RARE DISEASE
Classic hairy cell leukemia
Classic hairy cell leukemia
Classic hairy cell leukemia
Synonyms: HCL-C, Leukemic reticuloendotheliosis
Synonyms: HCL-C, Leukemic reticuloendotheliosis
Synonyms: HCL-C, Leukemic reticuloendotheliosis
Drug discovery
7
drugs
With orphan designations
Overview
Classic hairy cell leukemia (HCL) is a rare, indolent B-cell malignancy marked by pancytopenia, splenomegaly, and recurrent infections due to abnormal CD20+/CD11c+/CD25+/CD103+/BRAF V600E-mutated lymphocytes infiltrating bone marrow and spleen [1][4][14]. Diagnosis relies on morphology, flow cytometry, and molecular testing [1][11]. First-line therapy with purine analogs (cladribine/pentostatin) achieves >80% remission, while relapsed/refractory cases benefit from BRAF inhibitors (vemurafenib), anti-CD20 antibodies (rituximab), or immunotoxins (moxetumomab) [1][3][13][16].
Categories: rare hematological diseases, rare neoplastic diseases, rare transplant-related disorders
Research Papers
836 drug discovery papers about Classic hairy cell leukemia, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
836 drug discovery papers about Classic hairy cell leukemia, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
cell therapies
2025-03-24 | Hairy Cell Leukemia: A Differential Diagnosis of Hepatitis B-Associated Aplastic Anemia and Syphilis.
Aplastic anemia occurs with an incidence of 2-5: 1 million people worldwide. However, the frequency of newly diagnosed cases of bone marrow aplasia is greater, and some of these patients present to emergency departments initially. Description of Case: We present the case of a middle-aged man with pancytopenia. In this case, aplastic anemia associated with hepatitis B and syphilis was only the initial diagnosis. An indolent hematologic malignancy-hairy cell leukemia-was diagnosed as the real cause of the bone marrow failure in a clinic of hematology. Conclusions: This clinical case allows us to make a conclusion, albeit not definitively, about the contribution of hepatitis B and syphilis to the clinical manifestation of hairy cell leukemia. A detailed and consistent diagnostic plan is also required in patients presenting with pancytopenia. Failure to diagnose a hepatitis B infection in a patient with malignant hematologic disease would lead to fatal therapeutic errors.
2025-02-11 | Atypical Hairy Cell Leukemia-The Current Status and Future Directions.
Hairy cell leukemia (HCL) is a rare, chronic lymphoid leukemia characterized by circulating lymphocytes with pale, hair-like cytoplasmic projections, pancytopenia, marked monocytopenia, and splenomegaly. Classic HCL displays distinct morphological, immunophenotypical, and genetic features. Classic HCL cells exhibit central nuclei, abundant cytoplasm with hair-like projections, and expression of CD20, CD22, CD11c, CD103, CD25, CD123, TBX21, annexin A1 (ANXA1), FMC7, CD200, and weak cyclin D1 (CCND1). While the vast majority of classic HCL cases harbor the BRAF V600E somatic mutation, rare examples have been reported without splenomegaly, with bulky lymphadenopathy, or with an atypical morphology, immunophenotype or genotype. This review analyzes the atypical clinical, morphologic, immunophenotypic, and genetic presentations associated with classic HCL. PubMed, Web of Science, and Google Scholar were searched for articles of hairy cell leukemia, including atypical morphology, atypical immunophenotype, atypical genotype, and rare symptoms. Publications from October 2004 to December 2024 were reviewed, with additional relevant studies obtained by reviewing references from selected articles.
2024-11-13 | Hairy Cell Leukemia Following Acute Myeloid Leukemia, Concomitant or Secondary?
A 62-year-old man diagnosed with acute myeloid leukemia (AML) showed limited responses to two courses of azacitidine (AZA)+Venetoclax (VEN) therapy. Twenty days after being transferred to our hospital, flow cytometry with broad antigen coverage and mutation analysis confirmed the presence of a second malignancy, hairy cell leukemia (HCL). Following haploidentical combined umbilical cord blood transplantation, the patient achieved complete remission (CR) for both AML and HCL. This CR has been maintained for the past 14 months. Patients with dual hematologic malignancies may not respond well to conventional therapy regimens. Early initiation of hematopoietic stem cell transplantation is beneficial for improving prognosis and extending overall survival.
