In order to determine whether granulocyte colony-stimulating factor (G-CSF) alone initiated during steady state was able to mobilize peripheral blood stem cells (PBSC) in acute myeloid leukemia (AML) and to assess predictive factors for engraftment after autologous PBSC transplantation, we studied 49 successive adult AML patients for whom autologous transplantation was planned between July 1994 and November 1998. G-CSF was used as priming agent and was initiated at least 4 weeks after the last day of chemotherapy, while neutrophil count was >0.5 x 10(9)/l and platelet count was >30 x 10(9)/l. A median of three aphereses was performed resulting in a median collection of 14.8 x 10(8) nucleated cells/kg containing 7.7 x 10(8) mononuclear cells/kg, 47.1 x 10(4) CFU-GM/kg, and 3.8 x 10(6) CD34+ cells/kg. A significant correlation was observed between nucleated cell, mononuclear cell, and CFU-GM yields, while no correlation was found with CD34+ cell yield. Recruitment was not significantly different in patients with CD34+ leukemic cells at the time of initial diagnosis when compared to that of those presenting with CD34- blastic cells. Thirty-three patients actually underwent transplantation. Reasons for not autografting were inadequate stem cell harvest (ten patients), early relapse (two patients), prolonged neutropenia (one patient), organ failure (two patients), or patient refusal (one patient). Median time to achieve a neutrophil count greater than 0.5 x 10(9)/l and platelet count >50 x 10(9)/l untransfused was 13 and 36 days, respectively. A predictive factor for a shorter period neutropenia and a shorter thrombopenia was a higher count of harvested nucleated cells (p < 0.01 and p = 0.02, respectively). A higher count of harvested cells was also a predictive factor for less red cell and platelet transfusions (p=0.03 and p=0.02, respectively). The number of CD34+ harvested PBSC was not predictive for engraftment. We conclude that PBSC mobilization with G-CSF alone initiated in steady state is a feasible, safe, and suitable procedure for harvesting cells in sight of autologous transplantation in adult acute myeloid leukemia.

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We report 28 patients (pts) who experienced late onset severe neutropenia (NCI/CTC grade III/IV) after rituximab. Rituximab had been given for the treatment of DLCL(N=15), follicular lymphoma (N=9), mantle cell lymphoma (N=2), CLL (N=2). Rituximab was administered as a front line treatment (N=11), for recurrent disease (N=17), before ASCT (N=1) or after ASCT (N=5). Rituximab was given as a single agent (N=14), with CHOP (N=9) or with other regimen (N=5). Rituximab was given at a dose of 375mg/m2 at weekly intervals over a period of 4 weeks when used as a single agent, or as a single dose of 375mg/m2 with chemotherapy. Characteriscs of neutropenia are summarized in Table. At the time of the neutropenia, all the pts were in CR or VGPR. In 3 pts, the neutropenia had relapsed. All 3 pts were still in CR, and had not been retreated with rituximab. 3 patients were retreated with rituximab for a recurrence of their NHL after the outbreak of neutropenia and 1 pt experienced a further episode of neutropenia after the reintroduction of rituximab. Tests for anti PMN antibodies were performed in 6 pts. In 4 pts, antibodies bound to the surface of neutrophils were detected by the direct neutrophil immunofluorescence test. No antibody could be detected in the serum. A direct toxic effect of rituximab can be ruled out as granulocytes and uncommitted hematopoietic precursor stem cells do not express CD 20. We propose the following hypothesis. The rituximab-induced depletion of the normal B-lymphocyte population was followed by the acquisition of a new immune repertoire under non physiological condition which could promote the transient production of autoantibodies. Some of these antibodies might target either neutrophils or hematopoietic precursors. Some of these antibodies might also be directed against other cells since other delayed-onset cytopenia have been reported after the administration of rituximab, pure red aplasia in particular. An other possible mechanism can be proposed. Rituximab administration could lead to the production of antibodies directed against the complex formed when rituximab is bound to the FcγRIIIb receptor on the PMN. This hypothesis does not account for the delay between the administration of rituximab and the onset of the neutropenia. Characteristics of neutropenic episodes. Characteristics N *: interval between the last infusion of rituximab and the nadir of neutropenia. **: 1 pt was lost to follow-up for 4.5 months but had a normal blood count subsequently. Median time to neutropenia (range) (weeks)* 15 (4–33) Nadir PMN 10x9/L median (range) 0.135 (0–0.760) Bone marrow aspiration 14 Hypocellular marrow 7 Normocellular marrow with severe reduction in mature neutrophils 6 Normal 1 Fever/sepsis 6/1 Patients treated with G-CSF/duration (range) (days) 12/6 (3–21) Duration of neutropenia (range) (days) Patients treated with G-CSF N=12 4 (2-53) Patients not treated with G-CSF N=16 12 (4–105)** Follow-up from the nadir of neutropenia (range) (month) 6 (0.5–36) NHL/CLL status at follow-up CR or CRu 22 VGPR 1 Progression 5 Status of PMN count at follow-up Normal 26 Neutropenia 2

