Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia.

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.

Real-world data on diagnostics, treatment and outcomes of patients with hairy cell leukemia: The HCL-CLLEAR study.

Hairy cell leukemia (HCL) and HCL-like disorders have to be distinguished because of their different biology and treatment response. Thus, we conducted a retrospective study on patients with HCL and hairy cell leukemia variant (HCLv) to assess diagnostic algorithms and treatment outcomes in a real-world setting. We analyzed 225 HCL and 26 HCLv patients with median follow-up of 67.9 months (HCL) and 20.1 months (HCLv). Median age at diagnosis was 56.2 (HCL) and 69.5 years (HCLv), male predominance was observed in both groups (76.0% vs. 73.1%). Diagnostics was mostly based on morphological evidence of hairy cells in the peripheral blood and bone marrow. At diagnosis, BRAF V600E mutation was detected in 94.7% of examined HCL patients and in no HCLv patient. Front-line treatment was indicated in 205 (91.1%) HCL and 18 (69.2%) HCLv patients. The majority of HCL patients were administered a cladribine-based regimen (91.2%). Overall response rate (ORR) was higher in cladribine-treated patients compared to those given other treatments (97.7% vs. 81.3%), the same applied with achieving Complete remission (CR) (91.2% vs. 62.5%). HCLv treatment was heterogeneous, but cladribine remained the most frequent option (44.4%) with ORR 81.3% and CR rates 43.8%. Second-line treatment was indicated in 52 HCL and 8 HCLv patients, 25.4% and 44.4% of those treated in first-line. In the whole HCL group, median time to next treatment (TTNT) was not reached and 10-year TTNT was estimated at 74.1%. HCLv patients who underwent first-line treatment had a median TTNT of 56 months. The median overall survival (OS) in HCL patients was not reached compared to HCLv with a median OS of 9.5 years. These data confirm an excellent prognosis for HCL patients treated with cladribine-based therapy. On the contrary, HCLv with its aggressive behavior represents a group of patients in whom novel treatment approaches are needed.

The current role of interferon in hairy cell leukaemia: clinical and molecular aspects.

We investigated the current role of interferon-alpha (IFNα) in hairy cell leukaemia (HCL) in a retrospective analysis of patients with HCL. A cohort of 74 patients with HCL was divided in to three groups: (A) patients aged >65 years with first-line treatment; (B) patients with comorbidities with first-line treatment; (C) patients who were purine analogues resistant. In total, 94% achieved a response, with a complete response rate of 24%. After a median (range) follow-up of 60 (7-236) months, 55 patients (78%) are still responding. The 5-year progression-free survival was 95%, 68%, and 96% in groups A, B and C respectively. A proportion of patients were monitored through their B-Raf proto-oncogene, serine/threonine kinase (BRAF)-V600E status. IFNα remains a possible option in select patients with HCL, where minimal residual disease negativity is achievable.

Inhibitor of BRAFV600E Mutation as a Treatment Option for Hairy Cell Leukemia With Deep Neutropenia and Infectious Complications.

Standard therapy in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia/agranulocytosis with or without infectious complications; it is thus a complex therapeutic problem. Vemurafenib has been used to treat resistant HCL since 2012. Because vemurafenib does not have a myelotoxic effect, we thought that it could be used to treat HCL associated with deep neutropenia/agranulocytosis with or without the development of infectious complications as a preliminary stage before treatment with cladribine. We conducted a retrospective analysis of treatment with vemurafenib followed by a standard course of cladribine provided to 22 patients with deep neutropenia/agranulocytosis with or without infectious complications at diagnosis. Vemurafenib was provided to 22 patients with HCL. The response to therapy was evaluated by complete blood cell count (absolute neutrophil count [ANC], hemoglobin concentration, platelet count, absence of hairy cells), spleen size (assessed by ultrasound), and reduce infectious complications. After that, a standard course of cladribine was provided. Among the 22 patients, the male/female sex ratio was 2:1, and median (range) age was 52 (24-78) years. There were 7 patients with severe infectious manifestations admitted to the intensive care unit, including 1 patient during extracorporeal membrane oxygenation. The median (range) ANC at diagnosis was 0.3 (0.04-0.7) × 109/L. Vemurafenib was provided at a dosage of 240 mg 1 or 2 times a day. In 20 patients, vemurafenib was provided for 3 months or more. In 1 case, the effect was not obtained during 1 month of treatment, and the patient died from severe infectious complications during prolonged agranulocytosis. In 21 patients treated with vemurafenib, an increase of ANC was observed and the infectious complications resolved, thus allowing the application of cladribine therapy. After a standard course (0.1 mg/kg per day for 7 days) of cladribine chemotherapy, 18 patients (90%) experienced complete clinical remission and 2 patients (10%) experienced partial remission with residual splenomegaly. In 1 patient, vemurafenib therapy was still ongoing 2 months after initiating therapy. In cases of proven BRAFV600E mutation, vemurafenib can be successfully used as an effective preliminary therapy in patients with deep neutropenia/agranulocytosis with or without infectious complications before standard therapy with purine analogs.