1998-01-29 | Clonal populations of T-cells in patients with B-cell malignancies.
Patients with B-cell malignancies are often immunosuppressed and have defective T-cell function in vitro. In addition they frequently have unusual T-cell populations in the peripheral blood including an increase in the number of activated T-cells and an inverted CD4:CD8 ratio. More recently several reports have documented the presence of large, monoclonal populations of T-cells in patients with paraproteinaemia, B-CLL and hairy cell leukemia. Such cells can reach very high levels in the peripheral blood, occasionally representing over 50% of all CD8+ T-cells. These clonally expanded cells have a characteristic morphology and phenotype in that they are often large, granular cells with natural killer cells markers. Their properties have not been studied in detail but they appear to suppress immunoglobulin production and kill cell targets in an MHC-unrestricted manner. The relationship of clonal T-cells to the B-cell tumour is unclear. They may be directly interacting with the malignant clone or alternatively be nonspecifically activated secondary to a disruption of the immune homeostasis by tumour cells. If they indeed represent an attempt by the immune response to control the malignant cells it is possible that they may be utilised in future attempts at immunotherapy.
1991-11-06 | Immunotherapy of cancer with lymphokines and lymphokine-activated killer cells.
Our expanding knowledge of the immune system has provided a basis of rationality for immunotherapy. Some non-specific immunotherapy has achieved the status of standard treatment: interferon in hairy cell leukemia and chronic myelogenous leukemia, BCG in bladder cancer, and levamisole in colon cancer adjuvant therapy. Tumor infiltrating lymphocytes, moreover, offer a level of specificity heretofore unknown. Combined with the newly available synthetic cytokines that regulate the normal immune system there is the potential for a major breakthrough in biotherapeutics. Problems remain. We have yet to identify tumor antigens with the precision necessary for effective immunotherapy. Indeed, we have no assurance that tumors will regularly synthesize new antigens. In the broad spectrum of immune deficiency syndromes, we have yet to see an increase in the common epithelial tumors that account for the great bulk of human cancer. This suggests that we still have a great deal more to learn.
proteins
2025-11-03 | Clinically approved immunotoxins targeting hematological cancers: "the best of both worlds".
Hematological malignancies contribute significantly to the overall cancer burden. Certain subtypes, such as hairy cell leukemia (HCL), are chronic and characterized by residual disease after first-line therapy, while others, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN), are aggressive and associated with poor prognosis. Although cornerstone interventions such as radiation and chemotherapy are efficiently used to treat some malignant blood neoplasms, these treatments are often limited by resistance, relapse, lack of enduring disease-free survival/complete remission, and systemic toxicity. Immunotoxins were developed to improve tumor targeting and have evolved into recombinant immunotoxins (RITs). These novel bioengineered chimeras genetically combine potent cytotoxins with targeted binding domains. In this review, we analyze three FDA-approved RITs, namely, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from Pseudomonas and Corynebacterium diphtheriae to treat refractory/relapsed (R/R) HCL, BPDCN, and adult R/R cutaneous T-cell lymphoma (CTCL), respectively. We reviewed their comprehensive safety profiles, describe complications associated with these fusion proteins, and, finally, discuss potential risk management strategies that may enhance their clinical outcomes. Overall, RITs have demonstrated efficacy, and researchers continue to extend these findings to other indications.
2025-06-05 | Successful treatment of hairy cell leukaemia with pegylated interferon-alpha-2A.
Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. Interferon-alpha (IFN-alpha) was the first successfully used drug in HCL; its favourable effect has been known since the early 1980s. However, currently the first-line treatment of the disease consists of purine nucleoside analogs. The aim of our study was to assess the efficacy of pegylated IFN-alpha in HCL patients treated with this drug at a single university center. We report the treatment characteristics and outcome of seven classical HCL patients treated with pegylated IFN-alpha at the Department of Internal Medicine and Oncology, Semmelweis University. As a result of pegylated interferon-alpha treatment, 3 of 7 patients (3/7) achieved an unconfirmed complete remission, 3 of 7 patients (3/7) achieved partial remission. One patient had stable disease while receiving pegylated IFN-alpha. Only mild adverse effects and no infectious complications were observed during our treatment. Our clinical data support that pegylated IFN-alpha in monotherapy is effective and safe even in elderly and frail HCL patients. It may also be a preferred therapeutic option in patients with profound immunosuppression and in patients with severe active infections.
