Concomitantly Diagnosed Disseminated M kansasii Infection and Hairy Cell Leukemia With Review of Pathophysiology.

The association between Hairy Cell Leukemia (HCL) and non-tuberculous mycobacterial infections (NTMs) is well described, most notably Mycobacterium kansasii. The exact pathophysiology is not known. We report a case of a 31-year-old male with concomitantly diagnosed HCL and disseminated M kansasii infection who presented with rash, pancytopenia, and bulky axillary lymphadenopathy. The M kansasii was initially diagnosed through use of cell-free DNA detection and confirmed by bone marrow and lymph node cultures. Hairy Cell Leukemia was diagnosed with peripheral flow cytometry and confirmed via the same bone marrow sample. His HCL was put into remission with a single course of cladribine and rituximab chemotherapy; however, his M kansasii infection persisted for 6 months despite aggressive antimicrobial and surgical therapy. It was finally controlled using high-dose rifampin in combination with azithromycin and ethambutol. This case highlights the known link between HCL and M kansasii. Furthermore, it hints at potential causes beyond chemotherapy-induced immunocompromise. Notable possibilities include HCL cells acting as sanctuary sites for M kansasii to evade the immune system, and subclinical M kansasii infections causing NLRP3 inflammasome overactivation to trigger the oncogenic transformation to HCL. More research into the pathophysiologic link between HCL and M kansasii infections would allow for more effective prevention, diagnosis, and treatment of these severe atypical infections which are the major cause of morbidity in the cladribine era of HCL treatment.

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.

Single agent vemurafenib or rituximab-vemurafenib combination for the treatment of relapsed/refractory hairy cell leukemia, a multicenter experience.

BACKGROUND: Hairy cell leukemia (HCL) is a rare mature B-cell malignancy that is primarily treated with purine analogues. However, relapse remains a significant challenge, prompting the search for alternative therapies. The BRAF V600E mutation prevalent in HCL patients provides a target for treatment with vemurafenib. PATIENTS AND METHODS: This multicenter retrospective study included nine patients with relapsed/refractory (R/R) HCL from six different centers. Patient data included demographics, prior treatments, clinical outcomes, and adverse events. RESULTS: Patients received different treatment regimens between centers, including vemurafenib alone or in combination with rituximab. Despite the differences in protocols, all patients achieved at least a partial response, with seven patients achieving a complete response. Adverse events were generally mild with manageable side effects. The absence of myelotoxic effects and manageable side effects make BRAF inhibitors attractive, especially for patients ineligible for purine analogues or those with severe neutropenia. CONCLUSION: Single agent vemurafenib or in combination with rituximab appears to be a promising therapeutic option for R/R HCL. Further research is needed to establish standardized treatment protocols and to investigate long-term outcomes.

Drug-induced secondary haemophagocytic lymphohistiocytosis in hairy cell leukaemia.

Haemophagocytic lymphohistiocytosis (HLH) is a rare, aggressive, excess immune activation syndrome. Diagnosis can be challenging due to its several clinical mimics including sepsis. There are multiple aetiologies of HLH; in adults, it is most commonly triggered by infection, malignancy, drugs and autoimmune processes. Failure to rapidly diagnose and treat this condition can be fatal. The management of HLH includes identifying and removing the trigger, supportive management and immunosuppression. Identifying the trigger is essential to inform the most appropriate type of immunosuppression. Here, we report a case of likely drug-induced HLH in a patient recently treated for hairy cell leukaemia. The culprit drug was thought to be co-trimoxazole and this case report highlights a very rare complication of this commonly used drug. We discuss our management approach with steroid monotherapy and withdrawal of co-trimoxazole.

Long term follow-up of refractory/relapsed hairy cell leukaemia patients treated with low-dose vemurafenib between 2013 and 2022 at the Department of Internal Medicine and Oncology, Semmelweis University.

Introduction: Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. BRAF V600E mutation is detected in nearly all classical HCL cases which offers the possibility of targeted therapy. Objective: The aim of our study was to assess the efficacy of low-dose vemurafenib as well as to assess the long term outcome of HCL patients treated with this drug at the Department of Internal Medicine and Oncology at Semmelweis University. Methods: We report on 10 patients with classical HCL treated with low-dose vemurafenib at our Department between 2013 and 2022. Results: As a result of fixed time low-dose vemurafenib treatment, 5 of 10 patients (5/10) achieved partial remission, 4 (4/10) had stable disease, and 1 (1/10) had MRD positivity. No patients achieved complete remission. The median progression-free survival was 28.5 months while the overall survival was 82 months. Conclusion: We confirm that low dose of vemurafenib is effective and safe in the vast majority of patients with HCL. This small-molecule oral treatment allows to gain valuable time-months or even years-before further, usually parenteral treatment options have to be given or before previous treatment has to be repeated. There are also promising data supporting the combination of vemurafenib with other drugs for the treatment of HCL patients which could provide even further possibility to bridge treatment.

Cladribine Efficacy in a Patient with Hairy Cell Leukemia and Severe Renal Insufficiency.

BACKGROUND: Hairy cell leukemia commonly presents with pancytopenia, indolent course, and predisposition as infectious complications. Current first-line therapeutic options are purine analogues, particularly cladribine, with a high percentage of complete responses and durable remissions. However, their use is poorly investigated in patients affected by severe chronic renal insufficiency. CASE PRESENTATION: Here, we describe a case of HCL in a 68-year-old man affected by multiple comorbidities, including severe chronic renal failure. After a course of interferon-α, the patient received therapy with Cladribine every other week, obtaining a complete hematological remission and improvement of renal function. DISCUSSION: With a different soft schedule of cladribine, the patient was treated adequately, obtaining a complete remission. CONCLUSION: Cladribine can be administered with caution, even in patients with renal failure, with good results.

COVID-19 in patients with classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL), similar to its variant HCLv, is a B-cell malignancy associated with decreased humoral immunity. We prospectively monitored the largest cohort of patients with HCL/HCLv to date (n = 503) for COVID-19 by symptoms, antibody, and polymerase chain reaction (PCR) and/or antigen positivity. Fifty percent (253 of 503) of the patients with HCL/HCLv (238 HCL and 15 HCLv) had evidence of COVID-19, with 210 (83%) testing positive by PCR or rapid-antigen test. Of the 43 patients without positive tests, all had nucleocapsid antibodies indicating COVID-19 exposure, 7 recalled no symptoms, and 36 had mild symptoms. Of the 210 who tested positive, 23, 46, 129, and 12 cases occurred in 2020, 2021, 2022, and 2023, respectively. Among them, 175 began treatment for HCL/HCLv 0.4 to 429 (median, 66) months before, and 132 had their last dose of anti-CD20 monoclonal antibody 0.2 to 229 (median, 63) months before. Two patients died, including a young woman who began rituximab 2 months after first-line cladribine before vaccine availability. Nearly all patients with HCL/HCLv recovered uneventfully from COVID-19 including those without vaccination or those with significant immunosuppression and recent treatment. However, decreased normal B cells from HCL or treatment was associated with lower spike antibody levels as a response to COVID-19 (P = .0094) and longer recovery time (P = .0036). Thus, in a large cohort of patients with HCL/HCLv and in the first to determine relationships between COVID-19 outcome and immune markers, mortality was relatively low (∼1%), sequelae were uncommon, and recovery from COVID-19 was longer if normal B cells were low after recent treatment. The trials are registered at www.clinicaltrials.gov as #NCT01087333 and #NCT04362865.

Targeting the BRAF pathway in haematological diseases.

Since the recognition of BRAF V600E mutations in the majority of cases of hairy cell leukaemia, Erdheim-Chester disease and Langerhans cell histiocytosis, the targeted oral kinase inhibitors dabrafenib and vemurafenib have been adapted for their treatment. Like other targeted agents, these drugs produce high response rates and predictable but unique side effects. Physician familiarity is essential for the effective use of these agents. We review the Australian experience of BRAF/MEK inhibitor therapy in these rare haematological cancers.

[Clinical and molecular characteristics and prognosis of classical hairy cell leukemia and hairy cell leukemia variant].

Objective: To evaluate the clinical characteristics, treatment response, and outcomes in patients with classical hairy cell leukemia (cHCL) and HCL variant (HCL-V). Methods: This is a retrospective case series study. Between January 2011 and December 2021, clinical data of 30 patients newly with diagnosed HCL at Peking Union Medical College Hospital were analyzed. The main outcome measures include clinical characteristics, treatment efficacy and survival. The Kaplan-Meier method was used for survival analysis. Results: Twenty-one cases of cHCL and 9 cases of HCL-v were included. The median age at diagnosis was 55.5 (range, 30-86) years, with the ratio of male to female 2.75∶1. The main clinical manifestations included fatigue in 11 cases (36.7%), abdominal distension in 7 cases (23.3%), and infection in 4 cases, while 8 cases were asymptomatic. Splenomegaly was reported in 24 cases (80.0%), including 7 (23.3%) with megalosplenia. The white blood cell count, lymphocyte count, and the proportion of peripheral hairy cells in HCL-v group were significantly higher than those in cHCL group, whereas the development of anemia, thrombocytopenia, and monocytopenia in cHCL group was more remarkable than that in HCL-v group (all P<0.05). The BRAF-V600E gene mutation was detected only in cHCL patients (11/14 vs. 0/9, P<0.001). In terms of immunophenotype, the expression of CD25, CD103, CD123 and CD200 in cHCL group (20/20, 20/20, 4/7, 7/17) were all stronger than those in HCL-v group (3/9, 7/9, 0/4, 2/8). Twenty-two patients were treated, of which 13 cases (12 cases of cHCL and 1 case of HCL-v) with cladribine, and 9 cases (4 cHCL and 5 HCL-v) with interferon. Complete remission rate and overall response rate were comparable between cladribine and interferon treatment groups (both P<0.05). The median follow-up time was 31 (range, 1-125) months, and the median overall survival (OS) of the entire group was 125 months. The 5-year OS rate in HCL-v patients represented a trend of inferior (50.0% vs. 95.0%, P=0.207). Conclusions: The clinical features of HCL are unspecific, which includes fatigue, splenomegaly and recurrent infection. The clinical features, immunophenotype, treatment response and prognosis of HCL-v are different from those of cHCL. BRAF-V600E gene mutation is suggested as a key marker for differential diagnosis. Cladribine is recommended as front-line regimen of cHCL patients with satisfactory efficacy and prognosis. Conversely, response and clinical outcome in HCL-v patients still need to be improved.

Refractory and relapsed hairy-cell leukemia (HCL): casting light on promising experimental drugs in clinical trials.

INTRODUCTION: Hairy cell leukemia (HCL) is a rare subtype of indolent lymphoid leukemia originating from a mature B lymphocyte. The standard first-line treatment for classic HCL, and HCL variant (HCLv), consists of purine nucleoside analogs (PNA), with or without rituximab. However, almost half of patients relapse and require subsequent therapy. AREAS COVERED: This article summarizes recent achievements in the treatment of relapsed and refractory HCL. A literature search was conducted of the PubMed and MEDLINE database for articles in English. Publications from 2010 through January 2023 were scrutinized. The search terms used were hairy cell leukemia in conjunction with BRAF inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CD20 monoclonal antibodies, relapsed, refractory and variant.The growing understanding of HCL biology has allowed the design of several new, chemotherapy-free targeted drugs which have demonstrated encouraging efficacy in early clinical trials. EXPERT OPINION: Novel drugs will soon be available to assist standard therapy for HCL and HCLv among patients with suboptimal results following PNA treatment. In particular, the BRAF inhibitors vemurafenib and dabrafenib, with or without rituximab, have revolutionized treatment of patients with relapsed or refractory disease.

Long-term follow-up of patients with hairy cell leukemia in the south of Iran.

BACKGROUND: Hairy cell leukemia (HCL) is an indolent chronic lymphoproliferative disorder and first-line treatment with either intravenous or subcutaneous cladribine generally leads to long-lasting remissions. METHOD: All 131 patients with hairy-cell leukemia (HCL) were analyzed, with a median follow-up of 91 months. Data is from 2007 to 2020. We evaluated the response rate to cladribine as the first line and the response rate to cladribine with or without rituximab in relapsed patients. Further, we assessed relapse-free survival, complications, and secondary malignancy. RESULTS: After a median follow-up of 91 months, the recurrence rate was 24%. The 5-year and 10-year RFS rates were 85% and 66%, respectively. Adding rituximab to 2-CDA leads to a better response rate than just cladribine (90% vs. 27.3%, p-value = 0.002) in the relapsed patients. CONCLUSION: HCL patients have long-term survival when cladribine is the first line of treatment. Furthermore, adding rituximab to cladribine leads to a higher response rate.

Pulmonary damage in a patient with hairy cell leukemia - infectious involvement or hematological disease activity? Case report.

BACKGROUND: Hairy cell leukemia (HCL) is a rare indolent lymphoproliferative disease with an accumulation of mature B lymphocytes with fine reticular chromatin and cytoplasm with typical hairy-like cytoplasmic projections. Rarely, hairy cell leukemia manifests as a lung infiltration. The differential diagnosis between infection and malignant involvement with hairy cell leukemia is often challenging in such situations. METHODS AND RESULTS: We present a 53-year-old female with an uncommon pulmonary involvement with hairy cell leukemia. In addition, we discuss the complicated differential diagnosis of pulmonary disease in patients with hairy cell leukemia and the treatment approach to these patients. CONCLUSION: This case report describes the successful therapy management of a patient with pulmonary involvement by hairy cell leukemia. Therapy with interferon-alfa and cladribine resulted in long-term remission of the underlying disease.

BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2.

In classical hairy cell leukemia (HCL), standard treatments including purine analogs achieve a durable response (up to 90%), but lead to severe immunosuppression and long-lasting depletion of CD4 + T lymphocytes. The BRAF inhibitor vemurafenib is effective in HCL, but its use in first-line treatment is restricted to select clinical situations (e.g. active infection). Its impact on immune function or response to vaccines in HCL is unclear. We treated four HCL patients with vemurafenib during the COVID-19 pandemic and monitored immune reconstitution and response to SARS-CoV-2 immunization. All patients responded to HCL treatment with normalization of peripheral blood counts. No severe infections occurred. As an indication of limited immunosuppression by vemurafenib, stable CD4 + and CD8 + T lymphocyte counts and immunoglobulin levels were observed. Three out of four patients received SARS-CoV-2 vaccination (Pfizer-BioNTech) during treatment with vemurafenib. IgG antibody levels against the spike-protein of SARS-CoV-2 were detected (40-818 AE/ml). Our data suggest that vemurafenib has limited effects on cellular and humoral immune function in HCL, which allows for successful SARS-CoV-2 vaccination. These data support the use of BRAF inhibitors during the current pandemic where continued immune response is necessary for minimizing the COVID-19-related risk of non-vaccinated patients.

Dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive hairy cell leukemia.

BRAF V600E is the key oncogenic driver mutation in hairy cell leukemia (HCL). We report the efficacy and safety of dabrafenib plus trametinib in patients with relapsed/refractory BRAF V600E mutation-positive HCL. This open-label, phase 2 study enrolled patients with BRAF V600E mutation-positive HCL refractory to first-line treatment with a purine analog or relapsed after ≥2 prior lines of treatment. Patients received dabrafenib 150 mg twice daily plus trametinib 2 mg once daily until disease progression, unacceptable toxicity, or death. The primary endpoint was investigator-assessed objective response rate (ORR) per criteria adapted from National Comprehensive Cancer Network-Consensus Resolution guidelines. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Fifty-five patients with BRAF V600E mutation-positive HCL were enrolled. The investigator-assessed ORR was 89.0% (95% confidence interval, 77.8%-95.9%); 65.5% of patients had a complete response (without minimal residual disease [MRD]: 9.1% [negative immunohistochemistry of bone marrow {BM} biopsy], 12.7% [negative BM aspirate flow cytometry {FC}], 16.4% [negative immunohistochemistry and/or FC results]; with MRD, 49.1%), and 23.6% had a partial response. The 24-month DOR was 97.7% with 24-month PFS and OS rates of 94.4% and 94.5%, respectively. The most common treatment-related adverse events were pyrexia (58.2%), chills (47.3%), and hyperglycemia (40.0%). Dabrafenib plus trametinib demonstrated durable responses with a manageable safety profile consistent with previous observations in other indications and should be considered as a rituximab-free therapeutic option for patients with relapsed/refractory BRAF V600E mutation-positive HCL. This trial is registered at www.clinicaltrials.gov as #NCT02034110.