) followed by ASCT. The VTD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, subcutaneously (SC) D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Thalidomide 100 mg/d, PO D1 to D21. The VCD regimen consisted of four 21-day cycles of bortezomib 1.3 mg/m²/d, SC D1, 4, 8 and 11, Dexamethasone 40 mg/d, PO D1 to 4, D9 to 12 and Cyclophosphamide 500 mg/m²/d, PO D1, 8, 15. Patients were stratified according to ISS (1-2 versus 3) and cytogenetics (high-risk defined by 17p deletion and t(4;14) versus other).The primary endpoint was very good partial response (VGPR) rate following 4 cycles. Response was assessed in a central lab according to the IMWG criteria. Assuming a VGPR rate of 60% in the VTD arm versus 45% in the VCD arm (15% difference), the possibility to detect a statistically significant difference required the enrolment of 340 patients overall (170 per arm). Adverse events were graded using the NCI CTCAE catalogue, version 4.0. Results From 11/2013 to 02/2015, 358 patients were enrolled into the study. 18 were screening failures, and 170 were randomized each to arm A (VTD) and arm B (VCD). The median age was 60 years (range, 26-65), 62% of the patients were male, and overall, the patient characteristics were well-balanced across the 2 arms of the study. The median number of induction cycles administered in both arms was 4 (1-4). On an intent-to-treat basis, the overall response rate (> partial response [PR]) was 92.3% in arm A, including a 10.7% complete response (CR) rate and a VGPR rate of 66.7%, while in arm B the overall response rate was 84%, with a 9.5% CR and a 56.2% VGPR rate. VGPR and PR rates were significantly higher in the VTD arm with p-values of 0.04 and 0.02, respectively. Seven patients died during induction therapy (2%), 3 in arm A from infections (2) and pulmonary embolism (1), and 4 in arm B from progression to extramedullary myeloma (2) and infections (2). Grades 3 / 4 peripheral neuropathy occurred in 4% and 2.2% in Arm A and B, respectively. Grade 3/4 neutropenia was seen in 11.9% vs 22.5% in Arm A and B, respectively. Conclusion This trial is the first prospective randomized comparison of 4 cycles of VTD versus 4 cycles of VCD administered as induction therapy prior to ASCT. VTD was shown to be significantly superior to VCD in terms of VGPR and PR rates. Neuropathy rates low in both arms, while neutropenia was more frequent with VCD. Disclosures Moreau: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: 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; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin:Celgene Corporation: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. MACRO:celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Garderet:Bristol-Myers Squibb: Consultancy. Stoppa:Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Facon:Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Laribi:Hospira SAS: Research Funding. Avet-Loiseau:jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; jansen: Membership on an entity's Board of Directors or advisory committees; onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Attal:jansen: Honoraria; celgene: Membership on an entity's Board of Directors or advisory committees.

Background: Cancer-related anemia is a very frequent condition of complex physiopathology which impacts heavily on quality of life, morbidity and mortality of cancer patients. Treatment options are limited to red blood cell transfusion, erythropoiesis stimulating agents (ESA) and intravenous (IV) iron administration alone or combined. IV iron administration is being increasingly advocated over transfusion and ESA because of reduced costs and satisfactory safety profile. Efficacy was mainly evaluated in selected early phase cancer patients. Concerns about infection rates and tumor growth/promotion by systemic iron administration were not addressed. Aim of the study: To evaluate the efficacy of ferric carboxymaltose alone or combined with erythropoietin in a French cohort of advanced cancer patients Methods: This retrospective single-center study is derived from a pharmacy database recording 139 ferric carboxymaltose infusions for 137 patients in a cancer center between February 2012 and December 2013. Median age is 66 y (38-91), sex ratio is 81% F/M, 84% of patients are metastatic, distribution of primary tumor sites is: 52% breast, 22% gynecologic, 17% gastrointestinal, 9% others. Hematologic patients were excluded. Renal function is satisfactory for all patients. 78 patients are treated with iron alone, 61 with iron + ESA. Baseline median laboratory parameters are: 9.7 g/dl (7.2-14.1) for hemoglobin (Hb), 22 mg/l (0.06-305) for CRP, 391 µg/l (21-4248) for ferritin, 0.14% (0.03-0.32) for transferrin saturation. There is no statistical difference between the 2 groups for population and laboratory data. 77% and 97% of iron alone and combined group patients receive concomitant chemotherapy, respectively. Results: Median increase in Hb from baseline after 1 and 3 months of treatment for the total cohort is +0.8 g/dl (-2.9-+5.7) and +0.1 g/dl (-3.9-+4) respectively. Yet of modest magnitude, these 2 increments are statistically significant (p Conclusions: Carboxymaltose either alone or combined with ESA was well tolerated in an advanced cancer cohort. The 2 treatments could increase Hb at 1 month without difference between them. The increments obtained for Hb although statistically significant do not seem to be clinically relevant when considering potential dangers such as infection rate and potential iron diversion by tumor metabolism to promote cancer growth. Prospective controlled studies are warranted to evaluate the true clinical benefit of IV iron in cancer patients balancing Hb increase, quality of life and tumor evolution. Disclosures No relevant conflicts of interest to declare.

