Long-Term Treatment of Hairy Cell Leukemia Patients with Interferon: Clinical and Molecular Aspects

Introduction. Hairy cell leukemia (HCL) is a rare clonal B-cell chronic lymphoproliferative disorder. Current treatments for HCL include purine analogs (PA), which are used successfully as front-line therapy in young and fit patients. The therapeutic armamentarium has been recently extended by the introduction of rituximab, BRAF oral inhibitors and other novel agents. Interferon alpha (IFNα) has been the first agent capable of inducing a response in HCL patients and of changing the natural course of the disease. It has been extensively used up to the introduction of PA. Nowadays, IFNα front-line is limited to pregnant women (or desiring a pregnancy), to patients with severe neutropenia or frail, or to relapsed/refractory patients. We hereby report the experience of 74 patients treated continuously with IFNα at our Center in Rome. Methods. A retrospective analysis was performed on patients with HCL or with variant HCL treated between 1990 and 2020 with IFNα until progression or toxicity. The initial dosage was 3 MUI subcutaneously three times weekly (3d/week). In responding patients, after 12 months the dose was progressively tapered to reach a very low maintenance dose, ranging from 0.1 MUI 3d/week to 0.9 3d/week. After 12 months of treatment, the degree of response was based on peripheral blood count evaluation, bone marrow biopsy and IFNα front-line; C) patients resistant to PAs who received IFNα as second or further line of treatment. Results. After 12 months of treatment, 70 patients (95%) achieved either a PR or a CR in 52 (70%) and 18 (24%) cases, respectively. Four (5.4%) patients were considered as non-responders. After a median follow-up of 92 months (range 7-236), 55 patients (75%) still maintained their response while receiving maintenance IFNα. The estimated 5-year and 10-year PFS were 89% and 77%, respectively (Fig. 1). The median PFS for these patients has not been reached at 10 years. Patients in CR at 12 months of treatment showed a significantly superior PFS rate (p 0.001). The 10-year PFS was 94% for patients in CR compared to 73% for patients who obtained a PR during abdominal ultrasound. The mutational status of BRAF V600E by PCR analysis was assessed in a subset of patients during treatment. Three groups of patients were identified: A) patients >65 years who received IFNα front-line; B) patients <65 years with comorbidities or women desiring a pregnancy who received IFNα therapy. Univariate analysis showed a different PFS for groups A, B and C, the 5-year PFS being 95%, 68% and 96%, respectively (p 0.005) (Fig. 1). In group A, a CR was achieved by 28% of cases and a PR by 62%, in group B the rates were 16% and 80%, and in group C 28% and 68%, respectively. Group C received a median number of 2 prior lines of treatment; 89% received PAs. Patients with previous PA-based treatment obtained a PR in 55% of cases and a CR in 32%. No significant differences were observed in terms of PFS in the 10 patients with a variant HCL (p 0.5); 1/10 achieved a CR. The impact of Hb, WBC count, spleen size and platelet count were assessed in univariate analysis. A significant difference in the entire case series was observed in patients with a WBC >3500/mmc at the start of treatment: the estimated median PFS was 236 vs 108 months (p 0.004). Twenty-two patients in response during IFNα maintenance were tested for MRD basing on BRAF status: 32% were negative during treatment (7 out of 22). All patients with negative MRD were in CR. G1-2 extra-hematologic toxicity, occurred as flu-like syndrome and fatigue, was observed in 25 patients (76% in group A), 13/25 patients discontinued IFNα for toxicity; 1 case of alopecia was reported. No patient required discontinuation due to G3-4 hematologic toxicity. Four deaths occurred, 2 due to secondary neoplasms and 2 in very elderly patients. Conclusions. IFNα still retains a role in selected HCL patients. In young patients with comorbidities front-line IFNα remains a possible option, although not as effective as PAs. In elderly patients, the continuous administration allows remarkable results with acceptable toxicity. Also in patients resistant to PAs, INFα is capable of inducing durable responses in a considerable part of patients. The data on MRD demonstrate the possibility of achieving a molecular response. Although the role of IFNα is further limited by the advent of new agents, when administered in a continuous schedule it still represents a valid therapeutic option in specific subsets of HCL patients. Figure Disclosures Martelli: sandoz: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Foà:Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Tiacci:Roche: Research Funding; Abbvie: Other: Travel and meeting expenses. Pulsoni:Pfizer: Consultancy; Merk: Consultancy; Takeda: Consultancy; Gilead: Speakers Bureau; Sandoz: Consultancy; roche: Consultancy, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

Download Full-text

A Distributed International Patient Data Registry for Hairy Cell Leukemia

Blood ◽

10.1182/blood.v128.22.5986.5986 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5986-5986

Author(s):

Leslie A. Andritsos ◽

Michael R. Grever ◽

Mirela Anghelina ◽

Claire E Dearden ◽

Monica Else ◽

...

Keyword(s):

Board Of Directors ◽

Hairy Cell Leukemia ◽

Research Funding ◽

Patient Data ◽

Hairy Cell ◽

Cell Leukemia ◽

Advisory Committees ◽

Web Based ◽

Data Registry ◽

The Web

Abstract BACKGROUND: The study of rare diseases is limited by the uncommon nature of the conditions as well as the widely dispersed patient populations. Current rare disease registries such as the National Organization of Rare Diseases utilize centralized platforms for data collection; however because of their broad nature, these do not always capture unique, disease specific elements. Hairy Cell Leukemia (HCL) is a rare leukemia globally with approximately 900 new cases diagnosed in the US each year. The HCL Foundation undertook creation of a Patient Data Registry that collects data from multiple HCL Centers of Excellence (COE) around the globe to better understand the complications, treatment outcomes, disease subtypes, comorbid conditions, epidemiology, and quality of life of patients with HCL. METHODS: Investigators at The Ohio State University Department of Biomedical Informatics and Division of Hematology in collaboration with the HCL Foundation developed a Patient Data Registry (PDR) for the longitudinal capture of high quality research data. This system differs from other registries in that it uses a federated( rather than centralized) architecture, wherein data is queried and integrated in an on-demand manner from local registry databases at each participating site. Further, the data collected for use in the registry combines both automated exports from existing electronic health records (EHRs) as well as additional data entered via a set of web-based forms. All manually entered data comes from source documents, and data provenance spanning electronic and manually entered data is maintained via multiple technical measures. Patients may be enrolled at HCL COE, or, if they do not have access to a COE they may enroll via a web-based portal (www.hairycellleukemia.org). At this time due to regulatory requirements the web-based portal is available to US patients only. All data are de-identified (see Figure 1: De-Identification Workflow) which reduces regulatory burden and increases opportunities for data access and re-use. End users have access to data via a project-specific query portal. RESULTS: The Patient Data Registry has been deployed at The Ohio State University, Royal Marsden Hospital, and MD Anderson Cancer Center, and is undergoing deployment at the University of Rochester. Up to 25 international HCL COE may participate. In addition, US patients are actively entering the registry via the web-based portal. To date, 227 patients have been consented to the registry with 119 of these being via the web-based entry point. CONCLUSION: We created an international and web-based patient data registry which will enable researchers to study outcomes in HCL in ways not previously possible given the rarity of the disease. This work was made possible by research funding from the Hairy Cell Leukemia Foundation. Figure De-Identification Workflow Figure. De-Identification Workflow Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lele:Hairy Cell Leukemia Foundation: Research Funding. Burger:Pharmacyclics: Research Funding. Delgado:Gilead: Consultancy, Honoraria; Novartis/GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Infinity: Research Funding. Jones:AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding; Boehringer Ingelheim: Research Funding. Montserrat:Morphosys: Other: Expert Testimony; Vivia Biotech: Equity Ownership; Gilead: Consultancy, Other: Expert Testimony; Pharmacyclics: Consultancy; Janssen: Honoraria, Other: travel, accommodations, expenses. Parikh:Pharmacyclics: Honoraria, Research Funding. Park:Genentech/Roche: Research Funding; Amgen: Consultancy; Juno Therapeutics: Consultancy, Research Funding. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Tam:janssen: Honoraria, Research Funding; Roche: 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. Heckler:Hairy Cell Leukemia Foundation: Research Funding. Payne:Hairy Cell Leukemia Foundation: Research Funding.

Download Full-text

Efficacy and Safety of the Bruton Tyrosine Kinase Inhibitor Ibrutinib in Patients with Hairy Cell Leukemia: Stage 1 Results of a Phase 2 Study

Blood ◽

10.1182/blood.v128.22.1215.1215 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1215-1215 ◽

Cited By ~ 14

Author(s):

Jeffrey Jones ◽

Leslie Andritsos ◽

Robert J. Kreitman ◽

Farhad Ravandi ◽

Charles Schiffer ◽

...

Keyword(s):