Background. New standards with increasing efficacy that are also characterized with improving the quality of life are needed for elderly myeloma patients. Although MPT and MPV regimens are remarkable in terms of efficacy, quality of life while on treatment with these 2 regimens remain an issue. The Carmysap twice weekly carfilzomib-based phase 2 study has demonstrated that Carfilzomib at the MTD of 36mg/m² might challenge bortezomib in the VMP standard. However, it has become routine practice to use bortezomib on a weekly schedule, with maintained efficacy and an improved safety profile. We sought to demonstrate that Carfilzomib Weekly plus Melphalan and Prednisone will prove strongly efficacious with acceptable safety profile and quality of life to newly diagnosed elderly multiple myeloma (eNDMM). Methods . IFM2012-03 (also called carmysap weekly) is a phase 1/2 multicenter open label single arm study to determine MTD during the phase 1 part and VGPR+CR rate during the phase 2 part of the study. The inclusion/exclusion criteria of interest were eNDMM (65 and older), with symptomatic and measurable disease, with absolute neutrophils ≥1 G/L, untransfused platelet count ≥75 G/L, hemoglobine ≥8.5 g/dL and clairance creatinine ≥ 30ml/min. We report herein the phase 1 part of the study which last cohort was completed at ASH abstract deadline. For the phase 1 part of the study, each cohort was 6 patients based, and started at 36mg/m² of carfilzomib on days 1, 8, 15, 22 using IV, 30 minutes infusion, route followed by a 13-day rest period per 35-days cycles, melphalan given at 0.25mg/kg/j and oral prednisone 60mg/m², both on days 1 to 4. The subsequent cohorts' doses for carfilzomib were 45, then 56 and finally 70mg/m². 9 cycles were planned as induction followed by a maintenance phase of weekly carfilzomib monotherapy given at 36mg/m² weekly for one year. The MTD was determined when ˃2 DLTs were observed. DLTs were considered during cycle 1 if any hematologic toxicity of grade 4 intensity or preventing administration of 2 or more of the 4 carfilzomib doses of the first treatment cycle, grade ≥3 febrile neutropenia, grade ≥3 gastrointestinal toxicities, any other grade ≥3 nonhematologic toxicity considered related to CMP by the principal investigator, grade ≥ 3 peripheral neuropathy persisting for more than 3 weeks after discontinuation of study drugs. Results. 26 NDMM patients recruited, 24 treated in the study, 6 per cohort at 36 mg/m² carfilzomib +MP, then 45 then 56, and finally at 70mg/m² which cohort cycle 1 is up and running. The median age was 74 with 10 patients older than 75 and sex ratio M/F 65. There was a DLT at 36 mg/m² carfilzomib (grade 4 lymphopenia), one at 45 (lysis syndrome complicated with grade 4 renal insufficiency, two at 56 (cardiac insufficiency grade 3 and febrile neutropenia grade 3). At ASH deadline, all patients from cohort 36 of carfilzomib have completed induction and maintenance up to cycle 6, 5/6 of cohort 45 have completed induction and started the maintenance phase, 5/6 of cohort 56 have completed cycle 6 of induction and pursue within the induction phase, and finally all patients from cohort 70 of carfilzomib are undergoing cycle 1. There are 22 SAE reported for a total of 171 cycles administered of carfilzomib +MP. So far, 3 patients (out of 24) have stopped treatment, including the 2 patients with DLTs, lysis syndrome and cardiac failure, and one patient that presented with pulmonary hypertension later in the disease course on cycle 5 of the 56mg/m² carfilzomib +MP cohort. And, an extra 3 patients have had Carfilzomib dose reduction, 2 patients at 36 from 45 and one at 45 from 56, for neutropenia grade 4, thrombocytopenia grade 4, and Dyspnea grade 3, respectively. Conclusion. The MTD of weekly carfilzomib in the combination to Melphalan and Prednisone could be determined at 70mg/m² in elderly NDMM, demonstrating the good safety profile of carfilzomib in this regimen and fragile population. The complete dataset of the entire study will be updated at ASH with response rate, survival and safety profile. Disclosures Leleu: Chugai: Honoraria; LeoPharma: Honoraria; Pierre Fabre: Honoraria; BMS: Honoraria; Novartis: Honoraria; TEVA: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Karlin:Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria; Sandoz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Fitoussi:Sandoz: Membership on an entity's Board of Directors or advisory committees. Moreau: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; Celgene: 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; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees.