Vemurafenib As First Treatment of Hairy Cell Leukemia

Blood ◽  
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.

A Distributed International Patient Data Registry for Hairy Cell Leukemia

Blood ◽  
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.

scholarly journals 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 ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1215-1215 ◽  
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.

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

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5598-5598 ◽  
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.

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

Blood ◽  
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

scholarly journals Minimal Residual Disease, Its Detection and Significance in Hairy-Cell Leukemia

1999 ◽  
Vol 42 (3) ◽  
pp. 85-88 ◽  
Author(s):  
Pavel Žák ◽  
Ladislav Chrobák ◽  
Karel Dědič
Keyword(s):  
Complete Remission ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Hairy Cells ◽  
Minimal Residual

As minimal residual disease (MRD) is considered the detection of hairy cells (HCs) in a patient with hairy cell leukemia (HCL) in complete remission with the absence of detectable HCs by routine morphology of peripheral blood, aspirates and bone marrow core sections, using more sensitive methods of identification as immunohistological staining or polymerase chain reaction (PCR) to detect immunoglobulin heavy chain genes rearrangement. Various monoclonal antibodies (MoAbs) as CD20, DBA.44, B ly-7, HC2, CD25 and CD11c have been applied using immunological staining. There is no standardized technique for identification of MRD. According to the technique used the MRD has been detected in 13% to 100% of patients in complete remission (CR). It may be concluded that many patients, if not all, in stable CR may have residual HCs. Whether MRD will have impact on early relapse or on long term outcome, or whether patients in CR with persistant MRD will remain so, is a matter of a longer follow-up.

Potential Predictive Patterns of Minimal Residual Disease Detected by Immunohistochemistry on Bone Marrow Biopsy Specimens During a Long-term Follow-up in Patients Treated With Cladribine for Hairy Cell Leukemia

2006 ◽  
Vol 130 (3) ◽  
pp. 374-377 ◽  
Author(s):  
Paulette Mhawech-Fauceglia ◽  
Martin Oberholzer ◽  
Senait Aschenafi ◽  
Audrey Baur ◽  
Michael Kurrer ◽  
...  
Keyword(s):  
Complete Remission ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Biopsy Specimens ◽  
Patients At Risk ◽  
Minimal Residual

Abstract Context.—Minimal residual disease (MRD) in patients treated for hairy cell (HC) leukemia as assessed by immunohistochemistry has not been included routinely in evaluation of treatment results. Objective.—To assess the presence of persistent HCs after treatment, as detected by immunohistochemistry, and to evaluate the correlation between the level of MRD and clinical outcome. Design.—Percentages of DBA.44-positive HCs were assessed on 116 biopsy specimens from 17 patients. The patients had a median follow-up of 55.4 months. Results.—Minimal residual disease was seen in 3 patterns. Group 1 (7 patients) had MRD levels ranging from “rare scattered suspicious HCs” to less than 1%. The MRD levels were stable throughout follow-up, and all patients remained in complete remission. Group 2 (6 patients) had MRD levels ranging from 1% to 5%, and 3 patients were in complete remission at 77.9, 63.8, and 108.0 months. Another patient showed evidence of disease activity (partial remission) at 47.6 months. Two other patients relapsed at 12.3 months and at 25.7 months, respectively, with greater than 1% HCs. Group 3 (4 patients) had MRD levels greater than 5%. Three patients relapsed at 11.3, 12.1, and 29.6 months, respectively, with greater than 5% HCs. The fourth patient had MRD levels of 5% at 14.6 months and 2% at 20.0 months but was subsequently lost to follow-up. Conclusions.—Quantitative assessment of MRD may be of value in identifying patients at risk for relapse of hairy cell leukemia.

Loss Of Major Molecular Response As a Trigger For Restarting Tyrosine Kinase Inhibitor Therapy In CP-CML Patients Who Have Stopped Imatinib After Durable Undetectable Minimal Residual Disease

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 381-381 ◽  
Author(s):  
Philippe Rousselot ◽  
Aude Charbonnier ◽  
Pascale Cony-Makhoul ◽  
Philippe Agape ◽  
Franck E Nicolini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Chronic Phase ◽  
Lymphoid Cells ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Advisory Committees ◽  
Number Of Patients