Board Of Directors ◽

Dose Level ◽

Clinical Benefit ◽

Hairy Cell Leukemia ◽

Research Funding ◽

Single Agent ◽

Hairy Cell ◽

Cell Leukemia ◽

Advisory Committees ◽

Grade 3

Abstract Background : Effective therapy for classical hairy cell leukemia (c-HCL) refractory to purine nucleoside analog (PNA) treatment is limited, and there are no accepted treatment standards for variant hairy cell leukemia (v-HCL). Ibrutinib, an oral small molecule inhibitor of Bruton tyrosine kinase (BTK), has shown single-agent efficacy and acceptable tolerability in patients with various B-cell malignancies, including chronic lymphocytic leukemia, mantle cell lymphoma, and Waldenstrom's. While BTK is expressed in HCL cells, the clinical activity of ibrutinib in this disease has not been previously assessed. We conducted a single-arm, multi-center phase 2 study (NCI #9268) of single-agent ibrutinib to characterize the overall response rate (complete + partial response) and safety of single-agent ibrutinib treatment for HCL. Methods : Patients with c-HCL (unfit for or relapsed after PNA) and v-HCL (relapsed or treatment-naïve) were eligible. Enrolled patients required treatment, had ECOG ≤ 2, no active infection, and preserved end-organ function. Patients received continuous once daily ibrutinib in 28-day cycles. Using a Simon 2-stage design, the first 13 patients were treated at 420 mg daily, and a second cohort of 13 patients was accrued at the 840 mg dose-level. Ultimately, the pre-specified number of objective responses was reached at the 420 mg dose-level, and accrual to the second stage of the design continues at that dose. Response, including bone marrow biopsy with immunohistochemistry for minimal residual disease (MRD), was assessed after 8 and 12 cycles. Patients experiencing clinical benefit may continue ibrutinib until unacceptable toxicity or progressive disease. Results: As of 15 May 2016, 28 patients had been enrolled and were evaluable for response: 420 mg/day (n=15) and 840 mg/day (n=13). Enrolled patients (1 treatment-naïve v-HCL, 10 relapsed v-HCL, 17 relapsed c-HCL) included 22 male and 6 female patients with median age 65 years (range: 43-78). Relapsed patients received median 4 prior therapies (range: 1-11); all had prior PNA, 81% had prior rituximab, and 3 c-HCL patients had prior vemurafenib. Response data are summarized by dose and histology in the table. To date, the ORR is 46% [4 CR (all c-HCL) and 9 PR (6 c-HCL)], with objective responses more commonly observed in patients with c-HCL. Eight additional patients (29%) with stable disease have experienced clinical benefit (resolution of symptoms, improvement in peripheral blood cell counts) not meeting criteria for PR, most commonly attributable to persistent thrombocytopenia, and continue on treatment. At median follow-up of 22 months, 20 patients (71%) remain on treatment, 3 patients (1 v-HCL, 2 c-HCL) have progressed, 2 patients (c-HCL) with severe neutropenia at baseline (c-HCL) had early deaths from pneumonia, 1 (c-HCL) discontinued during cycle 8 for failure to resolve baseline neutropenia, and 2 other patients (v-HCL) have discontinued for adverse events. Estimated 24-month progression-free survival (PFS) was 79% (95% CI: 57-91%) and the median PFS has not been reached. Redistribution lymphocytosis was observed in patients with circulating disease at baseline. Soluble interleukin-2 receptor (sIL2R) level was increased at baseline in all c-HCL patients for whom data were available and correlated with response. In general, toxicity did not differ by dose level or disease histology. The most frequent (>10%) grade ≥3 adverse events (AEs) were lymphopenia (21%), neutropenia (18%), lung infection (18%), thrombocytopenia (14%), hypophosphatemia (11%), and hypertension (11%). Common grade 1/2 non-hematologic toxicities included myalgia (57%), diarrhea (54%), fatigue (50%), nausea/vomiting (46%), bruising (46%), and rash (46%); grade 1/2 atrial fibrillation (no grade ≥3) was observed in 5 patients. Grade ≥3 infection was observed in 25%, but no grade ≥3 bleeding AEs were reported. Conclusions: Ibrutinib can induce remission in both c-HCL and v-HCL patients, including heavily pre-treated patients, but complete remissions have only been observed in c-HCL to date. The drug is generally well-tolerated during long-term administration, and durable clinical benefit is observed in the majority of treated patients even when objective response criteria are not met. Table 1. Table 1. Figure 1. Figure 1. Disclosures Jones: Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lozanski:Stemline Therapeutics Inc.: Research Funding; Beckman Coulter: Research Funding; Genentech: Research Funding; Boehringer Ingelheim: Research Funding.

Download Full-text

Trametinib for the Treatment of IGHV4-34, MAP2K1 Mutant Variant Hairy Cell Leukemia

Blood ◽

10.1182/blood.v128.22.5598.5598 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5598-5598 ◽

Cited By ~ 3

Author(s):

Leslie A. Andritsos ◽

Mirela Anghelina ◽

Nicole R. Grieselhuber ◽

Sameek Roychowdhury ◽

Julie Reeser ◽

...

Keyword(s):

