Multicenter Long Term Follow-up in Hairy Cell Leukemia Patients Treated with Cladribine: A Thirty-Year Experience

Criscuolo, Marianna

Oral and Poster Abstracts
Oral
623. Mantle Cell, Follicular, and Other Indolent B-Cell Lymphoma—Clinical Studies: Clinical studies in Waldenstrom's Macroglobulinemia, Marginal Zone Lymphoma and Hairy Cell Leukemia

Non-Biological, Diseases, Therapies, chemotherapy, Lymphoid Malignancies, Clinically relevant

Marianna Criscuolo¹^*, Alessandro Broccoli²^*, Eugenio Galli, MD³^*, Alfonso Piciocchi, MS⁴^*, Alessio Maraglino³^*, Antonella Anastasia, MD⁵^*, Ombretta Annibali⁶^*, Maria Cantonetti⁷^*, Maria Lucia De Luca, MD⁸^*, Luana Fianchi, MD⁹^*, Annamaria Frustaci¹⁰^*, Elettra Galli¹¹^*, Luca Guarnera¹²^*, Sofia Kovalchuk, MD¹³^*, Francesco Marchesi¹⁴^*, Marina Motta, MD⁵^*, Maria Elena Nizzoli¹⁵^*, Massimo Offidani¹⁶, Lorella Orsucci, MD¹⁷^*, Angelica Spolzino¹⁸^*, Caterina Stelitano, MD¹⁹^*, Sergio Storti, MD²⁰, Alessandra Tedeschi, MD²¹^*, Livio Trentin, MD^22,23, Marzia Varettoni²⁴^*, Andrea Visentin, MD PhD²⁵^*, Stefano Volpetti²⁶^*, Brunangelo Falini²⁷^*, Alessandro Pulsoni, MD⁸^*, Enrico Tiacci²⁸^*, Pier Luigi Zinzani, MD²⁹ and Livio Pagano, MD³⁰^*

¹Hematology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy
²Institute of Hematology "L. e A. Seràgnoli", University of Bologna, Bologna, Italy
³Hematology, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
⁴GIMEMA Foundation, Rome, Italy
⁵Department of Hematology, ASST Spedali Civili di Brescia, Brescia, Italy
⁶Unit of Hematology, Stem Cell Transplantation, University Campus Bio Medico, Rome, Italy
⁷University of Rome Tor Vergata, Rome, ITA
⁸Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
⁹Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy
¹⁰Department of Hematology, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
¹¹Università degli Studi Firenze, Firenze, Italy
¹²Hematology, Department of Biomedicine and Prevention, University of Rome "Tor Vergata", Roma, Italy
¹³Hematology Department, University of Florence and AOU Careggi, Firenze, Italy
¹⁴Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute Rome, Italia, Roma, ITA
¹⁵Fondazione IRCCS Policlinico San Matteo, PAVIA, Italy
¹⁶Ematologia, Azienda Ospedaliero Universitaria Ospedali Riuniti di Ancona, Ancona, Italy
¹⁷Hematology Division, Città della Salute e della Scienza Hospital, Turin, Italy
¹⁸Hematology and BMT Unit, Università di Parma, Parma, Italy
¹⁹Department of Haematology, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria, Italy
²⁰Oncoematologia, Fondazione di Ricerca e Cura Giovanni Paolo II, Campobasso, ITA
²¹Department of Haematology, Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milano, Italy
²²Hematology and Clinical Immunology Unit, Department of Medicine-DIMED, University of Padua, Padua, Italy
²³Hematology and Clinical Immunology, Department of Medicine, Dipartimento di Medicina Clinica e Sperimentale dell'Universita, Padova, Italy
²⁴Fondazione IRCCS Policlinico S. Matteo University of Pavia, Pavia, Italy
²⁵Hematology and Clinical Immunology Unit, Department of Medicine, University of Padua, Padua, Italy
²⁶Clinica Ematologica, Centro Trapianti e Terapie Cellulari “C. Melzi”, DAME, Università degli Studi, Udine, Italy
²⁷Department of Medicine, Division of Hematology and Clinical Immunology, University of Perugia, Perugia, Italy
²⁸Institute of Hematology, University and Hospital of Perugia, Perugia, Italy
²⁹Seragnoli Institute of Hematology, S. Orsola-Malpighi University Hospital, Bologna, Italy
³⁰Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with specific morphologic and molecular features and excellent prognosis. Although high rate of complete response (CR) has been reported after treatment with purine analogs, expecially cladribine (2CDA), relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long term remission rate and overall survival (OS) in those patients (pts) that received 2CDA as first line treatment.

