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4398 Efficacy and Safety of Obinutuzumab in Relapsed or Refractory Hairy Cell Leukemia (R/R HCL): An Italian Multicenter Phase-2 Academic Trial (HCL-PG04)

Program: Oral and Poster Abstracts
Session: 623. Mantle Cell, Follicular, and Other Indolent B Cell Lymphomas: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Biological therapies, Lymphoid Leukemias, Antibody Therapy, Clinical Research, Diseases, Therapies, Lymphoid Malignancies
Monday, December 11, 2023, 6:00 PM-8:00 PM

Enrico Tiacci1*, Luca De Carolis1*, Monia Capponi1*, Flavio Falcinelli1*, Francesco Zaja, MD2,3*, Alessandro Pulsoni, MD4*, Edoardo Simonetti1*, Elisa Montechiarello5*, Alessandra Romano, MD6*, Jacopo Olivieri7*, Alessandro Mancini8*, Gianna Maria D'Elia9*, Robin Foa10*, Maurizio Frezzato11* and Brunangelo Falini1

1Institute of Hematology and Center for Hemato-Oncology Research, University and Hospital of Perugia, Perugia, Italy
2DSM, University of Trieste, Trieste, Italy
3UCO Ematologia, Azienda Sanitaria Universitaria Giuliano Isontina, Trieste, Italy
4Hematology, University Sapienza, S.M. Goretti Hospital, Latina, Italy
5Hematology, Hospital of Reggio Calabria, Italy, Reggio Calabria, Italy
6Hematology, University and Hospital of Catania, Italy, Catania, ITA
7Clinica Ematologica, Centro Trapianti e Terapie Cellulari "Carlo Melzi", Azienda Sanitaria Universitaria Integrata di Udine, Udine, Italy
8Institute of Hematology and Center for Hemato-Oncology Research, University and Hospital of Perugia, PERUGIA, Italy
9Hematology, University Sapienza and Hospital Umberto I, Rome, Rome, Italy
10Hematology, University Sapienza and Hospital Umberto I, Rome, Italy
11Hematology, Hospital of Vicenza, Italy, Vicenza, ITA


About 50% of HCL patients (pts) relapse after chemotherapy with purine analogs (PA). After identifying the BRAF-V600E mutation as the genetic cause of HCL (Tiacci et al. NEJM 2011), we documented a high efficacy of the BRAF inhibitor vemurafenib in R/R pts (Tiacci, Park et al. NEJM 2015), especially when added to rituximab (Tiacci et al. NEJM 2021). HCL expresses bright CD20 and obinutuzumab (OBI) is a more effective anti-CD20 agent than rituximab (RTX) in other indolent B-cell neoplasms such as chronic lymphocytic leukemia and follicular lymphoma. RTX produces ~20% complete remissions (CR) in R/R HCL (Kreitman, ASH Educ Program 2012), while OBI activity in this setting is unknown.


In the ongoing academic, phase-2, multi-center trial HCL-PG04, R/R HCL pts needing treatment due to cytopenia(s) received OBI 1000 mg intravenously on days 1-8-15 of cycle 1 and on day 1 of cycles 2-6 (1 cycle = 28 days). CR required resolution of cytopenias (platelets ≥ 100,000/mmc; neutrophils ≥ 1500/mmc; hemoglobin ≥ 11 g/dl), no palpable splenomegaly and no leukemic cells on morphologic analysis of the bone marrow biopsy, as assessed one month after the last OBI dose. Minimal residual disease (MRD) was analyzed by BRAF-V600E specific PCR in the bone marrow aspirate (sensitivity: 0.05% mutant alleles).


We enrolled 26 pts (M/F 24/2; median age 62 years, range 39-80) with a median of 2 prior therapies (range 1-7), including 7 refractory to PA (26%) and 2 to RTX (8%). Median values of disease burden parameters at baseline were: 70% BM HCL infiltration, 830 neutrophils/mmc, 62000 platelets/mmc, 14 g/dl hemoglobin, and 16 cm of longest spleen diameter (in 16/26 splenomegalic patients; 1 pts. had been splenectomized and 9 were not splenomegalic at baseline).

Toxicity was as expected, largely of grade (G) 1-2, always reversible and mainly consisting in: infusion reactions (G1-2 92%; G3 4%, in a single pt allergic to previous RTX who discontinued OBI); asymptomatic increase of liver enzymes (G1-2 19%; G3 GGT 15%; G3 ALT 4%); transient worsening of baseline G1-G3 thrombocytopenia to G3 (23%) or G4 (35%), with only 1 minor bleeding (4%, G1 epistaxis); transient neutropenia (G2 4%; G3 15%; G4 15%); and rare infections (G1-2 herpes labialis 8%; G3 pneumonia 4%).

CR was reached in 12/25 evaluable pts (48%), including 2 pts with incomplete platelet recovery (~70000-90000/mmc) and 2 pts with delayed resolution of palpable splenomegaly. Notably, CR was achieved in 5/7 pts refractory to PA and 1/2 pts refractory to RTX. Furthermore, CR was negative for MRD in 9/12 pts (75%, including 3 pts with delayed MRD clearance), something never observed with vemurafenib. However, the kinetics of cytopenia resolution was slower compared to our previous vemurafenib trial, in that in pts obtaining CR with OBI neutrophil recovered to ≥1500/mmc after a median of 7 weeks (vs 4 weeks with vemurafenib) and platelets recovered to ≥100000/mmc after a median of 8 weeks (vs 2 weeks with vemurafenib). Prior exposure to RTX (n=12 pts) did not compromise OBI efficacy (5 CR, all MRD-negative, in 11 evaluable pts).

In pts achieving CR with OBI, progression-free and MRD-free survival were both 100% at 56 months (range 20-66) and 48 months (range 6.5-60) of median follow-up, respectively (Fig.1). The 13 non-CR pts (minor response 7; no response 3; progression 3) were effectively salvaged with another course of OBI combined with vemurafenib, which will be presented at the meeting.


OBI frequently produced deep and durable responses in R/R HCL, to an extent apparently greater than RTX, thus qualifying as an active and safe chemotherapy-free strategy in this setting.

Disclosures: Tiacci: Kite-Gilead: Consultancy; Deciphera: Consultancy; Innate Pharma: Consultancy. Zaja: Sobi: Honoraria, Research Funding; Grifols: Consultancy, Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pulsoni: MSD: Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; SANDOZ: Honoraria, Speakers Bureau; TAKED: Consultancy, Honoraria, Speakers Bureau; GILEAD: Consultancy, Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; JANSSEN: Honoraria.

OffLabel Disclosure: This presentation include information regarding obinutuzumab (anti-CD20 antibody) in the context of Hairy Cell leukemia.

*signifies non-member of ASH