Board Of Directors ◽

Skin Rash ◽

Hairy Cell Leukemia ◽

Research Funding ◽

Unrelated Donor ◽

Hairy Cell ◽

Cell Leukemia ◽

Advisory Committees ◽

Skin Nodules ◽

Skin Biopsies

Abstract Background: Mutations of MAP2K1, which encodes MEK1, have been identified in up to half of patients with variant Hairy Cell Leukemia (vHCL).[Waterfall et al., Nat Gen 2014, Mason et al., Leukemia & Lymphoma 2016], and have been associated with vHCL with IGHV4-34 gene usage, which This form of HCL tends to have a worse prognosis than classic HCL or wild type vHCL (Arons et al., Blood 2009), with inferior responses to chemotherapy and shorter durations of remission. Trametinib, an oral inhibitor of MEK1 and MEK2, is FDA approved for treatment of patients with BRAF p.V600E mutant melanoma. We hypothesized that this MEK inhibitor would have activity in MAP2K1 mutant vHCL. Case Report: The patient is a 52 year old man with a history of CD25+, BRAF wildtype, IGHV4-34 usage vHCL diagnosed in 2005. His previous treatments included cladribine, BL22, pentostatin/rituximab, splenectomy, single agent rituximab, ibrutinib, bendamustine/rituximab, and allogeneic transplantation from a matched unrelated donor. The patient experienced disease relapse day +350 post transplant when he developed skin nodules as well as a generalized skin rash. The skin rash appeared clinically consistent with acute GVHD. However, when biopsies of both the skin nodules and skin rash were performed he was found to have relapsed vHCL. He was consented for paired tumor and germline next generation sequencing with a 25-gene amplicon panel which revealed a somatic MAP2K1 K57N mutation that has been shown to constitutively activate MEK [Marks et al., Cancer Res 2008]. As the patient had exhausted the majority of available treatment options, he was prescribed trametinib 2 mg po daily (commercial supply, according to approved melanoma dosing). Within a week of therapy initiation his skin nodules were markedly diminished in size and his generalized rash had resolved. He did develop a new acneiform rash over his face consistent with drug toxicity. This was managed with topical agents with improvement and did not require a dose reduction. Disease restaging following cycle 2 of therapy showed near complete resolution of skin nodules, with disappearance of visible skin rash. Repeat bone marrow biopsy showed unchanged hairy cell index. Skin biopsies were repeated and phospho-ERK (T202/Y204) staining of skin biopsies pre- and post-trametinib were performed (Figure 1). This showed diminished lymphocyte involvement on H&E staining with a decrease in p-ERK expression on immunostaining, indicative of decreased signaling downstream of MEK and consistent with on target trametinib effects. As of this writing, the patient has remained on trametinib for 12 weeks with no recurrence of leukemia cutis rash. Discussion: MEK inhibition with the oral MEKi trametinib is a well tolerated therapy with clinical activity in MAP2K1 mutant vHCL. Additional studies of this agent are warranted. Optimal dose and duration of therapy will need to be explored in prospective clinical trials. Figure 1 Skin biopsies pre- and post-trametinib. (A)(C) H&E staining shows diminished lymphocyte involvement. (B)(D) PhosphoERK immunostaining shows decrease of phosphoERK expression. Bar = 500 μm Figure 1. Skin biopsies pre- and post-trametinib. (A)(C) H&E staining shows diminished lymphocyte involvement. (B)(D) PhosphoERK immunostaining shows decrease of phosphoERK expression. Bar = 500 μm Disclosures Andritsos: Hairy Cell Leukemia Foundation: Research Funding. Anghelina:Hairy Cell Leukemia Foundation: Research Funding. Lozanski:Boehringer Ingelheim: Research Funding; Beckman Coulter: Research Funding; Genentech: Research Funding; Stemline Therapeutics Inc.: Research Funding. Jones:Pharmacyclics, LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Download Full-text

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

Blood ◽

10.1182/blood-2019-124478 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3998-3998

Author(s):

Jae H. Park ◽

Madhulika Shukla ◽

Jose M Salcedo ◽

Shreya Vemuri ◽

Julie C Kinoshita ◽

...

Keyword(s):