Abstract Purpose More than half of patients with chronic phase chronic myelogenous leukemia (CP-CML) in complete molecular response (CMR) experience molecular relapse after imatinib discontinuation. We investigated loss of major molecular response (MMR) as a criterion for resuming therapy. Patients and methods A multicenter observational study (A-STIM, According to STop IMatinib) evaluating MMR persistence was conducted in 80 CP-CML patients who had stopped imatinib after prolonged confirmed CMR (24 months or more). Patients with confirmed CMR with 1 or 2 occasional weak positive samples before study entry were also considered eligible. CMR was defined as undetectable BCR-ABL transcript with a sensitivity of at least 40000 amplified copies of the ABL control gene, in accordance with the level of sensitivity routinely applied within laboratories participating in the French GBMHM Network. Results Median time from imatinib initiation to discontinuation was 79 months (range 30-145), median duration of CMR before imatinib discontinuation was 41 months (24-96), and median follow-up after discontinuation was 31 months (8-92). Twenty-nine patients (36%) lost MMR after a median of 4 months off-therapy (2-17). Cumulative incidence of MMR loss was estimated as 35% (95% CI, 25%-46%) at 12 months and 36% (95% CI, 26%-47%) at 24 months whereas probability of losing CMR was estimated as 51% at 12 months (95% CI, 41%-63%) and 54% at 24 months (95% CI, 44%-66%). Fivety two percent of the patients met the criteria for cCMR but experienced occasional BCR-ABL positivity (unstable cCMR). Those patients were not at higher risk of losing MMR as compared to patients with stable cCMR. This observation may potentially increase by two-fold the number of patients eligible for TKI discontinuation. Fluctuation of BCR-ABLtranscript levels below the MMR threshold (≥ 2 consecutive positive values) were observed in 31% of patients after imatinib discontinuation. Using cell sorting in three fluctuating patients, we were able to confirm that BCR-ABL signal was mostly present in the CD15 positive fraction, demonstrating first that BCR-ABL residual signal was not related to long living lymphoid cells and second that residual CML cells retain a clonogenic potential. Treatment-free remission was estimated as 64% (95% CI, 54%-75%) at 12 and 24 months and 61% (95% CI, 51%-73%) at 36 months. Treatment was resumed in 31 patients after loss of MMR. Twenty-three patients regained CMR4.5 and 8 patients are in MMR under therapy after 2+ to 17+ months. Median to time to a second CMR was estimated as 7.3 months in retreated patients. Conclusion The probability of losing MMR after imatinib discontinuation was estimated as 36% in the long-term. Loss of MMR is a practical and safe criterion for restarting therapy in CML patients with prolonged CMR and could be used for future discontinuation studies. Disclosures: Rousselot: Novartis: Research Funding; BMS: Research Funding. Cony-Makhoul:BMS: Honoraria; Novartis: Research Funding. Nicolini:BMS, Teva, Ariad, Pfizer, Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Etienne:Novartis: Consultancy; Pfeizer: Consultancy; Novartis: Honoraria; BMS: Honoraria. Guerci-Bresler:Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Membership on an entity’s Board of Directors or advisory committees. Turhan:BMS: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; BMS: Honoraria; Novartis: Research Funding. Guilhot:BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy; Pfizer: Consultancy; BMS: Research Funding; Novartis: Research Funding. Mahon:Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Brisol Myers Squibb: Consultancy, Honoraria; Ariad: Honoraria; Pfizer: Honoraria.

scholarly journals Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia

Blood ◽  
1994 ◽  
Vol 84 (12) ◽  
pp. 4310-4315 ◽  
Author(s):  
DJ Ellison ◽  
RW Sharpe ◽  
BA Robbins ◽  
JC Spinosa ◽  
JD Leopard ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Positive Staining ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Bone Marrow Biopsies ◽  
Hairy Cells

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA) induces complete remissions in 85% of patients. Complete remission has been defined as the absence of hairy cells in the bone marrow after routine morphologic examination. To determine if hairy cells could be detected in complete remission bone marrows using immunohistochemical techniques with antibodies L26 (CD20) and DBA.44, 154 bone marrow biopsies performed between 3 months and 25 months after therapy were studied. Of the biopsies, 50% exhibited staining with L26 and/or DBA.44 in five or more cells with morphologic features of hairy cells. Minimal residual disease was usually less than 1% of the total cellular population. DBA.44-positive cells were demonstrated in 91% of the biopsies, although in 48% of these the morphologic features of the positive cells were not sufficiently distinctive for hairy cells. The proportion of biopsies with residual hairy cells was similar over the 25 months of follow up, indicating a relatively stable amount of residual disease. Immunomorphologic analysis is a more sensitive method for detecting residual hairy cells than morphology alone. Although further follow up is necessary to determine the clinical significance of the L26/DBA.44-positive staining in cells with and without distinctive morphologic features of hairy cells, we conclude that many patients in a stable clinical remission may have residual hairy cells.

scholarly journals First Line Treatment with Venetoclax and Ibrutinib Induction Followed By Obinutuzumab Intensification Exclusively in CLL/SLL Patients Not in Complete Remission and/or with Detectable Bone Marrow Minimal Residual Disease (NEXT STEP trial)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1753-1753
Author(s):  
Sabina Kersting ◽  
Mark-David Levin ◽  
Carsten Utoft Niemann ◽  
Yvette Norden ◽  
Arnon P. Kater
Keyword(s):  
Bone Marrow ◽  
Complete Remission ◽  
Board Of Directors ◽  
Research Funding ◽  
Residual Disease ◽  
Treatment Intensification ◽  
Advisory Committees ◽  
Educational Grant ◽  
Pet Ct ◽  
Travel Grant