Phase 2 study of ibrutinib in classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Targeted therapy for treatment of patients with classical hairy cell leukemia.

Most patients with treatment naïve classical hairy cell leukemia (cHCL) have durable responses with purine nucleoside analogues. In contrast, options are limited for cHCL patients with co-morbidities, purine analogue intolerance, or resistant disease. We report the utility of targeted therapy for nine cHCL patients presenting with treatment naïve cHCL and severe neutropenia and infection (n = 3), purine analogue intolerance (n = 2), or purine analogue resistant disease (n = 4). BRAF inhibitor vemurafenib was started at 240-480 mg twice daily (planned 90-day treatment) and combined with rituximab in seven patients. Therapy was tolerable with no severe adverse events. All patients responded with rapid blood count recovery (median time 1.52 months, range 0.43-4.33). Median progression free and overall survival was not reached at a median follow up of 18.1 months (range 3.2-68.9). These data suggest targeted therapy could be an option for patients unable to be treated with purine analogues.

A population-based study of hairy cell leukemia over a period of 20 years.

There are limited population-based studies of hairy cell leukemia (HCL), a rare chronic lymphoproliferative disorder of B-cells. We conducted a population-based study that included all patients diagnosed with HCL between 1996 and 2016 in Western Normandy. Recorded data focused on medical history, clinical presentation, biological results, treatment modalities in the first line and in relapsed/refractory patients and the occurrence of secondary malignancies. One hundred and twenty-three HCL patients were registered in the database. HCL represented 0.7% of all malignant hematological disorders and 3.0% of all leukemia. The overall age-standardized incidence ratio (SIR) was 0.39/100,000 inhabitants in men and 0.09/100,000 in women, and it remained stable over the 20-year period analyzed. One hundred and seven patients (88%) received first-line treatment, 33 patients (27%) received at least 2 lines of treatment and 14 patients (11%) received more than 2 lines. Cladribine used as first-line treatment induced a high hematological complete response (HCR) rate of 92%. The median overall survival (OS) was over 15 years, with 5-year and 10-year survival rates of 84% and 70.5%. No significant differences in OS were observed between men and women, between the calendar periods studied or between patients who received a single line treatment with IFN-α or PNA. The risk of relapse was higher with IFN-α treatment, requiring subsequent treatments in that patients. The time to next treatment (TTN) tends to be longer for PNAs compared to IFN-α even if difference is not significant. Secondary cancers were observed in 9/123 patients (7.3%) with solid tumors in 8 patients and hematological malignancy in one patient. Our data confirm in real life that single courses of cladribine administered to patients with HCL induce high response rates, the majority of which are HCR. Relapses seem less frequent than with IFN-α and the administration schedule is less restrictive for the patients. The emergence of chemo-immunotherapy and the development of effective new drugs such as recombinant immunotoxins and BRAF targeting will offer new possibilities in the management of HCL patients.

Treatment of hairy cell leukemia.

INTRODUCTION: Purine analogs made dramatic improvements for patients with hairy cell leukemia (HCL), but patients often relapse, require multiple treatments, and may become refractory. Major developments in treatment of relapsed/refractory HCL occurred with discovery of disease biology. New agents increase the complexity of clinical decision-making. AREAS COVERED: Anti-CD22 recombinant immunotoxin Moxetumomab Pasudotox (Moxe), CD20 Mabs rituximab and obinutuzumab, BRAF/MEK inhibitors vemurafenib and dabrafenib-trametinib, and Bruton's tyrosine kinase (BTK) inhibitor ibrutinib have been tested in HCL. All show efficacy but with different treatment durations and response rates, including for eradicating minimal residual disease (MRD). Side effects differ and must be considered when selecting treatment. Studies from PubMed indexed papers and abstracts presented at major international conferences are included. EXPERT OPINION: Rituximab with either purine analog or BRAF-inhibitor achieves high rates of MRD-free complete remission (CR). Moxe achieves MRD-free CR without chemotherapy toxicities. Moxe should be considered prior to splenectomy or development of adenopathy. BRAF/MEK inhibition and ibrutinib are effective options but most patients remain MRD+, requiring indefinite treatment or rituximab to prevent relapse. Under investigation is MRD elimination with CD20 antibody combined with Moxe or BRAF inhibitor. High-risk diseases including HCL variant and IGHV4-34+ unmutated HCL require further investigation.