Board Of Directors ◽

Hairy Cell Leukemia ◽

Research Funding ◽

Braf Inhibitor ◽

Digital Pcr ◽

Hairy Cell ◽

Cell Leukemia ◽

Advisory Committees ◽

Dose Reductions

Background: We have previously reported initial high response rates of the BRAF inhibitor, vemurafenib, in patients (pts) with relapsed or refractory hairy cell leukemia (HCL) (Tiacci and Park et al. NEJM 2015). However, complete response (CR) rates were low at 35-40% with detectable minimal residual disease (MRD) in most patients, and a longer follow up revealed a relapse rate of 50% (Park JH et al. Blood 2018, 132;392). Based on the recent data suggesting improved CR rate in combination with rituximab in relapsed HCL (Tiacci et al. Blood 2016, 128:1214), we initiated a phase II clinical trial to investigate the efficacy of vemurafenib and obinutuzumab in patients with newly diagnosed HCL (NCT03410875). Methods: Adult pts with previously untreated HCL who met the treatment initiation criteria (i.e. ANC <1.0k/ul, Hgb <10.0g/dL or PLT <100k/ul) are eligible for the study. Patients received vemurafenib 960mg bid from months 1-4 and obinutuzumab from months 2-4, for a total treatment duration of 4 months. Obinutuzumab was administered at 1000mg IV on days 1, 8, and 15 of month 2, and day 1 of month 3 and 4. Vemurafenib dose reductions were allowed for drug-related adverse events (AEs). Response was assessed at the end of month 4 with bone marrow (BM) biopsy and CT scans. The primary objective was to determine the efficacy of vemurafenib and obinutuzumab combination as assessed by CR rates, and the secondary objectives include assessment of safety, duration of response, MRD negativity, and BRAF allele burden by digital PCR. The study adopted a Simon's minimax 2-stage design and required ≥7 CR in the first 9 pts in the first stage to continue accrual for a total of 28 pts. We report the result of the first 9 pts in the first stage of the study. Results: A total of 11 pts have been enrolled to the study to date. The median age of the patients is 49 years old (range, 35-79). The median pretreatment ANC, Hgb and PLT is 0.7k/ul (range, 0.0-2.6), 11.5g/dL (range, 7.0-15.0), and 83k/ul (range, 21-153), respectively. Nine of 11 pts had a baseline splenomegaly. Nine pts completed all treatments to date, and 2 pts remain on active therapy. Among the 9 pts who completed the treatment, all pts achieved a response with normalization of cytopenia, including 7 pts with MRD negative CR and 2 pts with PR at the end of month four. Two pts with PR at month 4 converted to MRD+ and MRD negative CR by month 7 and 10, respectively, with no further treatment, with the best overall CR rate of 100% (9/9 pts) (Figure). All MRD negative CR had undetectable BRAFV600E by highly sensitive digital PCR. After 1 month of vemurafenib and before the first dose of obinutuzumab, 7 of 9 pts had ANC recovery to >1.0K/ul and 8 of 9 pts had Hgb >10 g/dL and PLT 100k/uL. With a median follow-up of 9.7 months (range, 4.6-15.4), all pts remain in remission with no relapse. The most common vemurafenib-related AEs were rash (73%; Gr2-9%, Gr3-64%), arthralgia (64%; Gr1-27%, Gr2-27%, Gr3-18%), alopecia (45%, all Gr1), dry skin (27%, all Gr1), and fatigue (27%, Gr1). Two pts experienced obinutuzumab infusion reaction but were able to complete all intended doses of obinutuzumab. No case of cutaneous squamous cell carcinomas has been observed. No pt discontinued the therapy due to toxicity but 8 pts had vemurafenib dose reductions due to rash (n=5) and arthralgia (n=2). Conclusion: Vemurafenib and obinutuzumab combination therapy induced a high CR rate of 100% and high rates of MRD negativity (89%) in patients with HCL in the frontline setting and appears to be a promising chemo-free targeted therapeutic approach for HCL. A majority of the pts achieved a normalization of cytopenia within 4 weeks of starting therapy. A longer follow-up is needed to assess durability of remission and degree of immunosuppression compared to cladribine-treated cohorts. Figure Disclosures Park: Kite Pharma: Consultancy; Incyte: Consultancy; GSK: Consultancy; Autolus: Consultancy; AstraZeneca: Consultancy; Allogene: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Winer:Jazz Pharmaceuticals, Pfizer: Consultancy. Tallman:Cellerant: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KAHR: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nohla: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Biosight: Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; UpToDate: Patents & Royalties; Tetraphase: Consultancy, Membership on an entity's Board of Directors or advisory committees; Delta Fly Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellerant: Research Funding. OffLabel Disclosure: Vemurafenib and obinutuzumab for treatment of hairy cell leukemia

Download Full-text

The Treatment of Hairy Cell Leukemia with a Focus on Long Lasting Responders to Cladribine: A Thirty-Year Experience from the Institute of Hematology of Bologna

Blood ◽

10.1182/blood-2019-122832 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4005-4005

Author(s):

Alessandro Broccoli ◽

Carolina Terragna ◽

Vittorio Stefoni ◽

Cinzia Pellegrini ◽

Beatrice Casadei ◽

...

Keyword(s):

Board Of Directors ◽

Peripheral Blood ◽

Hairy Cell Leukemia ◽

Braf V600e Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

First Line ◽

Advisory Committees ◽

Purine Analogs

The treatment of hairy cell leukemia (HCL) has deeply changed over years. Purine analogs, namely cladribine (2CdA) now represent the treatment of choice. The BRAF V600E mutation is now regarded as the pathogenic event. One hundred and eighty-four patients were followed between 1986 and 2018 and treated according to era-specific guidelines. This is the largest monocentric series reported. Responses were classified by combining Consensus Resolution criteria and marrow immunohistochemistry. Patients were grouped according to the number of treatment lines they received (table). Ten patients treated with frontline 2CdA and in complete response (CR) for at least 5 years were tested for the presence of the BRAF V600E mutation in peripheral blood by droplet digital PCR as a molecular marker for active disease. Patients treated first line responded in 86% of cases, with 44% CR. Response rates remained high throughout the first 4 lines (84%, 81%, 79% for the second line onward, with CR in 38%, 37%, 15% of cases respectively), although decreasing progressively with the number of treatments received. One hundred and twenty-two patients received 2CdA as first line treatment, with a response rate of 86% and a CR rate of 54%. Among the 66 CR patients, 45 (68%) have never received further therapy: 11 patients are in continuous CR between 5 and 10 years after treatment, 14 between 10 and 20 years and 3 patients at more than 20 years. Median time-to-next treatment (TTNT) for patients after receiving 2CdA was 8.2 years: partial responders had a significantly shorter median TTNT than CR patients (5.3 years versus median not reached at 25.8 years, p=0.0001) (figure). Seven patients in CR for more than 5 years after front line 2CdA were BRAF V6500E negative in peripheral blood. One of these displayed disease recurrence and required further treatment roughly 2 years later. Three patients were positive for the BRAF V600E mutation at 6.5, 8.4 and 13.7 years after treatment and developed an overt disease relapse between 4 months and 2 years. Patients with HCL require subsequent lines of therapy in more than 50% of cases. Purine analogs allow significant response rates when applied first line and upon retreatment. Some patients may enjoy long lasting responses after one course of 2CdA and display no evidence of BRAF V600E mutation in peripheral blood. A PCR-based evaluation of the allelic burden in peripheral blood may provide information regarding disease activity over time. Figure Disclosures Cavo: Celgene, Janssen, Amgen, BMS, Abbvie, Takeda: Honoraria; Janssen, Celgene: Other: Travel Accommodations; Janssen, Celgene: Speakers Bureau; Janssen, Celgene, Amgen, Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees. Zinzani:TG Therapeutics: Honoraria, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, 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; Sandoz: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Honoraria, 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; Portola: 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.

