Vemurafenib Plus Rituximab in Hairy Cell Leukemia: A Promising Chemotherapy-Free Regimen for Relapsed or Refractory Patients

Abstract BACKGROUND: Hairy cell leukemia (HCL) responds well to purine analogs, but up to 50% of patients relapse. We previously identified the BRAF-V600E mutation as the genetic lesion underlying HCL (NEJM 364:230-2315, 2011), and successfully targeted this mutation in the clinic with the oral BRAF inhibitor vemurafenib through an academic phase-2 multi-center Italian trial in HCL patients relapsed after or refractory to purine analogs (NEJM 373:1733-1747, 2015). In these heavily pre-treated patients, vemurafenib given for a median of 16 weeks produced 96% of responses, including 9/26 (35%) complete remissions (CR) and 16/26 (61%) partial remissions (PR), which were obtained after a median of 8 weeks of treatment. Even in complete responders, immunohistochemistry showed residual (~10%) bone marrow HCL cells at the end of treatment, and relapses were common, occurring at a median of 19 months and 6 months in CR and PR patients respectively. Residual HCL cells resisting vemurafenib treatment might be targeted by concomitant immunotherapy with an anti-CD20 monoclonal antibody, an attractive strategy to potentially achieve a more profound response and a better clinical outcome through a chemotherapy-free approach. METHODS: We started an academic, phase-2, single-center trial (EudraCT 2014-003046-27) in relapsed/refractory HCL, which tests vemurafenib in combination with rituximab, another targeted non-myelotoxic drug with known single-agent activity in HCL. Eligibility was extended to patients relapsed also after monotherapy with a BRAF inhibitor. Vemurafenib was given at its standard dose (960 mg twice daily orally) for 8 weeks. Rituximab infusions (375 mg/m2intravenously) were given concomitantly with vemurafenib every 2 weeks, as well as sequentially (after the end of vemurafenib dosing) four times every 2 weeks. RESULTS: We have so far enrolled 22 patients in 16 months. Adverse reactions were reversible, usually mild and consistent with the known toxicity profile of the two drugs when used alone. Notably, a CR was achieved by all 14 patients already evaluable for efficacy (100%), including 4 who had relapsed after a BRAF inhibitor and 1 previously refractory to rituximab. Furthermore, 12/14 patients (86%) obtained the CR as early as after 4 weeks of vemurafenib and 2 concomitant rituximab infusions. This CR rate appears higher than that observed by us and others using vemurafenib alone in BRAF inhibitor-naive patients relapsed after or refractory to purine analogs (CR rate 35-42%; NEJM 373:1733-1747, 2015). Moreover, minimal residual disease (MRD) was undetectable in the bone marrow biopsy and aspirate of 8/11 patients evaluated (73%), both by immunophenotyping and by allele-specific PCR (limit of detection: 0.05% BRAF-V600E copies). In 5 of these 8 patients, MRD clearing was reached even before sequential rituximab dosing post-vemurafenib. In the remaining 3/11 patients, MRD was at most 5% in 2 vemurafenib-naive patients, and 10% in 1 patient relapsed after prior BRAF-inhibitor treatment. In contrast, residual bone marrow disease was a constant feature of all 26 patients treated by us with vemurafenib alone for a longer time period (NEJM 373:1733-1747, 2015). CONCLUSIONS: This study - which is the first one combining vemurafenib and rituximab in relapsed/refractory HCL - suggests that this non-myelotoxic regimen produces more numerous, faster and deeper CRs than vemurafenib alone. Enrollment continues. Disclosures Gaidano: Karyopharm: Consultancy, Honoraria; Morphosys: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.

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Genomics of Hairy Cell Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.1556 ◽

2017 ◽

Vol 35 (9) ◽

pp. 1002-1010 ◽

Cited By ~ 25

Author(s):

Enrico Tiacci ◽

Valentina Pettirossi ◽

Gianluca Schiavoni ◽

Brunangelo Falini

Keyword(s):

