Untangling hairy cell leukaemia (HCL) variant and other HCL-like disorders: Diagnosis and treatment.

The variant form of hairy cell leukaemia (HCL-V) is a rare disease very different from hairy cell leukaemia (HCL), which is a very well-defined entity. The 5th WHO edition (Leukemia, 36, 2022 and 1720) classification (WHO-HAEM5) introduced splenic lymphomas/leukaemias including four different entities: (1) HCL, (2) splenic marginal zone lymphoma (SMZL) with circulating villous cells in the peripheral blood, (3) splenic lymphoma with prominent nucleolus (SLPN), which replaced HCL-V and CD5 negative B-prolymphocytic leukaemia (B-PLL), and (4) splenic diffuse red pulp lymphoma (SDRPL). All these entities have to be distinguished because of a different clinical course and the need for a different treatment. The diagnosis can be challenging because of complex cases and overlap and/or grey zones between all the entities and needs integrating clinical, histologic, immunophenotypic, cytogenetic and molecular data. We review the diagnostic criteria including clinical, immunophenotypic and molecular characteristics of patients with HCL-V and other HCL-like disorders including HCL, SDRPL, SMZL, B-PLL and the Japanese form of HCL. We also discuss the different criteria allowing us to separate these different entities and we will update the recent therapeutic options that have emerged, in particular the advances with chemoimmunotherapy and/or targeted therapies.

Early clearance of hairy cell leukaemia in the bone marrow after first-line treatment with cladribine predicts a favourable outcome.

First-line purine nucleoside analogues (PNAs) in hairy cell leukaemia (HCL) allow deep and long-lasting responses. We retrospectively analysed 53 HCL patients treated frontline with cladribine and assessed for response at 2 and 6 months after treatment to evaluate the kinetics of response. The estimated median progression-free survival was significantly different according to the degree of residual HCL infiltrate detected by immunohistochemistry at the bone marrow biopsy at 2 months (≤5% vs. >5%, 247 vs. 132 months, respectively, p = 0.033), but not at 6 months (p = 0.79). Our data suggest a favourable prognostic impact of early marrow HCL clearance in patients treated with cladribine.

Understanding splenic B-cell lymphoma/leukaemia with prominent nucleoli: Diagnosis, underpinnings for disease classification and future directions.

The 5th edition of the WHO classification of haematolymphoid tumours (WHO-HAEM5) introduced a new category, splenic B-cell lymphoma/leukaemia with prominent nucleoli (SBLPN). The diagnostic entity B-cell prolymphocytic leukaemia (B-PLL) has been discontinued and the category of hairy cell leukaemia variant (HCLv) has been conceptually reframed. B-PLL and HCLv diagnoses were uncommon. Overlap existed between B-PLL and other indolent lymphomas like chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). HCLv lacked consistent cytomorphological, immunophenotypic and genetic features. To address these issues, the WHO-HAEM5 classification has introduced SBLPN to serve as a temporary holding ground for entities that do not neatly fit into the existing classification. Cases previously classified as CD5-negative B-PLL and HCLv fall under the SBLPN category. Some splenic marginal zone lymphoma and splenic diffuse red pulp small B-cell lymphoma cases with higher number of medium or large nucleolated B cells would also be classified as SBLPN under the WHO-HAEM5. This review explores the rationale for discontinuing B-PLL and HCLv diagnoses. It then examines the concept of SBLPN, offers practical guidance for diagnosis and discusses future directions in classifying splenic B-cell lymphomas.

Hairy cell leukaemia with unusual BRAF mutations.

Hairy cell leukaemia (HCL) diagnosis is based on the morphologic detection of circulating abnormal hairy cells in the peripheral blood and/or bone marrow, an HCL immunological score of 3 or 4 based on the expression of the CD11c, CD25, CD103 and CD123 and also the presence of a BRAF V600E activating mutation in the B-raf proto-oncogene (BRAF gene) (7q34). When using new generation sequencing of 21 targeted genes in 124 HCL patients, we identified a cohort of 6/124 (2%) patients with unusual BRAF mutations: two patients presented non-V600 mutations (BRAF F595L, BRAF W604L respectively) and four other patients silent BRAF mutations. When using droplet digital PCR (ddPCR) three of the four patients with concomitant BRAF V600E and silent mutation were negative. The respective role of these mutations in the occurrence of HCL or its progression remains to be clarified, but BRAF sequencing is necessary in case of negative BRAF V600E by ddPCR.

SARS-CoV-2 infection and vaccination in patients with hairy-cell leukaemia.

Little is known of the course of COVID-19 and the antibody response to infection or vaccination in patients with hairy-cell leukaemia (HCL). Among a total of 58 HCL cases we studied in these regards, 37 unvaccinated patients, mostly enjoying a relatively long period free from anti-leukaemic treatment, developed COVID-19 between March 2020 and December 2021 with a usually favourable outcome (fatality rate: 5/37, 14%); however, active leukaemia, older age and more comorbidities were associated with a worse course. Postinfection (n = 11 cases) and postvaccination (n = 28) seroconversion consistently developed, except after recent anti-CD20 or venetoclax therapy, correlating with perivaccine B-cell count. Vaccination appeared to protect from severe COVID-19 in 11 patients with breakthrough infection.

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.

Hairy Cell Leukaemia: From Hairy Beginnings to a BRAF New World.

For a disease initially described in 1958 as a leukaemic reticulo-endotheliosis associated with poor outcomes, we have come a long way in our understanding of Hairy cell leukaemia. The vast majority of patients diagnosed with this rare, often diagnostically challenging, leukaemia can now expect a lifespan that is similar to the general population. This article covers some of the highlights from the last 6 decades that have led to our current understanding of this fascinating leukaemia - from elucidation of its B-cell origin to discovery of the almost universal occurrence of the BRAF V600E mutation; from the initial successes reported with splenectomy to the more recent development of targeted therapies such as Vemurafenib and Moxetumomab Pasudotox. It also pays tribute to some of the outstanding research in this field focusing particularly on the significant contributions made by the clinical and scientific community in the UK.

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.

How I manage patients with hairy cell leukaemia.

Patients with hairy cell leukaemia (HCL) have highly favourable outcomes after purine analogue therapy. However, most patients subsequently relapse and require re-treatment. A minority of patients develop purine analogue-refractory disease. Targeted therapies have improved outcomes for such patients. Recently, the BRAF V600E mutation was identified in most patients with classical HCL, resulting in constitutive mitogen-activated protein kinase pathway activation; impressive responses are achieved in heavily pre-treated patients with BRAF inhibition. The CD22-targeted immunoconjugate moxetumomab pasudotox and BTK inhibitor ibrutinib also achieve responses in relapsed and refractory patients. HCL variant and the IGHV4-34 molecular variant of HCL lack BRAF mutation and have inferior outcomes with standard purine analogue therapy. The addition of rituximab to purine analogues achieves very high rates of minimal residual disease-negative complete remission and improves outcomes for patients with HCL variant. Given the rarity of HCL, optimal integration of novel therapies into treatment algorithms will require well-designed, collaborative studies.

Long-term durable remission by cladribine followed by rituximab in patients with hairy cell leukaemia: update of a phase II trial.

Nucleoside analogues are highly active in patients with hairy cell leukaemia (HCL); however, patients continue to relapse. This phase II study evaluated the efficacy and safety of cladribine followed by rituximab in patients with untreated HCL (N = 59), relapsed HCL (N = 14) and HCL variant (HCLv, N = 7). Cladribine 5·6 mg/m(2) was given intravenously (IV) daily for 5 d and was followed approximately 1 month later with rituximab 375 mg/m(2) IV weekly for 8 weeks. Complete response rate in patients with untreated HCL, relapsed HCL and HCLv was 100%, 100% and 86%, respectively. With a median follow up of 60 months, 5-year failure-free survival (FFS) in patients with untreated HCL, relapsed HCL and HCLv was 95%, 100% and 64%, respectively. Median duration of response to the cladribine followed by rituximab was significantly longer than the first-line cladribine single agent in patients who received this treatment as second-line treatment (72 months vs not reached, P = 0·004). Almost all patients (94%) achieved negative minimal residual disease (MRD) after the treatment. Positive MRD during the follow up did not necessarily result in clinically relevant relapse. Cladribine followed by rituximab is highly effective even in patients with relapsed disease and HCLv, and can achieve durable remission.

Treatment outcomes and secondary cancer incidence in young patients with hairy cell leukaemia.

Repeated therapy of hairy cell leukaemia (HCL) with treatments that have potential long-term toxicities has raised concerns regarding increased risk for younger patients. We compared clinical outcomes and disease complications in 63 patients with HCL aged ≤40 years at diagnosis with 268 patients >40 years treated at Memorial Sloan Kettering Cancer Center. The rate of complete remission following initial therapy was 87% and 83% (P = 0·71) and estimated 10-year overall survival was 100% and 82% (P = 0·25) in younger and older patients, respectively. Younger patients required therapy earlier and had a significantly shorter time between first and second therapy (median: 63 months vs. 145 months) (P = 0·008). Younger patients required significantly more lines of therapy during follow-up. The 10-year cumulative incidence of secondary malignancies in young and old patients was 0·205 and 0·287, respectively (P = 0·22). The incidence of secondary cancers in patients aged >40 years at diagnosis increased with the number of treatments for HCL (P = 0·018). These results highlight that young patients with HCL have shorter responses to treatment and require more lines of therapy to maintain disease control, while attaining similar long-term survival. This has implications in the design of future clinical trials given our findings that secondary malignancies increase with more chemotherapy exposure.

An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.

We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years.

Melanoma and non-melanoma skin cancers in hairy cell leukaemia: a Surveillance, Epidemiology and End Results population analysis and the 30-year experience at Memorial Sloan Kettering Cancer Center.

Few studies have examined melanoma and non-melanoma skin cancer (NMSC) incidence rates after a diagnosis of hairy cell leukaemia (HCL). We assessed 267 HCL patients treated at Memorial Sloan Kettering Cancer Center (MSKCC) and Surveillance, Epidemiology and End Results (SEER) data for melanoma and NMSC incidence rates after HCL. Incidence data from MSKCC patients demonstrated a 10-year combined melanoma and NMSC skin cancer rate of 11·3%, melanoma 4·4% and NMSC 6·9%. Molecular analysis of skin cancers from MSKCC patients revealed activating RAS mutations in 3/9 patients, including one patient with melanoma. Of 4750 SEER patients with HCL, 55 (1·2%) had a subsequent diagnosis of melanoma. Standardized incidence ratios (SIRs) did not show that melanoma was more common in HCL patients versus the general population (SIR 1·3, 95% CI 0·78-2·03). Analysis of SEER HCL patients diagnosed before and after 1990 (approximately before and after purine analogue therapy was introduced) showed no evidence of an increased incidence after 1990. A better understanding of any potential association between HCL and skin cancer is highly relevant given ongoing trials using BRAF inhibitors, such as vemurafenib, for relapsed HCL, as RAS-mutant skin cancers could be paradoxically activated in these patients.

Lymphomatous variant of hairy cell leukaemia: a distinctive presentation mimicking low-grade B-cell lymphoma.

AIMS: Hairy cell leukaemia (HCL) is an indolent B-cell neoplasm that primarily involves the peripheral blood, bone marrow, and spleen. Rarely, patients with HCL present with a lymphoma-like clinicopathological picture mimicking other types of low-grade B-cell lymphoma. Distinguishing HCL from other types of lymphoma is essential, given the different treatments and prognoses. We report two cases of the lymphomatous variant of HCL to draw attention to this unusual presentation. METHODS AND RESULTS: Two cases of HCL presented initially as salivary gland and soft tissue masses. Morphologically, the neoplastic cells showed a typical fried-egg or monocytoid appearance with reniform nuclei, and were positive for CD11c, CD20, CD25, CD103, annexin A1, and cyclin D1. Both cases were positive for the BRAF V600E mutation, as shown by pyrosequencing and mutation-specific immunohistochemistry. The diagnosis was challenging in both patients, and one patient experienced 5 years of disease relapse and progression after treatment with multiple lymphoma-type regimens before the final diagnosis of HCL was established and complete remission was achieved following cladribine therapy. CONCLUSIONS: HCL can very rarely present as an extranodal mass. Being aware of this unusual presentation of HCL is essential to avoid diagnostic confusion with other types of low-grade B-cell lymphoma and to facilitate appropriate therapy.

Alternative BRAF mutations in BRAF V600E-negative hairy cell leukaemias.

The BRAF V600E mutation in exon 15 is considered the disease-defining mutation in hairy cell leukaemia (HCL), but single HCL cases lacking this mutation have been described. In 24 HCL, as well as in 194 various mature B- and T-cell neoplasms, we extended the search for BRAF mutations to exon 11. Two V600E-negative HCL contained novel, potentially functionally relevant mutations in exon 11 (F468C and D449E), while one other HCL was BRAF wild-type in exons 2-17. All non-HCL lymphomas lacked BRAF mutations. We therefore suggest screening of BRAF V600E-negative HCL for alternative exon 11 mutations in the diagnostic setting.

Peripheral blood 8 colour flow cytometry monitoring of hairy cell leukaemia allows detection of high-risk patients.

Although purine analogues have significantly improved the outcome of hairy cell leukaemia (HCL) patients, 30-40% relapse, illustrating the need for minimal residual disease (MRD) markers that can aid personalized therapeutic management. Diagnostic samples from 34 HCL patients were used to design an 8-colour flow cytometry (8-FC) tube for blood MRD (B/RD) analysis (188 samples) which was compared to quantitative IGH polymerase chain reaction (Q-PCR) on 83 samples and to qualitative consensus IGH PCR clonality analysis on 165 samples. Despite heterogeneous HCL phenotypes at diagnosis, discrimination from normal B lymphocytes was possible in all cases using a single 8-FC tube, with a robust sensitivity of detection of 10(-4) , comparable to Q-PCR at this level, but preferable in terms of informativeness, simplicity and cost. B/RD assessment of 15 patients achieving haematological complete remission after purine analogues was predictive of a clinically significant relapse risk: with a median follow-up of 95 months; only one of the nine patients with reproducible 8-FC B/RD levels below 10(-4) (B/RD(neg) ) relapsed, compared to 5/6 in the B/RD(pos) group (P = 0.003). These data demonstrate the clinical interest of a robust 8-FC HCL B/RD strategy that could become a surrogate biomarker for therapeutic stratification and new drug assessment, which should be evaluated prospectively.