Download Full-text

Vemurafenib As First Treatment of Hairy Cell Leukemia

Blood ◽

10.1182/blood.v124.21.5482.5482 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5482-5482

Author(s):

Gregory Cheng ◽

Gym Cheng ◽

Natalie Pui Ha Chan ◽

Chris Wong ◽

Raymond S Wong

Keyword(s):

Complete Remission ◽

Board Of Directors ◽

Hairy Cell Leukemia ◽

Research Funding ◽

Residual Disease ◽

Lymphoid Cells ◽

Hairy Cell ◽

Cell Leukemia ◽

Advisory Committees ◽

Braf V600 Mutation

Abstract 44 years old lady presented with fever and pancytopenia in March 2014.CXR showed bilateral pneumonia. Hb 7.5xg/dl, plt 42x x109/l, wbc 1.2 x19neutrophils22%, lymphocytes75%.Circulating lymphocytes with hairy cytoplasmicprojections and indented nuclei were noted. Flow cytometry showed these abnormal lymphoid cells were CD19+ve, CD5-ve, CD 23-ve, FMC7+ve, CD25+ve, CD11c+ve and CD103+ve.Bone marrow biopsy revealed a hypercellular marrow with dense infiltration of lymphoid cells of the same immunophenotype. Braf V600 mutation was detected. Cladribine or pentostatin was out of stock and import of these drugs would take at least 2 months. In view of the severe pancytopenia and on -going infection, various treatment options were discussed with, the patient .Patient decided to start on vemurafenib 960mg twice daily while awaiting cladribine. After 8weeks of treatment, the peripheral blood counts were normalized. Hb 12.2g/dl, plt 153x x109/l, wbc 3.1x109/l, neutrophils 53%,lymphocytes 40%. Braf V600 mutation was no longer detected. Vemurafenib was well tolerated and the patient received treatment mainly as outpatient. Vemurafenib was discontinued after 8 weeks and the patient then received a 5-day course of cladribine. She remained in complete remission Discussion Vemurafenib had shown to be safe and effected in hairy cell leukemia patients who were refractory to or who relapsed after purine analogs.1,2 Still to be determined are the correct vemurafenib dosing strategy, the best timing , duration and scheduling of vemurafenib. Due to unusual circumstances, our patient received 8 weeks of vemurafenib as first line therapy. The patient achieved a complete remission with minimal residual disease. Follow data is needed to see how long the patient remains in remission 1. N Engl J Med 2014; 370:286-288 2. 19th Congress of the European Hematology Association (EHA): Abstract S696. Disclosures Off Label Use: Vemurafenib as first treatment of Hairy Cell Leukemia. Wong:johnson &johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer, MSD, Roche, BMS, Baxter, Amgen, Alexion: Research Funding.

Download Full-text

Recombinant alpha-2-interferon for hairy cell leukemia

Blood ◽

10.1182/blood.v65.4.1017.1017 ◽

1985 ◽

Vol 65 (4) ◽

pp. 1017-1020 ◽

Cited By ~ 66

Author(s):

AD Jacobs ◽

RE Champlin ◽

DW Golde

Keyword(s):

Hairy Cell Leukemia ◽

Bacterial Infections ◽

Hematologic Toxicity ◽

Corneal Transplant ◽

Hairy Cell ◽

Cell Leukemia ◽

Short Term ◽

Open Label ◽

Bone Marrow Biopsies ◽

The Mean

Abstract Twenty-two patients with hairy cell leukemia were treated with biosynthetic (recombinant) alpha-2-interferon in an open-label, single- arm efficacy study. Patients received 2 X 10(6) U/m2 recombinant alpha- 2-interferon three times weekly. Therapy was well tolerated subjectively with minimal short-term hematologic toxicity. Two patients had bacterial infections during the period of study, and one patient experienced a short-lived readily reversible rejection of a corneal transplant. Statistical comparison of the mean hematologic indices at study entry and after three to six months of therapy with recombinant alpha-2-interferon indicates a significant improvement in hemoglobin, granulocyte, and platelet counts. Bone marrow biopsies in six of 14 patients after six months of therapy showed a greater than 50% decrease in the infiltration of leukemia cells. We conclude that recombinant alpha-2-interferon is highly effective therapy for hairy cell leukemia.

Download Full-text

Rituximab, Bendamustine and Cytarabine (RBAC500) As Induction Therapy in Elderly Patients with Mantle Cell Lymphoma: Final Results of a Phase 2 Study from the Fondazione Italiana Linfomi

Blood ◽

10.1182/blood.v128.22.472.472 ◽

2016 ◽

Vol 128 (22) ◽

pp. 472-472 ◽

Cited By ~ 2

Author(s):

Carlo Visco ◽

Annalisa Chiappella ◽

Luca Nassi ◽

Caterina Patti ◽

Simone Ferrero ◽

...