B Cell ◽

Hairy Cell Leukemia ◽

Ex Vivo ◽

Braf Inhibitor ◽

Braf V600e ◽

Leukemic Cells ◽

Splenic Marginal Zone Lymphoma ◽

Hairy Cell ◽

Cell Leukemia ◽

Purine Analogs

Hairy cell leukemia (HCL) is a chronic mature B-cell neoplasm with unique clinicopathologic features and an initial exquisite sensitivity to chemotherapy with purine analogs; however, the disease relapses, often repeatedly. The enigmatic pathogenesis of HCL was recently clarified by the discovery of its underlying genetic cause, the BRAF-V600E kinase-activating mutation, which is somatically and clonally present in almost all patients through the entire disease spectrum and clinical course. By aberrantly activating the RAF-MEK-ERK signaling pathway, BRAF-V600E shapes key biologic features of HCL, including its specific expression signature, hairy morphology, and antiapoptotic behavior. Accompanying mutations of the KLF2 transcription factor or the CDKN1B/p27 cell cycle inhibitor are recurrent in 16% of patients with HCL and likely cooperate with BRAF-V600E in HCL pathogenesis. Conversely, BRAF-V600E is absent in other B-cell neoplasms, including mimickers of HCL that require different treatments (eg, HCL-variant and splenic marginal zone lymphoma). Thus, testing for BRAF-V600E allows for a genetics-based differential diagnosis between HCL and HCL-like tumors, even noninvasively in routine blood samples. BRAF-V600E also represents a new therapeutic target. Patients’ leukemic cells exposed ex vivo to BRAF inhibitors are spoiled of their HCL identity and then undergo apoptosis. In clinical trials of patients with HCL who have experienced multiple relapses after purine analogs or who are refractory to purine analogs, a short course of the oral BRAF inhibitor vemurafenib produced an almost 100% response rate, including complete remission rates of 35% to 42%, without myelotoxicity. To further improve on these results, it will be important to clarify the mechanisms of incomplete leukemic cell eradication by vemurafenib and to explore chemotherapy-free combinations of a BRAF inhibitor with other targeted agents (eg, a MEK inhibitor and/or an anti-CD20 monoclonal antibody).

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Immunoconjugates and new molecular targets in hairy cell leukemia

Hematology ◽

10.1182/asheducation.v2012.1.660.3798659 ◽

2012 ◽

Vol 2012 (1) ◽

pp. 660-666 ◽

Cited By ~ 19

Author(s):

Robert J. Kreitman

Keyword(s):

Hairy Cell Leukemia ◽

Poor Prognosis ◽

Residual Disease ◽

Single Agent ◽

Braf V600e ◽

Late Relapse ◽

Hairy Cell ◽

Cell Leukemia ◽

Purine Analogs ◽

Purine Analog

Abstract Hairy cell leukemia (HCL) is a B-cell malignancy that in its classic form is exquisitely sensitive to single-agent purine analog therapy, but that is associated in many patients with late relapse and eventual purine analog resistance. Minimal residual disease, which is present in most patients achieving complete remission with purine analogs, retains Ags that are ideal for targeted therapy. Rituximab, which targets CD20, is active as a single agent, particularly if combined with purine analogs. Recombinant immunotoxins targeting either CD25 or CD22 and containing truncated Pseudomonas exotoxin have achieved major responses in relapsed/refractory HCL. Moxetumomab pasudotox in phase 1 testing achieved responses in 86% of such patients (complete in 46%) without dose limiting toxicity and often without MRD. Soluble CD22 has been used for improved detection and monitoring of HCL, particularly the poor-prognosis variant that lacks CD25. Ig rearrangements unique for each HCL patient have been cloned, sequenced, and followed by real-time quantitative PCR using sequence-specific reagents. Analysis of these rearrangements has identified an unmutated IGVH4-34–expressing poor-prognosis variant with immunophenotypic characteristics of either classic or variant HCL. The BRAF V600E mutation, reported in 50% of melanomas, is present in > 85% of HCL cases that are both classic and express rearrangements other than IGVH4-34, making HCL a potential target for specific inhibitors of BRAF V600E. Additional targets are being defined in both classic and variant HCL, which should improve both detection and therapy.

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Efficacy and Safety of the BRAF Inhibitor Vemurafenib in Hairy Cell Leukemia Patients Refractory to or Relapsed after Purine Analogs: A Phase-2 Italian Clinical Trial

Blood ◽

10.1182/blood.v124.21.150.150 ◽

2014 ◽

Vol 124 (21) ◽

pp. 150-150 ◽

Cited By ~ 2

Author(s):

Enrico Tiacci ◽

Luca De Carolis ◽

Pier Luigi Zinzani ◽

Alessandro Pulsoni ◽

Francesco Zaja ◽

...