Biology and Treatment of Hairy Cell Leukemia.

OPINION STATEMENT: Despite its rarity, hairy cell leukemia (HCL) remains a fascinating disease and the physiopathology is becoming more and more understood. The accurate diagnosis of HCL relies on the recognition of hairy cells by morphology and flow cytometry (FCM) in the blood and/or bone marrow (BM). The BRAF V600E mutation, an HCL-defining mutation, represents a novel diagnostic parameter and a potential therapeutic target. The precise cellular origin of HCL is a late-activated postgerminal center memory B cell. BRAF mutations were detected in hematopoietic stem cells (HSCs) of patients with HCL, suggesting that this is an early HCL-defining event. Watch-and-wait strategy is necessary in approximately 10% of asymptomatic HCL patients, sometimes for several years. Purine analogs (PNAs) are the established first-line options for symptomatic HCL patients. In second-line treatment, chemoimmunotherapy combining PNA plus rituximab should be considered in high-risk HCL patients. The three options for relapsed/refractory HCL patients include recombinant immunoconjugates targeting CD22, BRAF inhibitors, and BCR inhibitors. The clinical interest to investigate blood minimal residual disease (MRD) was recently demonstrated, with a high risk of relapse in patients with positive testing for MRD and a low risk in patients with negative testing. However, efforts must be made to standardize MRD analyses in the near future. Patients with HCL are at risk of second malignancies. The increased risk could be related to the disease and/or the treatment, and the respective role of PNAs in the development of secondary malignancies remains a topic of debate.

Prognostic Value of Baseline Serum Lactate Dehydrogenase Level in Patients With Hairy Cell Leukemia.

BACKGROUND: Hairy cell leukemia is a rare B-cell lymphoproliferative disorder. It has an indolent course with relapse and remission periods. The aim of this study was to investigate the clinical characteristics and risk factors affecting the outcome of patients with hairy cell leukemia. PATIENTS AND METHODS: The retrospective data of 65 patients were evaluated according to initial hematologic and biochemical parameters, response rates, progression-free survival, and overall survival. Factors effecting response and survival rates were analyzed. RESULTS: The median follow-up duration was 62.8 months (range, 5.7-229.3 months). The result of the analysis showed that the patients with relapse/progressive disease had higher lactate dehydrogenase (LDH) levels at the time of diagnosis than patients without relapse/progression (median [range], 243 [137-540] vs. 179 [99-334] U/L, P = .01). Patients with LDH ≥ 200.5 IU at the time of diagnosis were demonstrated to have a shorter progression-free survival than those with LDH < 200.5 IU (P = .010). CONCLUSION: Serum LDH level is significantly associated with relapse/progression in hairy cell leukemia patients. Patients with higher LDH levels at diagnosis should be monitored closely even if they experience complete remission.

Hairy Cell Leukaemia.

PURPOSE OF REVIEW: To summarise diagnostic clinical/laboratory findings and highlight differences between classical hairy cell leukaemia (HCLc) and hairy cell leukaemia variant (HCLv). Discussion of prognosis and current treatment indications including novel therapies, linked to understanding of the underlying molecular pathogenesis. RECENT FINDINGS: Improved understanding of the underlying pathogenesis of HCLc, particularly the causative mutation BRAF V600E, leading to constitutive activation of the MEK/ERK signalling pathway and increased cell proliferation. HCLc is caused by BRAF V600E mutation in most cases. Purine nucleoside analogue (PNA) therapy is the mainstay of treatment, with the addition of rituximab, improving response and minimal residual disease (MRD) clearance. Despite excellent responses to PNAs, many patients will eventually relapse, requiring further therapy. Rarely, patients are refractory to PNA therapy. In relapsed/refractory patients, novel targeted therapies include BRAF inhibitors (BRAFi), anti-CD22 immunoconjugate moxetumomab and Bruton tyrosine kinase inhibitors (BTKi). HCLv has a worse prognosis with median overall survival (OS), only 7-9 years, despite the combination of PNA/rituximab improving front-line response. Moxetumomab or ibrutinib may be a viable treatment but lacks substantial evidence.

Moxetumomab pasudotox for hairy cell leukemia: preclinical development to FDA approval.