Keyword(s):

Elderly Patients ◽

Board Of Directors ◽

Cell Lymphoma ◽

Hematologic Toxicity ◽

Phase 2 ◽

Advisory Committees ◽

Ki 67 ◽

Phase 2 Study ◽

Mantle Cell ◽

Grade 3

Abstract Background: The combination of rituximab (R, 375 mg/m2 intravenously [IV], day 1), bendamustine (B, 70 mg/m2IV, days 2 and 3), and cytarabine (800 mg/m2, IV on days 2 to 4) was highly active in patients with mantle-cell lymphoma (MCL) in a phase 2 study [R-BAC; Visco et al, JCO 2013]. This regimen was well tolerated, but hematologic toxicity was quite relevant, especially in terms of transient grade 3 to 4 thrombocytopenia (76% of cycles). Aiming at reducing hematologic toxicity, the Fondazione Italiana Linfomi (FIL) designed a phase 2 trial adopting the R-BAC schedule, but lowering cytarabine dose to 500 mg/m2 (RBAC500). Materials and Methods: Patients with newly diagnosed MCL, aged 61 to 80 years, not eligible for autologous transplant and fit according to the comprehensive geriatric assessment, were enrolled. Patients presenting with non-nodal leukemic disease were excluded. The primary endpoints were complete remission rate (CR) measured by FDG-PET according to Cheson criteria 2007, and safety. Secondary endpoints included rate of molecular response (MR) by nested-PCR using patient specific IGH or BCL1 based targets, progression-free (PFS) and overall survival (OS). The study was conducted according to the Bryant and Day two-stage design. Results: From May 2012 to February 2014, 57 patients with MCL from 29 centers were recruited and treated. Central pathology revision was performed in 87% of cases. Median age was 71 years (range 61-79), 75% were males, and 91% had Ann Arbor stage III/IV disease. Mantle Cell International Prognostic Index (MIPI) was low in 15%, intermediate in 40%, high in 45%, Ki-67 was ≥30% in 31%, and 9% had the blastoid cytological variant. Overall, 53 patients (91%) received at least 4 cycles, while 36 (63%) had 6 cycles (median 5.3 cycles per patient). Fifteen patients (26%) discontinued treatment before reaching cycle 6 because of toxicity/adverse events, that mainly consisted of prolonged hemato-toxicity between cycles. Only one patient discontinued due to progressive disease. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 49% and 52% of administered cycles, respectively. Febrile neutropenia occurred in 6% of cycles. Extra-hematologic toxicity was mainly cardiac (5%). Overall response rate was 96%, and CR was 93%. The MR rate at the end of treatment was 76% on peripheral blood and 55% on bone marrow (BM) samples. With a median follow-up of 34 months (28-52), the 2-years PFS (± confidence interval) was 81%±5% and the OS 85%±4%. Elevated Ki-67 (≥30%), and the blastoid variant were the strongest independent predictors of adverse PFS. Patients with either of these two features (33%), had a significantly inferior PFS (41% vs 97% after 34 months) compared to patients with classical/pleomorphic variants and low proliferative index (p<0.0001, Figure 1). Conclusions: The R-BAC500 regimen can be safely administered as first line therapy to elderly patients with MCL. Hematologic toxicity is substantially reduced compared to our previous experience. With 93% of FDG-PET negative CR, and a 2-years PFS of 81% without maintenance therapy, the R-BAC500 regimen is a highly effective treatment for patients with MCL, and compares favourably with previously reported regimens in this patient population, including R-bendamustine. Figure 1 Figure 1. Disclosures Visco: Gilead: Speakers Bureau; Lundbeck: Consultancy; Mundipharma: Research Funding; Celgene: Speakers Bureau. Spina:Mundipharma: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee; Teva Pharmaceuticals Industries: Membership on an entity's Board of Directors or advisory committees, Other: Speaker Fee. Di Rocco:Celgene: Honoraria. Carella:Millenium: Speakers Bureau; Genentech: Speakers Bureau. Vitolo:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Gilead: Honoraria; Celgene: Honoraria.

Download Full-text

Rituximab For Hairy-Cell Leukemia (HCL): A Multicentric Retrospective Study Of 41 Cases

Blood ◽

10.1182/blood.v122.21.5308.5308 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5308-5308

Author(s):

Mathieu Leclerc ◽

Felipe Suarez ◽

Marie-Pierre Noël ◽

Anne Vekhoff ◽

Xavier Troussard ◽

...