2025-04-29 | B Cell Activating Factor Induces Drug Resistance in Hairy Cell Leukemia Variant.
Background: Chemoresistance is an existing challenge faced in the treatment of the hairy cell leukemia variant (HCL-v). Classical hairy cell leukemia (HCL-c) is very sensitive to the standard of care with purine nucleoside analogs (PNAs) cladribine (cDa) and pentostatin. However, almost half of these patients eventually become less sensitive to chemotherapy and relapse. HCL-variant (HCL-v) is a biologically distinct entity from HCL-c that is not sensitive to frontline PNA therapy, and this treatment is not recommended for these patients. To address these treatment challenges, we investigated the role of B-cell activating factor (BAFF) in promoting HCL-v cell chemoresistance. Methods: Flow cytometry and quantitative PCR were used to measure the levels of BAFF and its receptors. To determine BAFF activated pathways in HCL-c and HCL-v, the Bonna-12 HCL-c cell line or HCL-v patient-derived cancer cells were stimulated with recombinat BAFF and activation of common BAFF-activated pathways, including the nonclassical nuclear factor kappa B (NF-κB) pathway, the Extracellular Signal-Regulated Kinase (Erk) and phosphatidylinositol-3 (PI-3) kinase (PI3K)/AKT serine/threonine kinase (AKT) pathways were measured by western blotting. To test whether BAFF signaling promotes chemoresistance in HCL-v, we stimulated patient-derived HCL-v cells with BAFF and performed RNA sequencing. Lastly, to confirm the functional implications of BAFF signaling in HCL-v, we treated patient-derived HCL-v cells with exogenous BAFF before treatment with cladribine. Results: We found that HCL-v patient-derived cancer cells express receptors of BAFF at varying degrees and express relatively lower levels of membrane-bound BAFF ligand expression. BAFF stimulation of these cells resulted in substantial activation of the nonclassical NF-κB pathway, which is known to promote anti-apoptotic and pro-survival effects in B-cell cancers. Conversely, in the Bonna-12 cell line, we observed constitutive activation of the nonclassical NF-κB pathway. Through RNA sequencing, we found that BAFF upregulates a myriad of genes that are known to promote chemoresistance in various cancers, including IL1, CXCL1/2, CXCL5, CXCL8, TRAF3, and PTGS2. Lastly, we found that BAFF protects these cells from cladribine-induced cell death in vitro. Conclusions: We conclude that BAFF provides chemo-protection in HCL-v cells by activating nonclassical NF-κB signaling, which results in the upregulation of multiple pro-survival or anti-apoptotic genes. Our results highlight an important role of BAFF in HCL-v resistance to chemotherapy and suggest that the BAFF blockade may enhance the chemosensitivity to PNAs in drug-resistant HCL-v patients.
2025-04-21 | Abstract 6102: BAFF ligand CAR-T cells for hairy cell leukemia variant treatment
Abstract Hairy cell leukemia variant (HCL-v) is a rare B-cell malignancy that is biologically distinct from the classical form (HCL-c) and presents unique treatment challenges. The characteristic genetic or molecular markers of classical HCL include CD11c, CD25, CD103, CD123, the BRAFV600E point mutation, and tartrate resistant acid phosphatase (TRAP) expression. However, HCLv cells have a low immunologic score and don’t carry the BRAFV600E mutation or express TRAP. Treatment with the purine nucleoside analogs (PNAs) is effective in a majority of HCLc patients, who can look forward to a normal lifespan. However, HCLv patients are resistant to this treatment, which likely contributes to the significantly shorter prognosis of 6-9 years, in addition to the relative lack of druggable targets. To address poor clinical outcomes for HCL-v patients, we aimed to test a novel cellular therapy for HCL-v. We recently developed a third generation BAFF-ligand chimeric antigen receptor (CAR-T) cell product. B-cell activating factor (BAFF) is a critical factor that promotes B-cell maturation and survival. BAFF binds to three receptors, including BAFF-Receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B-cell maturation antigen (BCMA). Because of the pro-survival signaling that BAFF enhances upon binding to its receptors, B-cell cancers tend to exploit this signaling, and serum BAFF levels are often elevated. In a panel of HCLv cell lines and patient-derived splenocytes, we found that HCLv cells have high expression levels of all three receptors. In co-culture assays with fluorescently labeled HCLv patient samples and cell lines, CAR-T cells express significantly elevated