Moxetumomab pasudotox (MP) is an immunotoxin that recently received US Food and Drug Administration (FDA) approval for the treatment of hairy cell leukemia (HCL) that has failed at least 2 prior lines of therapy, including a purine analog. MP is a recombinant immunotoxin that consists of an anti-CD22 immunoglobulin variable domain genetically joined to Pseudomonas exotoxin (PE38). Unlike most antibody-drug conjugates, which use a chemical linker, recombinant DNA techniques are used to produce MP. MP and its predecessor, BL22, were initially developed to treat non-Hodgkin lymphoma, acute lymphoblastic leukemia, and HCL. However, MP was found to be particularly effective in HCL due to the high level of CD22 cell-surface expression. The recent pivotal phase 3 trial of MP in relapsed/refractory HCL demonstrated a durable complete remission rate of 30%, and 85% of complete responders achieved minimal residual disease negativity, which is associated with improved disease-free survival outcomes in HCL. In addition to an exceptional depth of response, MP appears to be less immunosuppressive than purine analogs. MP is generally well tolerated but has unique toxicities, including capillary leak syndrome and hemolytic uremic syndrome, which are poorly understood. This review will encompass the preclinical and clinical development of MP, with particular attention to its current indication in HCL.

Primary peg-filgrastim prophylaxis versus filgrastim given "on demand" for neutropenia during therapy with cladribine for hairy cell leukemia.

BACKGROUND: Major advances in the treatment of patients with hairy cell leukemia (HCL) have been made following the introduction of purine analogues. The major significant short-term toxicity of cladribine therapy are neutropenia and neutropenic fever (NF) which may be life-threatening. AIM: In this retrospective study, we compared the incidence and duration of neutropenia and hospitalization in patients with HCL treated with cladribine followed by peg-filgrastim as primary prophylaxis versus daily filgrastim given "on demand" according to absolute neutrophil count (ANC). METHODS: Medical records of patients with HCL diagnosed and followed in 12 medical centers in Israel during 1985-2015 were examined for details of disease at diagnosis. The efficacy of peg-filgrastim and filgrastim was assessed by evaluating the incidence of neutropenia (ANC < 1.0 × 10 [9]/L), number and length of hospitalizations, and number of days from the last day of therapy to recovery of ANC to >1.0 × 10 [9]/L. RESULTS: The study population included 202 patients with HCL, 159 of whom (80.7%) were treated with cladribine; 78 patients (49%) required hospitalization for the administration of broad-spectrum antibiotics due to NF. Twenty-eight (19%) patients were treated with peg-filgrastim as primary prophylaxis, while 74 (64%) received filgrastim "on demand" due to neutropenia. Median length of hospitalization, and nadir duration were 8 and 18 days respectively (p = 0.71, p = 0.44). CONCLUSIONS: Infectious complications post-cladribine treatment remain high. No difference was found in terms of incidence of NF, number of febrile days, and nadir duration in patients receiving primary peg-filgrastim prophylaxis compared to filgrastim given on demand. Both approaches are justifiable, and the choice remains at the physician's discretion.

Outcomes and second neoplasms in hairy cell leukemia: A retrospective cohort.

Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disease which is treated on the basis of small studies, making the literature still scarce of reports, especially of those conducted in Latin America. Here we intend to describe clinical characteristics, rates of response, survival and second neoplasms in HCL patients treated in a reference center in Brazil. All patients diagnosed with HCL between July/1987 and Jun/2018 were included in this analysis. Fifty-four patients were included in this analysis. Median age at diagnosis was 55 years (range, 26-88), with 37% being above 60 years-old. Most patients were treated with cladribine in our cohort (n = 36; 68%), administered through intravenous continuous infusion. Remaining patients were firstly managed with splenectomy (n = 7; 13%), IFN (n = 6; 11%) and rituximab (n = 2; 4%). In a univariate analysis, platelet count and B2M level at diagnosis were statistically associated with CR achievement (p = 0.004 and p = 0.024, respectively). A median follow-up time of 9 years was calculated. Estimated 10-year overall survival was 91.1% (95% confidence interval, 77-97). In this cohort, 10 patients had any second neoplasm, diagnosed before or after HCL. Regarding the sites of cancer, 69% were of skin - 8/16 carcinoma-type and 3/16 melanoma-type. Our response and survival data are similar to those reported by literature, which reaffirms the role of purine analogs in current HCL management. With a very long follow-up we also have observed a high incidence of second neoplasm.

Moxetumomab Pasudotox: Clinical Experience in Relapsed/Refractory Hairy Cell Leukemia.