Keyword(s):

Bone Marrow ◽

Hairy Cell Leukemia ◽

Braf Inhibitor ◽

Post Treatment ◽

The Other ◽

Braf V600e ◽

Morphological Evidence ◽

Hairy Cell ◽

Cell Leukemia

Abstract BACKGROUND AND AIMS: Hairy cell leukemia (HCL) is very sensitive to purine analogs (PAs), but ~40% of patients relapse and become progressively less responsive to these myelotoxic and immune-suppressive drugs. Having discovered the BRAF-V600E kinase-activating mutation as the genetic lesion underlying HCL (Tiacci et al, NEJM 2011;364:2305), we performed the first clinical trial of a BRAF inhibitor (vemurafenib) in refractory/relapsed HCL. In particular, this is a phase-2, academic, single-arm, Italian, multi-center (n=8) study (HCL-PG01; EudraCT 2011-005487-13). METHODS: In 11 months we enrolled 28 BRAF-V600E+ HCL patients, needing therapy due to cytopenias and including: i) 6 patients primary refractory to a PA; ii) 21 patients who relapsed early and/or repeatedly after PAs and had received a median of 4 previous therapies; and iii) a 81-year old patient showing severe myelotoxicicity after a PA (discouraging its further use). Previous treatments other than PAs included interferon, rituximab and splenectomy in 12, 14 and 8 patients, respectively. Complete remission (CR) required resolution of cytopenias (N≥1500/mmc, PLT≥100000/mmc, Hb≥11 g/dl), no morphological evidence of HCL cells in the bone marrow biopsy and blood smear, and no splenomegaly. Partial remission (PR) required resolution of cytopenias, and a ≥50% reduction of splenomegaly and of marrow and blood HCL involvement by immunophenotyping. Two patients were not evaluable as they went off-study after ≤1 week of treatment (due to drug-unrelated acute myocardial infarction and consent withdrawal after grade-3 drug-related reversible pancreatitis). RESULTS: Vemurafenib, given orally at the dose of 960 mg twice daily on an outpatient basis for a median of 16 weeks, was generally well tolerated. Drug-related adverse events (mainly arthralgias, skin toxicities, pancreatitis; no myelosuppression) were frequent, but reversible in all patients, and were typically grade 1-2. Only 7 patients developed grade 3 events, and none grade 4 events. Although we did not observe any cutaneous squamous cell carcinomas/keratoachantomas (as reported in BRAF-V600E+ melanoma patients treated with vemurafenib), 3 patients developed 2 basaliomas and 1 superficial melanoma, all treated with a simple excision. Notably, overall response rate was 96% (25/26 patients): 9/26 (34.6%) CRs and 16/26 (61.4%) PRs, obtained after a median of 8 and 9 weeks respectively. CR and PR patients included 1 and 5 primary refractory ones, respectively, as well as 4 and 10 not responding to the last prior treatment, respectively. In all CR patients immunohistochemistry showed minimal residual disease (≤10%) at the end of treatment. Six of 9 (67%) CR patients enjoyed normal blood counts at a median of 13 (range 12-15) months from the end of treatment (see Figure): 3 of these 6 patients showed no morphological evidence of HCL in the bone marrow biopsy (complying with a continuous CR) at 12, 13 and 15 months, respectively, whereas the other 3 lost the bone marrow CR status, all at 12 months. The remaining 3/9 CR patients (33%) developed a mild cytopenia (N ~1000/mmc or PLT ~80000/mmc) 5, 9 and 12 months post-treatment, respectively: in the 2nd patient the cytopenia remained stable until the last follow-up at 15 months, whereas in the other two cases it worsened requiring therapy 9 and 18 months post-treatment, respectively (see Figure). These two latter patients were recently retreated with vemurafenib for 12 and 4 weeks, and obtained a PR and a second CR. Among the 16 PR patients, 5 (31%) mantain normal blood counts at a median of 12 (range 8-17) months post-treatment (see Figure). The other 11 PR patients developed cytopenia(s) after 3 months of median follow-up (range 5-10): in 6 patients (38%) no anti-leukemic therapy was started at a median of 9 (range 6-12) months post-treatment, whereas in the remaining 5 cases (31%) cytopenia(s) worsened requiring therapy at a median of 8 (range 5-11) months of follow-up (see Figure). Four of these latter 5 patients were retreated with vemurafenib for 12 weeks: 3 cases had a minor response and the last one witnessed a second PR that lasted less than the first PR (3 versus 9 months). CONCLUSIONS: In heavily pre-treated HCL patients, a short oral course of vemurafenib was safe, and proved quickly and highly active. Retreatment with vemurafenib was able to reinduce remissions in patients relapsing after a CR, but was less effective in patients relapsing after a PR. Figure 1 Figure 1. Disclosures Off Label Use: Off-label use of vemurafenib in hairy cell leukemia will be discussed as part of a clinical research protocol..