Background Keeping the balance between long-term efficacy and toxicity of treatment in patients with chronic lymphocytic leukemia (CLL) is of utmost importance. Ibrutinib impacts BCR/adhesion signaling resulting in efficient lymph node (LN) responses and prolonged disease control despite a lack of deep remissions. Venetoclax directly kills CLL cells by antagonizing the pro-survival Bcl-2 protein leading to deep remissions (undetectable minimal residual disease (uMRD)) in the blood and bone marrow (BM) but incomplete LN clearance. Synergy between these agents is shown in our relapsed/refractory CLL HOVON 141 study with complete remission (CR) rates of 69% and blood uMRD rate of 55% after 12 full dose combination cycles with acceptable toxicity (abstract submitted; Niemann et al.). Extrapolating these data, we hypothesize that a fixed duration of a combination of venetoclax and ibrutinib will result in a substantial proportion of patients in CR and with undetectable MRD, who will have very good outcome after treatment cessation. Yet, not all patients will achieve this level of disease clearance and therefore, intensification approaches are of interest. A prior study has shown that addition of the CD20 antibody obinutuzumab lead to considerably higher uMRD rates when added after 1 year of prior ibrutinib monotherapy than when given simultaneously (BM uMRD rate of 50% versus 6% respectively; Hillmen et al. 2018). This suggests an opportunity for treatment intensification in the subset of patients who do not respond optimally to initial I+V combination treatment. In CLL, 3 compartments exist with putative differential sensitivity for targeted agents. Although the predictive role of residual leukemia cells in blood and bone marrow, as measured by MRD is increasingly appreciated, the biological and prognostic relevance of residual LN, which is often observed in venetoclax treated patients, is uncertain. 18F-fluorodeoxyglucose (FDG) PET-CT is widely used for response evaluation of lymphoma, but has not proven its value in CLL. (Conte et al. 2014) However, radiomics with computational processing of the PET/CT may provide biologic and clinical relevant information on the characteristics of residual LN and warrants exploration for guidance of treatment intensification as an MRD proxy for spleen and LN. (Lee et al. 2018) Objectives To evaluate the efficacy of 6 cycles ibrutinib+obinutuzumab in converting patients who are not in CR or who have detectable MRD after 12 cycles of ibrutinib+venetoclax to a CR with uMRD (BM). Moreover, PET/CT with radiomics is employed to assess clearance of CLL from LN and spleen. Primary endpoint CR with uMRD (BM) 3 months after end of intensification with ibrutinib+obinutuzumab in patients who are not in CR and/or uMRD on combination ibrutinib/venetoclax. Design The trial is designed as a single arm phase 2 study for treatment naïve CLL patients requiring treatment according to IWCLL criteria. 85 patients will be included. Study Treatment Patients will receive 3 lead-in cycles of ibrutinib 420 mg/day. Here-after, patients will continue with 13 induction cycles (including one bridging cycle) combining ibrutinib 420 mg/day and venetoclax 400 mg/day including a ramp up of 5-weeks starting in cycle 4 day 1. Patients with measurable disease at evaluation after 15 cycles will continue with 6 intensification cycles of ibrutinib/obinutuzumab. day 1, 2, 8, 15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles in combination with ibrutinib (Figure 1). Major inclusion criteria Treatment naïve CLL or SLL patients requiring treatment by iwCLL WHO performance status 0-3 Adequate BM function defined as: Hb > 8 g/dLNeutrophil count ≥75 x 109/LPlatelet count ≥ 50,000 /μLcreatinine clearance ≥ 30ml/min Major exclusion criteria Active fungal, bacterial, and/or viral infection that requires systemic therapy; Patients requiring treatment with strong cytochrome P450 (CYP) 3A inhibitor or with vitamin K antagonists Statistical methods For the primary endpoint analyses, all patients registered and eligible for intensification treatment with ibrutinib+obinutuzumab (not in complete remission and/or uMRD) will be included. Perspective This trial helps in personalizing CLL treatment by selecting sequential time limited therapies guided by MRD. Figure 1 Disclosures Levin: Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Educational Grant; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant ; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Educational grant . Niemann:Janssen: Consultancy, Other: Travel grant, Research Funding; Roche: Other: Travel grant; CSL Behring: Consultancy; Acerta: Consultancy, Research Funding; Sunesis: Consultancy; Astra Zeneca: Consultancy, Research Funding; Novo Nordisk Foundation: Research Funding; Gilead: Other: Travel grant; Abbvie: Consultancy, Other: Travel grant, Research Funding. Kater:Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Combination of ibrutinib and venetoclax Combination of ibrutinib and obinutuzumab

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

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-37
Author(s):  
Giovanni Manfredi Assanto ◽  
Costantino Riemma ◽  
Francesco Malaspina ◽  
Salvatore Perrone ◽  
Maria Lucia De Luca ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Board Of Directors ◽  
Hairy Cell Leukemia ◽  
Univariate Analysis ◽  
Hematologic Toxicity ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Front Line ◽  
Advisory Committees ◽  
Group A

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 &gt;65 years who received IFNα front-line; B) patients &lt;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 &gt;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.

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