Using an every 3-week-schedule of SAR3419 for six cycles, the MTD is 160 mg/m(2). SAR3419 can be safely administered to patients with relapsed B-cell lymphoma and demonstrates promising clinical activity, including patients who were refractory to rituximab.

The efficacy of anti-CD33 immunoconjugates had been previously demonstrated for gemtuzumab-ozogamicin. AVE9633 is an anti-CD33-maytansine conjugate created by ImmunoGen Inc. Phase I trials of AVE9633 were performed in patients with AML to evaluate tolerability, pharmacokinetics and pharmacodynamics. Three phase I studies of AVE9633 were performed in 54 patients with refractory/relapsed AML, evaluating drug infusion on day 1 of a 21-day cycle (Day 1 study), day 1 and 8 (Day 1/8 study) and day 1, 4 and 7 (Day 1/4/7 study) of a 28-day cycle. Toxicity was mainly allergic reaction during infusion (3 grade 3 bronchospasms). DLT was reached for the D1-D7 schedule at 150 mg/sqm (1 keratitis, 1 liver toxicity), and the MTD was set at 130 mg/sqm for this schedule. In the two other phases I, the DLT was not reached. In the Day 1/8 study, CD33 on peripheral blasts was saturated and down-modulated for doses of 75 mg/m(2) × 2 or higher, which was correlated with WBC kinetics and plasma levels of AVE9633. Decrease of DM4/CD33 ratio on the blasts surface between day 1 and 8 was the rational for evaluating day 1/4/7 schedule. This induced relatively constant DM4/CD33 levels over the first 8 days, however no activity was noted. One CRp, one PR and biological activity in five other patients were observed in this study. The Day 1 and Day 1/4/7 studies were early discontinued because of drug inactivity at doses significantly higher than CD33 -saturating doses. No myelossuppression was observed at any trial of AVE9633. The pharmacokinetics/pharmacodynamics data obtained in these studies will provide very useful information for the design of the next generation of immunoconjugates.

Summary:In order to study the influence of bone marrow CD34 + cell dose on the outcome of allogeneic bone marrow transplantation (BMT), we analysed the results of BMT from HLA-identical siblings donors in 50 patients with chronic myeloid leukaemia (CML). The median numbers of nucleated cells (NC) and CD34 + cells infused were 2.18 × 10 8 /kg (0.05-4.14 × 10 8 /kg) and 3.12 × 10 6 /kg (0.35-8.52 × 10 6 /kg), respectively. All patients engrafted. In univariate analysis, there was no correlation between the number of CD34 + cells infused and the time to neutrophil recovery (P = 0.17). The Kaplan-Meier estimate of grade II-IV acute graft-versus-host disease (GVHD) at day 100 was 53 ± 14% and 2-year survival was 46 ± 15%. A number of CD34 + cells infused greater than the median was the main factor increasing survival (P = 0.0006) and decreasing 100 day transplant-related mortality (P = 0.009). Patient-, disease-and transplantrelated characteristics were not statistically different among patients receiving more or less than the median number of CD34 + cells. The rate of infectious deaths was significantly higher in patients receiving less than 3.12 × 10 6 CD34/kg (48% vs 16%, P = 0.01). In a multivariable analysis, two factors associated with increased risk of death were advanced disease status at transplant (HR: 2.5 (95% CI: 1.09-5.75), P = 0.03) and a lower number of marrow CD34 + cells infused/kg (HR: 4.55 (95% CI: 1.87-10.90), P = 0.0008). Bone Marrow Transplantation (2001) 27, 575-580. Keywords: CD34 cell dose; allogeneic bone marrow transplant; chronic myeloid leukaemia Since haematopoietic stem cells and progenitors were identified by the expression of the CD34 antigen at their surface, CD34 + cell counts using flow cytometry have been used for estimating the haematopoietic stem cell content of the Correspondence: Pr E Gluckman, Hopital Saint Luis, 1 Ave Claude Vellefaux,

Our objective was to evaluate minimal residual disease (MRD) at the end of induction treatment with chemoimmunotherapy as a surrogate end point for progression-free survival (PFS) in chronic lymphocytic leukemia (CLL) based on 3 randomized, phase 3 clinical trials (ClinicalTrials.gov identifiers NCT00281918, NCT00769522, and NCT02053610). MRD was measured in peripheral blood (PB) from treatment-naïve patients in the CLL8, CLL10, and CLL11 clinical trials, and quantified by 4-color flow cytometry or allele-specific oligonucleotide real-time quantitative polymerase chain reaction. A meta-regression model was developed to predict treatment effect on PFS using treatment effect on PB-MRD. PB-MRD levels were measured in 393, 337, and 474 patients from CLL8, CLL10, and CLL11, respectively. The model demonstrated a statistically significant relationship between treatment effect on PB-MRD and treatment effect on PFS. As the difference between treatment arms in PB-MRD response rates increased, a reduction in the risk of progression or death was observed; for each unit increase in the (log) ratio of MRD rates between arms, the log of the PFS hazard ratio decreased by -0.188 (95% confidence interval, -0.321 to -0.055; = .008). External model validation on the REACH trial and sensitivity analyses confirm the robustness and applicability of the surrogacy model. Our surrogacy model supports use of PB-MRD as a primary end point in randomized clinical trials of chemoimmunotherapy in CLL. Additional CLL trial data are required to establish a more precise quantitative relationship between MRD and PFS, and to support general applicability of MRD surrogacy for PFS across diverse patient characteristics, treatment regimens, and different treatment mechanisms of action.