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Dabrafenib Is a Safe and Effective Therapy in Relapsed/Refractory Classical Hairy Cell Leukemia

Blood ◽

10.1182/blood-2020-137531 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-8

Author(s):

Matthew J Cross ◽

Paras Shah ◽

Kara Heelan ◽

Claire E. Dearden ◽

Dima El-Sharkawi ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Treatment Options ◽

Single Agent ◽

Braf Inhibitor ◽

Skin Lesions ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

Hematological Response

BACKGROUND: Hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder. The BRAF V600E mutation was shown to be the underlying genetic driver for the vast majority of classical HCL (HCLc) cases and treatment with the BRAF inhibitor (BRAFi), vemurafenib, has proven extremely successful. Dabrafenib is an oral BRAFi used in melanoma, often in conjunction with trametinib, a MEK inhibitor. Data exists on the use of dabrafenib combined with trametinib in HCLc but there is no efficacy or safety data on either single agent dabrafenib or dabrafenib combined with rituximab. We present a small series of 7 patients treated with either single agent dabrafenib or combination dabrafenib and rituximab. METHODS: Since 2018 dabrafenib was accessible via a Novartis managed access programme for BRAF V600E mutated HCLc patients who had no alternative treatment options. Six patients received dabrafenib, 2 as single agent due to recent prior ineffective rituximab therapy or severe rituximab infusion reaction and the remaining 4 patients with dabrafenib and rituximab. Dabrafenib was given at 150mg twice daily on a continuous 28 day cycle. Rituximab 375mg/m2 IV was given once every 2 weeks for a total of 8 doses. As there was no availability for re-treatment on cessation of therapy and no other suitable/accessible treatment options, patients with ongoing response and good tolerance were continued on indefinite therapy. One additional patient was treated with frontline dabrafenib and rituximab due to various comorbidities including end stage renal failure limiting other treatment options. RESULTS: Mean age on commencing dabrafenib was 73 (52-87) and in the relapsed patients the median number of prior lines of therapy was 5 (3-13). Four patients had undergone prior splenectomy. Two patients had received prior BRAFi therapy with vemurafenib and 3 had received prior Moxetumomab. Patients received a median of 8 cycles of dabrafenib. 4 patients received all 8 cycles of rituximab with 1 discontinuing rituximab due to adverse drug reaction. Adverse drug reactions to dabrafenib were mostly grade 1-2. The most common reaction was benign keratotic skin lesions occurring in 5/7 patients. Their onset was typically after 4 weeks of treatment, persisting whilst therapy continued. Other notable adverse drug reactions were hair thinning and palmar-plantar erythrodysesthesia both occurring in 3/7 patients. Hair thinning did seem to improve with decreasing the dosage and resolve on cessation of the drug. Palmar-plantar erythrodysesthesia was managed with dose reduction and non-steroidal anti-inflammatory drugs. Response assessment criteria used were from the 2017 hairy cell leukemia foundation consensus guidelines for the diagnosis and management of patients with HCLc. All patients responded to therapy. Hematological response was rapid, most patients achieving hematological CR after 2-3 cycles. Five patients achieved a CR, 2 were MRD+ve, 2 were MRD-ve and 1 was a radiological CR. The remaining 2 patients achieved a hematological response, 1 partial and 1 complete. Six patients had sufficient follow up for assessment with 2/6 having relapsed and 4/6 remaining in remission. Median follow up was 17 months, median DOR and median OS were not reached. The 2 patients in our cohort (patients 1 and 3) receiving prior vemurafenib each received 6 cycles, 1 achieving CR lasting 3 months, the other achieving PR lasting 11 months. Both responded rapidly to dabrafenib, one treated with dabrafenib and rituximab achieved an MRD+ve CR with DOR 21 months. The other received single agent dabrafenib and achieved a hematological response with DOR 15.2 months. Treatment response and survival are shown in table 1 and figure 1. Figures 2-7 show the hematological response at time points within the first year of therapy. DISCUSSION: In this small cohort we have shown that dabrafenib as a single agent or combined with rituximab is a safe and effective therapy in BRAF V600E mutated HCLc, even in those patients with prior time limited duration BRAFi therapy. There was no hematological toxicity noted. The main adverse drug effect was development of skin lesions however none were malignant. The only malignant lesion noted pre dated the commencement of dabrafenib. Dermatological surveillance is therefore recommended. Hematological response was rapid with significant improvement seen as early as 4 weeks from commencing therapy. Disclosures El-Sharkawi: Janssen:Honoraria, Membership on an entity's Board of Directors or advisory committees;Roche:Other: Conference fees. OffLabel Disclosure: Use of BRAF inhibitor Dabrafenib in BRAF V600E mutation positive classical Hairy Cell Leukemia.