The ubiquitination of nuclear proteins activated in human lymphocytes undergoing radiation-induced apoptosis and the subsequent downstream proteasomal protein processing, shown to be involved in apoptotic death control, may be dependent on an amino-terminal sequence identity of ubiquitin target proteins, the “N-end rule” pathway. Here we report that this selective pathway controls radiation-induced apoptosis and that it is involved in the initiation of this type of cell death. Dipeptide competitors of protein ubiquitination/processing dependent solely on the basic amino-terminal residues (type I) efficiently inhibited the radiation-induced apoptotic death phenotype, indicating that only the substrates of ubiquitination with basic NH2-terminal amino acids are involved in apoptotic death control. This selective inhibition was followed by an early, overall but also target-specific inhibition of ubiquitination and by an activation and stabilization of poly(ADP-ribose) polymerase (PARP) that occurs through inhibition of ubiquitination of its cleaved form (85 kDa). Interestingly, caspases-3 and -7 were not activated following irradiation, further suggesting that PARP cleavage may be regulated by an N-end rule pathway in a caspase-independent manner. These results highly suggest involvement of this subset of the ubiquitin system in the apoptotic death control and in the specific regulation of PARP activity.

Between March 1992 and August 1993, thirty patients with hairy cell leukemia (HCL) were treated in a single institution with 2-chlorodeoxyadenosine (2-CdA) for one course (N=27) or two courses at six month interval (N=3). Sixteen patients were previously untreated, 14 had been treated with alpha interferon (alpha IFN) (N=5), alpha IFN and splenectomy (N=8) and splenectomy, alpha IFN and Deoxycoformycin (N=1). Overall results in 29 evaluable patients were: 25 CR (86%), 3 PR (10%), one failure. The three PR patients relapsed after 18, 24 months and five years. Two were retreated successfully. Two CR patients relapsed after five years. Careful clinical survey, sequential bone marrow biopsies (BMB) with DBA44 immunostaining for assessment of response and detection of residual disease and serially evaluation of lymphocyte subsets counts were performed. Results of bone marrow biopsies study show 1) a progressive reduction in hairy cell infiltration during the first six months after therapy and not after that indicating that the best moment for the evaluation of response may be the sixth month, 2) the persistence of a very small number of DBA44+ cells (80% of BMB). There was a correlation between the presence of > 5% DBA44 positive cells on 6th month BMB and relapse. 60% had an absolute CD4+ lymphocyte count less than 0.2 10(9)/l at least on one examination after treatment. CD4+ lymphocyte level persisted less than baseline level in 8/18 patients tested after four and/or five years. Lymphopenia was less marked in splenectomized patients: 7/7 splenectomized patients tested have recovered a CD4+ lymphocyte count equal to pretherapy level compared to 3/11 non splenectomized patients (p: 0.004). Three opportunistic infections were observed early (first 6 months) after 2CdA therapy: pneumocystis pneumonia, retinitis due to toxoplasma in the patient who failed and legionella pneumonia in a patient retreated after relapse. Two patients developed a second carcinoma 6 and 12 months after therapy. Five patients died, three from a cause unrelated to HCL, one from HCL and one from infection while in second CR. At five years, overall survival is 83% and progression free survival is 66%. Our study shows 1) long-lasting response in the majority of patients after 2-CdA, 2) a correlation between persistent minimal residual disease detected with DBA44 immunostaining and occurrence of relapse and 3) a profound and persistent CD4+ lymphopenia more marked in non splenectomized patients.

Non-Hodgkin lymphoma (NHL) involving the pituitary gland is rare. Intense focal FDG uptake was found in the pituitary gland on F-18 fluorodeoxyglucose positron emission tomography combined with CT (FDG-PET/CT) performed for NHL pretherapeutic staging. Brain magnetic resonance imaging (MRI)

We report a high incidence of subacute, chronic and sometimes occult intracranial subdural haematoma (SDH) occurring during intensive chemotherapy for acute myeloid leukaemia (AML) with a monoblastic component. Between March 1990 and January 1993, 86 AML patients from our institution were randomized in the multicentric French AML 90 trial. Eight patients (9%) presented a grade > 2 haemorrhagic event, which was intracranial SDH in five of them. All these five SDH patients had hyperleucocytic AML4 or AML5 and had experienced at least one lumbar puncture (LP) before SDH diagnosis (with intrathecal chemotherapy in four cases). SDH diagnosis was assessed on a brain computed tomography scan which was performed 1-9 d after initial SDH symptoms (mainly mild headaches considered a result of prior LP). All these five patients recovered from this severe event after a specified therapy. SDH does not appear to be an uncommon complication of AML4 and AML5 therapy. Its incidence might be under-reported because of poor symptomatology. Lumbar punctures, known to cause exceptional SDH in nonleukaemic patients, might trigger these haemorrhagic events, eventually in combination with other predisposing factors such a haemostasis disorders or leukaemic CNS infiltration.