markers of degranulation (CD107a) and activation (CD69) and secrete elevated levels of pro-inflammatory cytokines and lytic enzymes relative to control T-cells. BAFF CAR-T cells also display significantly increased cancer cell killing relative to control T-cells. This enhanced cancer cell killing was also observed in an autologous model, where CAR-T cells were generated from a de-identified HCLv patient and co-cultured with the patients’ own cancer cells. Similar findings were seen in multiple novel in vivo HCL xenograft models, in which BAFF CAR-T cell treatment (intratumor or intravenous) resulted in decreased tumor burden without significant toxicities.While we have seen success in our in vivo models, we also aim to generate a novel patient-derived xenograft model of HCLv to more accurately model the disease, both for more CAR-T cell translational studies and for more basic investigations into HCLv mechanisms. An additional future direction is to explore whether our BAFF CAR-T cells, which bind three receptors can mitigate antigen escape, the process by which tumor cells downregulate a target to avoid killing. To do so, we will perform single and double receptor knockouts of BAFF-R, TACI, and BCMA and assess if cell killing is intact with in vitro co-culture assays. Citation Format: Claire Elizabeth Fritz, Derek P. Wong, Akshaya Radhakrishnan, Philip Rock, Richard Burack, Reshmi Parameswaran. BAFF ligand CAR-T cells for hairy cell leukemia variant treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6102.
2024-11-28 | Cell therapy for a rare disease- hairy cell leukemia variant.
Hairy cell leukemia variant (HCL-v) is a rare malignancy of clonal mature B-cells that follows a chronic disease course. HCL-v patients are often resistant to purine nucleoside analogs, which are the first-line therapy. To address the shortcomings of current therapy for HCL-v, we investigated the activity of a BAFF ligand-based CAR-T cell which binds to all three BAFF receptors, BAFF-receptor, TACI, and BCMA. Here, we demonstrate that HCLv patient-derived cells highly express all three BAFF receptors and that BAFF CAR-T cells induce significant cytotoxicity in vitro against both cell lines and HCL-v patient cells. This cytotoxicity corresponds with significant CAR-T cell activation, degranulation, and release of pro-inflammatory cytokines after co-incubation with HCLv cells. Furthermore, we successfully generated BAFF CAR-T cells directly from an HCLv patient and observed direct autologous killing against patient tumor cells in vitro. These HCLv patient-derived CAR-T cells were also effective in killing the Hair-M cell line and tumor cells derived from a different HCLv patient. Lastly, we also developed two mouse xenograft models for HCL, a subcutaneous Bonna-12 model and intravenous Hair-M xenograft model. We observed decreases in tumor burden and prolonged overall survival without significant toxicity. In conclusion, here we show that BAFF CAR-T cells exert anti-tumor effects in vitro and in vivo against multiple cell lines and patient-derived HCL-v samples and may be a successful therapeutic strategy for HCLv patients.
antibodies
2026-04-24 | Successful treatment of hairy cell leukemia with TP53 abnormality using cladribine combined with low-dose rituximab: a case report and literature review.
Hairy cell leukemia (HCL) is a rare mature B-cell malignancy characterized by the BRAF V600E mutation. TP53 abnormalities in HCL are associated with poor response to standard therapies and a higher risk of relapse. We report an elderly male patient diagnosed with classical HCL (BRAF V600E-positive) who also presented with a TP53 deletion detected by fluorescence in situ hybridization (FISH) and bone marrow fibrosis. The patient was treated with one cycle of cladribine combined with low-dose rituximab (100 mg). The treatment was well tolerated. At the 7-month follow up, the patient achieved complete molecular remission, characterized by normalized blood counts, recovery of bone marrow morphology, disappearance of the TP53 deletion by FISH, negative minimal residual disease by flow cytometry, and reversal of bone marrow fibrosis from MF-2 to MF-0. This case suggests that the combination of cladribine and low-dose rituximab may be an effective therapeutic strategy for classical HCL with TP53 abnormality, enabling deep molecular response and reversal of associated bone marrow fibrosis. Further prospective studies are warranted to validate these findings.
2025-10-08 | Phase 2 trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia.