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AVE9633/huMy9-6-DM4 is an immunoconjugate composed of a humanized monoclonal IgG1 antibody, huMy9-6, which specifically targets the CD33 antigen, conjugated through a disulfide link to the maytansine derivative DM4, a potent tubulin inhibitor. The CD33 antigen is expressed on the surface of myeloid cells. After the conjugate is bound to the CD33 antigen it is internalized and the cytotoxic is released within the target cell. We report preliminary results of the ongoing phase I dose escalation study of AVE9633 in patients with refractory/relapsed CD33+ AML. The study regimen consists of AVE9633 IV infusion on Day 1 and Day 8 of a 28-day cycle. To date, dose levels of 30 (n=1), 50 (n=3), 75 (n=3), 105 (n=3) and 130 (n=3) mg/m2 on Day 1 and Day 8 have been investigated. Patients received 1 (n=2), 2 (n=5), 3 (n=2) and 4 (n=4) cycles of AVE9633. No dose-limiting toxicity was noted so far. Nine patients experienced mild to moderate infusion reactions, mostly on Day1 of Cycle1. One patient at 130 mg/m2 presented grade 3 ALT elevation of 3 days duration. Free DM4, measured by LC/MS/MS was detectable at 105 and 130 mg/m2 in the range of 5 to 10 ng/mL. AVE9633/huMy9-6-DM4 exposure (measuring, by ELISA method, all antibodies containing at least one molecule of DM4) increased proportionally with the administered dose. Using Flow Cytometry Assay, saturation and down regulation of CD33 on peripheral and marrow blasts were observed from the dose of 50 mg/m2. There was one CRp in a 68-year old woman with refractory AML, achieved after 4 cycles of AVE9633 given at 105 mg/m2 × 2, with a 4-month continuing CRp as of 7/07 (she is receiving AVE9633 105 mg/m2 once monthly). One PR occurred in a 81-year old woman with refractory AML after one cycle at 130 mg/m2 × 2, persistent after the second cycle (third cycle is ongoing). Two patients had >50% decrease in bone marrow blasts, at 105 mg/m2 × 2 (from 25% to 8% after two cycles) and at 130 mg/m2 × 2 (from 35% to 9% after one cycle). One additional patient at 75 mg/m2 × 2 presented clearance of peripheral blasts by Day 10 of Cycle1. Mean DM4/IgG on the surface of peripheral blasts (available for one patient at 130 mg/m2) progressively decreased after the infusion, from 3.09 on day 1 to 0.28 on Day 8, and then increased to 2.64 after the second infusion of AVE9633 on Day 8. These preliminary results show that AVE9633 is well tolerated, with manageable safety profile, allowing outpatient treatment. Evidence of anti-leukemia activity was observed in 5 patients. The study is continuing with the evaluation of 150 mg/m2 × 2. Evaluation of closer drug administrations which might enhance efficacy appears warranted.