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Co-Treatment Of Hairy Cell Leukemia and Melanoma With The BRAF Inhibitor Dabrafenib

Blood ◽

10.1182/blood.v122.21.5311.5311 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5311-5311 ◽

Cited By ~ 2

Author(s):

Leslie A. Andritsos ◽

James S. Blachly ◽

Kari Kendra ◽

Gerard Lozanski ◽

Michael R. Grever

Keyword(s):

Bone Marrow ◽

Malignant Melanoma ◽

Hairy Cell Leukemia ◽

Braf Mutation ◽

Braf Inhibitor ◽

Braf V600e Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

Marrow Cellularity

Abstract The activating BRAF mutation V600E has been identified in many human cancers, including colon and lung adenocarcinoma, papillary thyroid cancer, malignant melanoma, and hairy cell leukemia. Here we report for the first time treatment of hairy cell leukemia and malignant melanoma both harboring the BRAF V600E mutation with the BRAF inhibitor dabrafenib. The patient is a 67-year-old man with a history of classic hairy cell leukemia (immunophenotype CD11c, CD19, CD20 (bright), CD25, and CD103). At the time of diagnosis he had pancytopenia and received therapy with cladribine 0.12 mg/kg/day as a 2 hour infusion daily for 5 days, achieving a complete hematologic remission (CHR). His disease recurred 2 years later and he was again treated with cladribine 0.9 mg/kg/day as a 7 day continuous infusion, achieving a CHR. He remained in remission for 5 years, and this time received salvage therapy with pentostatin 4 mg/m2 every 2 weeks for a total of 12 doses. He achieved a CHR with minimal residual disease on bone marrow biopsy (0.3% of lymphocytes). He also had dyserythropoiesis concerning for myelodysplastic syndrome in addition to neurologic toxicity with gait imbalance. He was managed expectantly for the next 2 years, during which time he developed an 8 mm red nodule on the extensor surface of his right forearm, and a shave biopsy showed nodular melanoma, Clark’s level IV. He underwent a wide local excision with a negative axillary sentinel lymph node biopsy followed by adjuvant sargramostim (GM-CSF) for 12 months. His melanoma then recurred at the site of the prior excision. A PET scan showed an additional lesion in the midportion of the right arm. The excised solitary recurrence was sent for BRAF V600E mutation testing, which was positive. He received a course of radiotherapy (30 Gy over 14 days) to the affected limb, after which he had no evidence of disease. During this time, he was found to have worsening thrombocytopenia and splenomegaly, as well as a rising IL2 receptor level (peak 3952 U/mL; normal < 970), while bone marrow biopsy showed a 20% cellular marrow with 40% involvement by classic HCL. BRAF testing of the bone marrow by Sanger sequencing was positive for the V600E mutation. Because both his HCL and melanoma harbored the BRAF V600E mutation, the patient was eligible for and enrolled on a phase I clinical trial of dabrafenib for BRAF V600E mutant malignancies. Dabrafenib was initiated orally at a dose of 150 mg twice daily. Each cycle was 28 days. After 3 cycles, the bone marrow cellularity had improved to 30% with a decrease in the leukemic content to 10-15% of marrow cellularity. After 6 cycles, the bone marrow cellularity was normal for age with no residual HCL detectable by immunohistochemical stains or flow cytometric immunophenotyping. PET/CT scan at this time demonstrated no FDG avid lesions and no splenomegaly. Toxicites have consisted of characteristic RAF-associated skin changes and one instance of squamous cell carcinoma, which was excised. He has otherwise had no side effects from therapy. The patient has now completed 12 cycles of therapy with dabrafenib without evidence of either HCL or melanoma. He will remain on therapy as long as he is deriving clinical benefit per protocol. Given the increased risk of second primary malignancies in HCL, BRAF mutation testing should be considered for patients developing solid tumors in which this has been described, as co-treatment may be possible. Disclosures: Off Label Use: Dabrafenib for treatment of hairy cell leukemia. Kendra:Glaxo Smith-Kline: Research Funding.

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Resolution of Hairy Cell Leukemia Minimal Residual Disease by Both BRAF and Clone-Specific Real-Time Quantitative PCR (RQ-PCR) After Treatment with Moxetumomab Pasudotox.