We retrospectively reviewed data of all HCL pts treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers. Among 553 pts reported, only 513 were evaluable because treated with 2CDA alone. Considering the clinical carachteristics, M/F ratio was 4.5 with a median age of 54 years (range 24-88) and ECOG 0 in 85% of cases. Splenomegaly and presence of circulating hairy cells recorded by morphology were reported in 241 (47%) and 138 (27%) pts, respectively. Thirty-seven (7%) pts presented with an infection. Other comorbidities were cardiovascular in 29 (6%) pts, a previous cancer or diabetes in 27 (5%) each, chronic hepatic disorders in 18 (3%), obstructive pulmonary disease in 16 (3%), chronic kidney disease in 3 (1%). Three hundred-thirty (64%) pts received 2CDA intravenously (253 as daily continuous infusion for 5-7 consecutive days and 77 as weekly infusion for 5-7 consecutive weeks) and 183 (36%) subcutaneously. Response criteria were defined as per recent consensus guidelines (Grever MR et al. Blood 2017). The overall response rate (ORR) was 83%: CR in 335 pts (65%) and partial response (PR) in 96 (19%); 40 (8%) pts obtained hematological improvement (HI) and in 42 (8%) no response was observed. Nine of 11 (82%) pts with HI and 18/25 (72%) non responders who received salvage therapy obtained a major response (fig. 1). A slightly higher hemoglobin value (12.4 vs 11.4 g/dl, p=0.044), a reduced frequency of circulating hairy cells (28.7% vs 31.8%, p=0.039), absence of palpable splenomegaly (p=<0.001) and a faster recovery of ANC (28 days vs 41 days, p= 0.006) were associated with CR compared to PR in univariable analysis. No differences in terms of quality and duration of response, infection rate and time to blood counts recovery were reported according to the 2 routes of administration. Among pts receiving intravenous 2CDA, ORR was 85% for continuous infusion and 78% for weekly infusion: no statistically significant difference could be observed. Median duration of response was 12.2 years: 75.1%, 53.6% and 45.5% of responding pts are expected to be free from relapse at 5, 10 and 15 years, respectively. A statistically significant difference in duration of response was identified between pts that obtained a CR compared to pts in PR (19.4 years versus 4.7 years, p<0.0001) (fig. 2). No other differences in relapse free survival (RFS) were identified. Non-hematological grade-3 or higher early toxicity was reported in 108 (21%) pts, due to infections in 102 cases (20%), mainly fever of unknown origin and pneumonia. In 6 cases infection due to invasive aspergillosis, bacteric pneumonia and bacteric sepsis caused the death of pts. Other non-hematological adverse events were almost all grade-1 allergy (47 pts, 9%). No late toxicity was reported, but 19 (4%) second cancers were observed. Among 118 pts relapsed after a median of 4.4 years (fig. 1), 85 (72%) were retreated with 2CDA, alone (65 cases) or associated with rituximab (20 cases); 11 (9%) with pentostatin, alone (7 cases) or associated with rituximab (4 cases), 8 (7%) with interferon α, 8 (7%) with rituximab alone, 1 (1%) with vemurafenib and zanubrutinib each; 2 were lost at follow-up and 2 died before retreatment. Overall, 58 (51%) retreated pts obtained a CR (42 after 2CDA), 37 (32%) a PR (32 after 2CDA), 7 (6%) a HI (4 after 2CDA) and 12 (11%) did not show any response (6 after 2CDA). Median OS was not reached; 95.7%, 92.8% and 82.3% of pts are expected to be alive at 5, 10 and 15 years, respectively (fig. 2). Overall 51 pts died (10%), during the induction phase in 6 cases and during follow-up in 45: overall, mortality was HCL-related in 14 patients (2 progression of disease and 12 infections) and HCL-unrelated in 37 patients (cardiovascular events in 16, natural causes in 15, a second cancer in 6).

2CDA is greatly effective in treating HCL, with an ORR of 83%. Early and long term adverse events were rare and easily managed: although HCL-related mortality is still possible, OS at 15 years is higher than 80%

Disclosures: Motta: Roche: Honoraria; Janssen: Honoraria. Offidani: Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Tedeschi: Abbvie: Honoraria, Speakers Bureau; Sunesis: Honoraria, Speakers Bureau; Acerta: Honoraria, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; Beigene: Honoraria, Speakers Bureau. Trentin: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Octapharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Shire: Honoraria. Varettoni: Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Travel/accommodations/expenses; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel/accommodations/expenses. Visentin: Janssen: Honoraria; Gilead: Honoraria; Abbvie: Honoraria. Falini: Roche: Research Funding. Pulsoni: Sandoz: Consultancy; Pfizer: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; roche: Consultancy, Speakers Bureau; Merk: Consultancy. Tiacci: Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Zinzani: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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341 Multicenter Long Term Follow-up in Hairy Cell Leukemia Patients Treated with Cladribine: A Thirty-Year Experience