Keyword(s):

Bone Marrow ◽

Combination Therapy ◽

Hairy Cell Leukemia ◽

Complete Response ◽

Median Number ◽

Hairy Cell ◽

Cell Leukemia ◽

Front Line ◽

Line Therapy ◽

Time To Relapse

Abstract Introduction the purine analogs (PA) cladribine (CDA) and pentostatin have dramatically improved the prognosis of HCL and are considered the standard of care both in front-line therapy and at relapse. However, some patients still fail to respond or will eventually relapse after treatment with PA. Chimeric anti-CD20 monoclonal antibody rituximab has shown significant activity in HCL and is an option for relapsed/refractory patients either alone or in combination with PA. Methods we retrospectively reviewed 49 treatments with rituximab for classical HCL, undertaken in 41 patients (pts) from 10 centers in France and Belgium between july 2002 and september 2012. Patients were included if they had received at least 3 infusions of rituximab. Eight pts were treated twice with rituximab. Complete hematologic response (CHR) was defined as recovery of normal blood counts (without circulating HCL cells) and absence of HCL-related symptoms. CHR was further divided into 3 groups: (i) stringent complete response (sCR), if bone marrow evaluation was normal; (ii) unconfirmed complete response (uCR), if bone marrow evaluation was not done and (iii) CHR with persistent medullar infiltration (iCHR). Partial response (PR) corresponded to a ≥ 50% improvement for every CHR-defining criterion or normalization of at least one blood count, without circulating HCL cells. Results characteristics of pts before treatment are summarized in table 1. Rituximab was given as front-line therapy in 8 cases (16.3%). When used at relapse/progression, the median number of previous lines was 3 (range 1-8) and all pts had already received PA (both CDA and pentostatin in one third of them). Rituximab was given alone in 55% of cases, while it was combined with a PA in the 45% remaining cases, mostly CDA (18 of 22 cases). The median number of infusions was 4 (3-12). After treatment, median absolute neutrophil count (ANC), hemoglobin (Hb) level and platelet count were 2.75 x 109/L, 135 g/L and 180 x 109/L respectively. Persistent significant neutropenia (ANC < 1 x 109/L) and anemia (Hb < 100g/L) were each found in only 2 cases and 10.6% of patients had platelets < 100 x 109/L. Overall response rate (ORR) was 89.6% with 70.8% CHR including 6 sCR (12.5%), 26 uCR (54.2%) and 2 iCHR (4.2%). PR was achieved in 9 cases (18.8%) and 5 pts were non responders (10.4%). All the 8 pts who received rituximab as front-line therapy (along with CDA in 5 of them) achieved CHR. In the relapsed pts, ORR was 87.5% (including 65% CHR) with a better outcome for those having received both rituximab and PA (100% ORR including 85.7% CHR versus 79.2% ORR and 54.2% CHR after rituximab alone). The 5 pts who failed to respond were relapsed pts treated with rituximab alone. Interestingly, all the 8 pts who were re-challenged with rituximab responded again to treatment (6 uCR, 1 iCHR and 1 PR). Multivariate analysis identified 3 independent prognostic factors for response to rituximab: absence of previous therapy (OR=0.027 [0,001-0,555], p=0,0192), combination therapy (OR=10,120 [1,227-83,485], p=0,0316) and ANC before treatment (OR=1,002 [1,001-1,004], p=0,006). The median follow-up is 36 months (4-117). Relapse or progression was observed in 15 cases (34.1%), with a median time to relapse of 19 months (2-39). Relapse rate was higher (54.5%) and time to relapse shorter (17.5 months) when rituximab was administered alone, as compared to combination therapy with a PA (10% and 38.5 months respectively). Overall, 3-year relapse-free survival is 68.3%. Six pts have died and 3-year overall survival is 90.3%. Conclusion this study confirms the efficacy of rituximab in HCL patients, mostly when combined to PA. Nevertheless, the relapse rate is high and time to relapse short when rituximab is used as monotherapy beyond front-line treatment. Further prospective studies are warranted to confirm the superiority of the combination PA + rituximab over PA alone. Disclosures: Off Label Use: Rituximab for the treatment of hairy-cell leukemia.

Download Full-text

Recombinant alpha-2-interferon for hairy cell leukemia

Blood ◽

10.1182/blood.v65.4.1017.bloodjournal6541017 ◽

1985 ◽

Vol 65 (4) ◽

pp. 1017-1020

Author(s):

AD Jacobs ◽

RE Champlin ◽

DW Golde

Keyword(s):

Hairy Cell Leukemia ◽

Bacterial Infections ◽

Hematologic Toxicity ◽

Corneal Transplant ◽

Hairy Cell ◽

Cell Leukemia ◽

Short Term ◽

Open Label ◽

Bone Marrow Biopsies ◽

The Mean

Twenty-two patients with hairy cell leukemia were treated with biosynthetic (recombinant) alpha-2-interferon in an open-label, single- arm efficacy study. Patients received 2 X 10(6) U/m2 recombinant alpha- 2-interferon three times weekly. Therapy was well tolerated subjectively with minimal short-term hematologic toxicity. Two patients had bacterial infections during the period of study, and one patient experienced a short-lived readily reversible rejection of a corneal transplant. Statistical comparison of the mean hematologic indices at study entry and after three to six months of therapy with recombinant alpha-2-interferon indicates a significant improvement in hemoglobin, granulocyte, and platelet counts. Bone marrow biopsies in six of 14 patients after six months of therapy showed a greater than 50% decrease in the infiltration of leukemia cells. We conclude that recombinant alpha-2-interferon is highly effective therapy for hairy cell leukemia.

Download Full-text