Blood ◽

10.1182/blood.v120.21.2896.2896 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2896-2896 ◽

Cited By ~ 1

Author(s):

Robert J. Kreitman ◽

Evgeny Arons ◽

Sapolsky Jeffrey ◽

Laura Roth ◽

Hong Zhou ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

Hairy Cell Leukemia ◽

Residual Disease ◽

Braf V600e Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

Specific Primer ◽

Minimal Residual

Abstract Abstract 2896 Background: Moxetumomab pasudotox is an anti-CD22 recombinant immunotoxin containing truncated Pseudomonas exotoxin which was recently reported to achieve a complete remission rate of 46% in 28 patients with relapsed/refractory hairy cell leukemia (HCL). An additional 20 patients were treated at the highest dose level and are now fully evaluable for response and minimal residual disease (MRD) determinations. RQ-PCR using clone-specific primers and a clone-specific TaqMan probe is capable of detecting one HCL cell in 106normal cells. Recently reported methods to detect the HCL-associated BRAF V600E mutation include pyrosequencing (5–10% sensitivity) and PCR (0.1–0.23% sensitivity). Methods: Moxetumomab pasudotox was administered to 16 patients at 5–40 ug/Kg every other day for 3 doses (QODx3) and to 32 patients at 50 ug/Kg QODx3, via 1–16 (median 4) cycles per patient at 4-week intervals. Complete remission (CR) required resolution of cytopenias and elimination of HCL in the blood and marrow by standard microscopy, but MRD could be present by flow cytometry of blood or bone marrow aspirate (BMA) or immunohistochemistry (IHC) of the bone marrow biopsy (BMBx). Blood and marrow from patients were also tested by PCR using consensus primers. When immunoglobulin (Ig) rearrangements could be cloned, RQ-PCR using clone-specific primer and probe was performed. To detect MRD by the BRAF V600E mutation, BRAF quantitative PCR (BRAF-qPCR) was performed on cDNA samples, using mutant-specific primer, and SYBR-Green detection followed by melting point analysis. MRD testing for BRAF-qPCR, unlike clone-specific RQ-PCR, did not require prior cloning of the Ig rearrangement. Results: All 198 cycles of moxetumomab administered to 48 patients were evaluable for toxicity and response. No dose limiting toxicity was observed, although 2 patients as previously reported had a grade 2 hemolytic uremic syndrome with transient grade 1 platelet and creatinine abnormalities. Of the 48 HCL patients at all dose levels, there were 26 (54%) CRs, with an overall response rate (ORR) of 88%. Of 32 at 50 ug/Kg QODx3, there were 19 (59%) CRs with an ORR of 91%. Of these 19 CRs, 11 (58%) achieved MRD negativity by repeated flow cytometry of both BMA and blood and IHC of BMBx. Flow cytometry of the BMA was the most sensitive conventional test of MRD. Of the 9 CRs at 50 ug/Kg QODx3 evaluable by clone-specific RQ-PCR of blood, 5 negative were also flow-negative, and 4 positive were also flow-positive (p=0.008). BRAF-qPCR on cDNA from limiting dilutions of BRAF V600E+ Colo-205 cells into BRAF wild-type cells achieved consistent detection at 1:105dilution (0.001%). Of 10 flow-negative CRs at 50 ug/Kg QODx3 evaluated by BRAF-qPCR, all 10 (100%) were BRAF-qPCR negative, including 4 which were nonevaluable by RQ-PCR due to inability to clone the Ig rearrangements prior to treatment. Currently 12 (63%) of the 19 CRs at 50 ug/Kg QODx3 are ongoing at 6–47 (median 21) months, including 10 (91%) of 11 MRD-negative vs 2 (25%) of 8 MRD+ CRs (p=0.006). Conclusions: Moxetumomab pasudotox is active in relapsed and refractory HCL and has a safety profile supporting further development for this disease. Retreatment on this trial could not necessarily be extended to achieve MRD-negative BMAs or molecular remission by RQ-PCR using sequence-specific or BRAF primers. However, these tests might be useful in the future to guide retreatment, optimize CR durability and possibly eradicate the HCL clone in selected patients. This summary contains investigator reported data. This study was sponsored by MedImmune, LLC, and supported by NCI's Intramural Research Program and the Hairy Cell Leukemia Research Foundation. Disclosures: Kreitman: NIH: Co-inventor on the NIH patent for Moxetumomab Pasudotox, Co-inventor on the NIH patent for Moxetumomab Pasudotox Patents & Royalties. Off Label Use: Moxetumomab Pasudotox is an experimental agent for CD22+ hematologic malignancies. FitzGerald:NIH: Coinventor on the NIH patent for Moxetumomab Pasudotox, Coinventor on the NIH patent for Moxetumomab Pasudotox Patents & Royalties. Fei:AstraZeneca: Stock, Stock Other; MedImmune, LLC: Employment. Ibrahim:AstraZeneca: Stocks, Stocks Other; MedImmune: Employment. Pastan:NIH: Coinventor on NIH patent for moxetumomab pasudotox, Coinventor on NIH patent for moxetumomab pasudotox Patents & Royalties.