Background Despite prophylaxis, GVHD remains a significant cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation (HCT). ITA is a potent, selective Janus kinase (JAK) 1 inhibitor that has been combined safely with steroids in patients (pts) with acute GVHD. We describe results from a proof-of-concept study evaluating ITA + CNI-based regimens for GVHD prophylaxis. Study Design and Methods GRAVITAS-119 (NCT03320642) was a single-arm, open-label study enrolling pts aged ≥18 y undergoing allogeneic HCT using peripheral blood stem cells from 8/8 or 7/8 matched related or unrelated donors for a hematologic malignancy. Eligible pts were candidates for reduced-intensity conditioning with Karnofsky Performance Status ≥70%. Pts were excluded for prior HCT, JAK inhibitor therapy, or active uncontrolled infection. Pts received oral ITA 200 mg once daily (QD) beginning 3 d before HCT + tacrolimus (Tac)/methotrexate (MTX) or cyclosporine A (CSA)/mycophenolate mofetil (MMF) ± antithymocyte globulin (ATG) per institutional practice. ITA dose reduction/interruption was permitted for toxicity. ITA was reduced to 100 mg QD by Day 90 and discontinued by Day 180 unless pts required systemic GVHD treatment (tx), had malignancy relapse or unacceptable toxicity, or withdrew consent. The primary endpoint was Day 28 hematologic recovery (absolute neutrophil count [ANC] ≥500/mm3 for 3 consecutive measurements and platelets [plt] ≥20,000/mm3 with no transfusions in the preceding 3 d). Secondary endpoints included incidence of acute and chronic GVHD, GVHD- and relapse-free survival (GRFS), overall survival, and safety. Results Sixty-five pts were enrolled and treated with ITA + Tac/MTX (n=41; +ATG, n=8; no ATG, n=33) or ITA + CSA/MMF (n=24; +ATG, n=16; no ATG, n=8). Median (range) age was 65 (25-76) y, and 57% were male. The most common underlying malignancies were acute myeloid leukemia (40%) and myelodysplastic syndrome (26%). Disease risk index was classified as low, intermediate, and high in 11%, 66%, and 23% of pts, respectively. Pts received grafts from matched related (51%), matched unrelated (40%), or single-antigen mismatched unrelated (9%) donors. Busulfan/fludarabine (51%) and a fludarabine/melphalan reduced-intensity regimen (18%) were the most common conditioning regimens; 11% of regimens contained total body irradiation. Median (range) exposure to ITA was 140 (10-187) d; 74% received ITA for >90 d. All pts achieved hematologic recovery. Median (range) time to ANC and plt recovery among patients who had count nadir (ANC <500/mm3 and/or plt <20,000/mm3) was 17 (4-31) and 14 (9-26) d, respectively. ANC recovery was on Day 31 for 1 pt with secondary myelofibrosis (MF). Two pts had secondary graft failure, 1 on tx (Tac/MTX/ATG; Day 65), with no evidence of viral infection, and 1 during post-tx follow-up (Tac/MTX; Day 182); both underwent retransplantation. Malignancy relapse (median follow-up, 363 d) occurred in 12 pts (18%), including 3 pts with molecular/cytogenetic relapse requiring intervention. In 63 evaluable pts, cumulative incidence of grade III/IV acute GVHD at Day 180 was 4.8% and 1-y GRFS was 38.5%. Secondary efficacy endpoints by tx group are in Table 1. The most common grade 3/4 hematologic adverse events (AEs) were thrombocytopenia (49%) and anemia (31%). 17 pts (26%) had cytomegalovirus reactivations (n=10 +ATG), 8 (12%) had Epstein-Barr virus (EBV) infection (no post-transplant lymphoproliferative disorder cases; all +ATG), and 1 pt (2%) had invasive bronchopulmonary aspergillosis (Tac/MTX +ATG). AEs (22%) and relapse (17%) were the most common reasons for ITA discontinuation; the most common AEs leading to discontinuation were mixed chimerism (6%), thrombocytopenia (3%), and hypertriglyceridemia (3%). 8 pts in the +ATG group received post-transplant rituximab for EBV infection (n=7) and/or azaciditine maintenance therapy (n=3). 15 pts (24%) in the per-protocol population died. 3 deaths occurred on tx due to infections (n=2) and intracranial hemorrhage (n=1; Table 2). Conclusions Results from this small open-label trial in a heterogeneous pt population demonstrated that GVHD prophylaxis with ITA + CNI-based regimens was well tolerated and rates of severe acute GVHD were low. 1 pt with MF did not achieve ANC recovery on Day 28. An ITA + Tac + post-transplant cyclophosphamide cohort is currently being investigated in GRAVITAS-119. Disclosures Shah: Cell Vault: Research Funding; Celgene: Consultancy, Honoraria; Miltenyi Biotec: Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Lily: Consultancy, Honoraria. Chevallier:Incyte Corporation: Honoraria. Rubio:Medac: Consultancy; MSD: Honoraria; Gilead: Honoraria; Neovii: Research Funding; Novartis: Honoraria. Schroeder:Astellas: Other; Dova Pharmaceuticals: Other; FlatIron Inc: Other; GSK: Other; Gilead Sciences Inc: Other; Novo Nordisk: Other; Genentech Inc: Research Funding; Merck: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Cellect Inc: Research Funding; Janssen: Research Funding; Partners Therapeutics: Other; Pfizer: Other; AbbVie: Consultancy, Honoraria, Speakers Bureau; Fortis: Research Funding; Seattle Genetics: Research Funding; Amgen: Other: served on advisory boards and received honoraria or consultant fees, Research Funding; Celgene: Research Funding; PBD Incorporated: Research Funding; Genzyme Sanofi: Other: served on advisory boards and received honoraria or consultant fees, Research Funding. Hardy:Incyte Corporation: Other: Advisory Board Member; Kite/Gilead: Other: Advisory Board Member; American Gene Technologies: Other: DSMB Member. Stiff:Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Delta-Fly: Research Funding; Macrogenics: Research Funding. Solano:Incyte Corporation: Other: Received fees for an advisory role. Yakoub-Agha:Celgene: Honoraria; Novartis: Honoraria; Gilead/Kite: Honoraria, Other: travel support; Janssen: Honoraria; Jazz Pharmaceuticals: Honoraria. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Duarte:Incyte Corporation: Other: Has received speaker and advisor fees. Morariu-Zamfir:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Arbushites:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Ding:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Perales:Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Nektar Therapeutics: 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; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cidara Therapeutics: Other; Servier: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. OffLabel Disclosure: Itacitinib is a novel JAK1 inhibitor that has not been approved for use in acute GVHD or for any other indication.