BACKGROUND: Moxetumomab pasudotox is a promising new therapy for the treatment of patients with relapsed/refractory hairy cell leukemia (R/R HCL), but practical guidance relating to its administration is limited. OBJECTIVES: This article describes clinical guidelines for the administration of moxetumomab pasudotox to patients with R/R HCL and presents related case studies. METHODS: A limited review of the literature on HCL was undertaken. FINDINGS: Nursing care of patients prescribed moxetumomab pasudotox includes monitoring clinical and laboratory parameters, managing side effects, being aware of signs of serious side effects, and maintaining patient hydration during administration.

Androgen Therapy for Acute Myeloid and Hairy Cell Leukemia.

OPINION STATEMENT: The purpose of this paper is to review the preclinical and clinical rationale for androgen therapy of acute myeloid (AML) and hairy cell leukemia (HCL). A major recent positive study should renew interest in this therapy, which has been reported to be effective in these leukemias for more than 50 years. Hopefully, renewed interest in this approach, which seems promising, will lead to well-designed modern studies that will precisely define a role for androgens in these leukemias. A recent large prospective, randomized study has demonstrated enhanced survival for elderly AML patients who present with WBC counts < 30,000/µL have improved overall survival when androgens are given post-remission, and numerous case reports suggest that androgens frequently restore normal peripheral blood counts in severely pancytopenic patients with HCL. Well-designed prospective studies are needed to precisely define which patients are most likely to benefit from androgen therapy and where in the treatment plan they should be incorporated.

sIL2R ratio as early marker for response in hairy cell leukemia and the prognostic relevance of IL28B genotype to interferon-α therapy.

Interferon-α (IFNα) was the first effective drug therapy for hairy cell leukemia (HCL). Nowadays, it is used as an alternative treatment in selected patients. Due to unlimited treatment time, monitoring and early prediction of response are important. Moreover, IFNα is used in the therapy of chronic hepatitis C, where a single nucleotide polymorphism of interleukin-28B gene (IL28B) correlates with therapy response. The role of this polymorphism in therapy response of IFNα-treated patients with HCL is unknown. Thirty-seven HCL patients treated between 1978 and 2014 were included in this study. Treatment strategy and response parameters (blood cell counts, soluble interleukin-2 receptor (sIL2R), and bone marrow examination) have been assessed. Relative decrease of sIL2R was correlated with outcome parameters. Response parameters of IFNα-treated patients were correlated with IL28B polymorphism. Twenty-one patients were analyzed for the correlation of sIL2R ratio and outcome. After 1 and 3 months of therapy (IFNα or cladribine (CDA)), the median sIL2R level showed a relative decrease of 79 and 91%. These decreases significantly correlate with time to complete remission (CR, p = 0.029 and p = 0.018). Correlation analyses of IL28B genotype with outcome parameters are not significant. Six patients (16%) were diagnosed with secondary malignancies, and one death was registered (median follow-up time 14 years). IFNα is a safe, effective, and well-tolerated long-term treatment in HCL. Relative decreases of sIL2R levels correlate with time to CR and are useful as early predictor for response. There is no significant correlation between IL28B polymorphism and treatment response to IFNα. Graphical abstract.

BRAF V600E mutation in hairy cell leukemia: from bench to bedside.

Hairy cell leukemia (HCL) is a distinct clinicopathological entity whose underlying genetic lesion has remained a mystery for over half a century. The BRAF V600E mutation is now recognized as the causal genetic event of HCL because it is somatic, present in the entire tumor clone, detectable in almost all cases at diagnosis (encompassing the whole disease spectrum), and stable at relapse. BRAF V600E leads to the constitutive activation of the RAF-MEK-extracellular signal-regulated kinase (ERK) signaling pathway which represents the key event in the molecular pathogenesis of HCL. KLF2 and CDNK1B (p27) mutations may cooperate with BRAF V600E in promoting leukemic transformation. Sensitive molecular assays for detecting BRAF V600E allow HCL (highly responsive to purine analogs) to be better distinguished from HCL-like disorders, which are treated differently. In vitro preclinical studies on purified HCL cells proved that BRAF and MEK inhibitors can induce marked dephosphorylation of MEK/ERK, silencing of RAF-MEK-ERK pathway transcriptional output, loss of the HCL-specific gene expression profile signature, change of morphology from "hairy" to "smooth," and eventually apoptosis. The overall response rate of refractory/relapsed HCL patients to the BRAF inhibitor vemurafenib approached 100%, with 35% to 40% complete remissions (CRs). The median relapse free-survival was about 19 months in patients who had achieved CR and 6 months in those who had obtained a partial response. Future therapeutic perspectives include: (1) combining BRAF inhibitors with MEK inhibitors or immunotherapy (anti-CD20 monoclonal antibody) to increase the percentage of CRs and (2) better understanding of the molecular mechanisms underlying resistance of HCL cells to BRAF inhibitors.