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Progress report on chlorambucil therapy in postsplenectomy patients with progressive hairy cell leukemia

Blood ◽

10.1182/blood.v57.3.464.464 ◽

1981 ◽

Vol 57 (3) ◽

pp. 464-467 ◽

Cited By ~ 46

Author(s):

HM Golomb

Keyword(s):

Bone Marrow ◽

Hairy Cell Leukemia ◽

Progressive Disease ◽

Single Agent ◽

Objective Response ◽

Hairy Cell ◽

Cell Leukemia ◽

Hairy Cells ◽

Total Bone Marrow ◽

Single Agent Chemotherapy

Abstract Of eight patients with progressive hairy cell leukemia who were treated with daily doses of an alkylating agent (chlorambucil, 4 mg) for at least 6 mo, seven have had an objective response, as measured by improved blood counts. Two patients were pancytopenic and had almost total bone marrow replacement with hairy cells at the initiation of chemotherapy; approximatley 6 mo later, their blood counts and bone marrow had improved dramatically. The five other patients had the leukemic form of the disease, and all responded to therapy. It is important to identify postsplenectomy patients with progressive disease in order to initiate low-dose single-agent chemotherapy.

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Primary Hairy Cell Leukemia/Lymphoma of the Breast: A Case Report and Review of the Literature

Case Reports in Pathology ◽

10.1155/2014/497027 ◽

2014 ◽

Vol 2014 ◽

pp. 1-5 ◽

Cited By ~ 3

Author(s):

Monika Pilichowska ◽

Ahmad Shariftabrizi ◽

Ian Mukand-Cerro ◽

Kenneth Miller

Keyword(s):

Bone Marrow ◽

Hairy Cell Leukemia ◽

Incidental Finding ◽

Reduction Mammoplasty ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

First Case ◽

Mutational Status ◽

Atypical Presentations

Hairy cell leukemia/lymphoma (HCL) is a rare B-cell neoplasm primarily involving spleen, bone marrow, and blood. However, other sites of primary involvement do occur and can present a diagnostic and therapeutic challenge. We present an unusual case of HCL involving predominantly the breast that was diagnosed as an incidental finding during an elective reduction mammoplasty in an otherwise healthy asymptomatic woman. Bone marrow performed for staging revealed limited involvement by HCL. Notably, there was no splenomegaly and/or involvement of other extramedullary sites. The peripheral blood revealed minimal involvement detected by flow cytometry. Extensive immunohistochemical studies supported by positive BRAF V600E mutational status confirmed the diagnosis of HCL. The patient remains asymptomatic without treatment one year following the diagnosis. This is the first case of a well-documented HCL presenting primarily in the breast in an asymptomatic patient. We review the literature on extramedullary, extrasplenic involvement by HCL and discuss the diagnostic challenges as well as the utility of immunohistochemistry and molecular studies in the diagnosis of atypical presentations of HCL.

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A Rare Case of Hairy Cell Leukemia with Unusual Loss of CD123 Associated with COVID-19 at the Time of Presentation

Case Reports in Oncology ◽

10.1159/000512830 ◽

2020 ◽

Vol 13 (3) ◽

pp. 1430-1440

Author(s):

Samah Kohla ◽

Feryal A. Ibrahim ◽

Mahmood B. Aldapt ◽

Hesham ELSabah ◽

Shehab Mohamed ◽

...

Keyword(s):

Bone Marrow ◽

Cancer Patients ◽

Hairy Cell Leukemia ◽

Bone Marrow Examination ◽

Assisted Ventilation ◽

Braf V600e ◽

Leukemic Cells ◽

Hairy Cell ◽

Cell Leukemia ◽

First Case

Coronavirus disease 2019 (COVID-19) pandemic has been a serious threat and has been reported with different presentations and complications. Older age, along with comorbidities such as diabetes, hypertension, or cardiac disease, increases the risk factors for COVID-19 severity and death [N Engl J Med. 2020;382(18):1708–20 and Lancet Respir Med. 2020 05;8(5):475–81]. It is proposed that cancer patients have a significantly higher incidence of severe incidents including admission to the intensive care unit, the necessity for assisted ventilation, and even death after catching the virus compared with non-cancer patients [Lancet Oncol. 2020;21(3):335–7]. It is also described that cancer patients appear to be twice as likely to contract infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) [JAMA Oncol. 2020;6(7):1108–10]. Hairy cell leukemia (HCL) is a rare B-cell lymphoproliferative disorder, with patients typically presenting with cytopenias, marked splenomegaly in 80–90% of patients, circulating leukemia cells, bone marrow infiltration and the presence of BRAF V600E somatic mutation [Indian J Hematol Blood Transfus. 2014;30(Suppl 1):413–7]. Leukemic cells classically have central nuclei and abundant cytoplasm with hairy-like projections and express CD11c, CD25, CD103, and CD123 [Indian J Hematol Blood Transfus. 2014;30(Suppl 1):413–7]. Loss of CD123 in HCL has been rarely reported in the literature [Am J Hematol. 2019;94(12):1413–22]. We describe a unique case of a COVID-19-positive male who presented with severe respiratory symptoms, deteriorated quickly, and was intubated. Workup of severe progressive pancytopenia and bone marrow examination revealed HCL without splenomegaly and with atypical unusual loss of CD123. To our knowledge, this is the first case of CD123-negative HCL without splenomegaly associated with COVID-19 infection as the initial presentation.

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Presence and Absence of the BRAF V600E Mutation in Hairy Cell Leukemia and Its Variants

Blood ◽

10.1182/blood.v118.21.931.931 ◽

2011 ◽

Vol 118 (21) ◽

pp. 931-931

Author(s):

Robert J. Kreitman ◽

Liqiang Xi ◽

Winnifred Navarro ◽

Maryalice Stetler-Stevenson ◽

Evgeny Arons ◽

...

Keyword(s):

Hairy Cell Leukemia ◽

Braf Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Cell Leukemia ◽

Wild Type ◽

Purine Analogs ◽

Ighv Gene ◽

Purine Analog ◽

Gene Usage

Abstract Abstract 931 Background: Hairy cell leukemia (HCL) is a B-cell malignancy with distinctive immunophenotype. Purine analog therapy achieves durable complete remissions in 65–90% of patients. HCL variant (HCLv), recognized by the World Health Organization (WHO) as a different disease, lacks CD25, annexin A1 and/or TRAP, and responds poorly to purine analogs with only partial responses (PR) in <50% and lower overall survival (OS) from diagnosis. The recently described HCL variant expressing the immunoglobulin rearrangement IGHV4-34 also has poor response to purine analogs and OS, but can resemble HCL or HCLv immunophenotypically. The V600E BRAF mutation was recently reported present in 100% of 48 patients with HCL and absent in 16 with related disorders including at least 1 case of HCLv. We wished to confirm these results and test well-characterized cases of HCLv and IGHV4-34+ HCL. Methods: DNA was prepared from the blood of 70 patients with HCL and HCLv, 64 of whom were molecularly characterized with respect to IGHV gene usage. The mutation analysis of BRAF c.1799T>A (V600E) and other variants among codons 599–601 within exon 15 was performed using a target-specific mutant allele enriching COLD-PCR technique followed by pyrosequencing. The apparent percentage of mutant versus wild-type alleles was calculated with allele quantification (AQ) mode using PyroMark Software. The threshold AQ value for classifying samples as positive as a mutation was calculated as 3 standard deviations above the mean value of 24 normal blood samples. Results: Out of 70 total patients tested, 16 (23%) were diagnosed as HCLv based on WHO criteria, and the other 54 were classic HCL. Thirteen (19%) of the 70 cases expressed IGHV4-34, 5 classic HCL and 8 HCLv immunophenotypically. All 6 cases not characterized for IGHV gene usage were classic HCL. The analytic sensitivity of the pyrosequencing assay using cell line controls containing BRAF mutations was <5% tumor cells, and all cases were required to have ≥10% of total white blood cells as HCL. As shown in the table, 28 (40%) of the cases were wild-type with respect to BRAF, including all cases of HCLv. In addition, all 13 cases of IGHV4-34+ HCL, including 5 with classic immunophenotype, were negative for the V600E mutation. Moreover, 7 classic HCL cases were wild-type at V600 of BRAF, including 1 with unknown IGHV and 6 expressing IGHV2-70, IGHV3-15, IGHV3-23, IGHV3-48, IGHV4-39 and IGHV4-59. These 7 cases were relatively resistant to purine analog therapy although numbers were too few for statistical comparisons. In one of these 7 classic HCL cases, CD25 expression had decreased over time. Conclusions: The V600E BRAF mutation is not present in HCLv or in HCL cases with typical immunophenotype expressing IGHV4-34. A significant minority of other classic HCL cases, 7 (14%) of 49, were negative for the V600E BRAF mutation. It is possible that the V600E BRAF mutation is related to factors other than those affecting immunophenotype, including those influencing prognosis. Additional studies will be needed to better understand the role of V600E-mutated BRAF in HCL and the molecular basis of variants of this disease (Supported in part by NCI, intramural research program, NIH). Disclosures: No relevant conflicts of interest to declare.

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