The primary objective in multiply relapsed hairy cell leukemia and variant (HCL/HCLv) was to determine whether pentostatin-rituximab (DCFR) and bendamustine-rituximab (BR) each achieve an overall response rate (ORR) exceeding that historically achieved by rituximab alone (∼40%) in favor of 65%. Prospective data were unreported for either regimen. Fifty-six patients received 6 28-day cycles of rituximab (375 mg/m2, days 1 and 15) with either bendamustine (90 mg/m2, days 1 and 2) or pentostatin (4 mg/m2, days 1 and 15). Eligibility required ≥2 purine analogs, or 1 purine analog plus rituximab for response of <1 year to the initial purine analog. Although patients were assigned to either regimen through randomization to increase homogeneity of the 2 treatment groups, the DCFR arm had fewer previous purine analogs (P = .021) and lower baseline marrow HCL/HCLv infiltration (P = .013). ORRs for DCFR and BR were 93% (95% confidence intervals [CI], 83-102) and 86%, (95% CI, 73-99), respectively, exceeding 40% (P< .0001) for each group. Rates for complete remission (CR) and minimal residual disease-free CR and median progression-free survival (141 vs 50 months; HR, 0.63; 95% CI, 0.32-1.25) numerically favored DCFR, but that arm was significantly enriched with less previous purine analogs and marrow infiltration, each of which was associated post hoc with better response. Post hoc subgroup analysis, particularly for 41 patients with classic HCL, suggested any superiority of DCFR vs BR might apply to patients with more favorable disease. DCFR and BR were highly effective in multiply relapsed HCL/HCLv. Possible DCFR superiority was hypothesis-generating, given uneven baseline risks and trial design. This trial was registered at www.clinicaltrials.gov as #NCT01059786.
2025-09-26 | Bacterial Protein Toxins as Anticancer Agents: Clinical Potential of Pseudomonas and Anthrax Toxins.
Protein toxins are biologically active polypeptides produced by a variety of organisms, including bacteria, plants, fungi, and animals. These molecules exert potent and specific toxic effects on target cells and are primarily associated with pathogenicity and defense mechanisms of the organisms. In the past few decades, significant progress has been made in understanding their structure, mechanisms of action, and regulation. Among these, bacterial protein toxins have emerged as valuable tools particularly in the development of targeted therapies. A notable example is Botulinum toxin, originally known for its neurotoxic effects, which was approved as a therapeutic agent in 1989 for strabismus treatment, paving way for repurposing bacterial toxins for clinical use. This review provides an overview of the different classes of bacterial toxin-based therapeutics, with a particular focus on Pseudomonas exotoxin A (PE) from Pseudomonas aeruginosa and anthrax toxin from Bacillus anthracis. The modular architecture and potent cytotoxicity of these A-B type toxins have enabled their successful adaptation into targeted cancer therapies. The clinical approval of the PE-based immunotoxin, moxetumomab pasudotox, for the treatment of hairy cell leukemia, underscores the potential of this strategy. This review also discusses current challenges and outlines future directions for the advancement of bacterial toxin-based therapeutics.
2024-12-17 | The role of the JunD-RhoH axis in the pathogenesis of hairy cell leukemia and its ability to identify existing therapeutics that could be repurposed to treat relapsed or refractory disease.
Hairy cell leukemia (HCL) is an indolent malignancy of mature B-lymphocytes. While existing front-line therapies achieve excellent initial results, a significant number of patients relapse and become increasingly treatment resistant. A major molecular driver of HCL is aberrant interlocking expression of the transcription factor JunD and the intracellular signaling molecule RhoH. Here we discuss the molecular basis of how the JunD-RhoH axis contributes to HCL pathogenesis. We also discuss how leveraging the JunD-RhoH axis identifies CD23, CD38, CD66a, CD115, CD269, integrin β7, and MET as new potential therapeutic targets. Critically, preclinical studies have already demonstrated that targeting CD38 with isatuximab effectively treats preexisiting HCL. Isatuximab and therapeutics directed against each of the other six new HCL targets are currently in clinical use to treat other disorders. Consequently, leveraging the JunD-RhoH axis has identified a battery of therapies that could be repurposed as new means of treating relapsed or refractory HCL.
2024-11-04 | Tumour assessment of ROR1 levels in various adult leukaemia and lymphoma types.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.
small molecules
2026-07-08 | Hairy cell leukemia in a 51-year-old Syrian male: a case report.
Hairy cell leukemia (HCL), a rare B-cell lymphoproliferative disorder, originates from the splenic marginal zone B cell. However, diagnosis can be particularly challenging in resource-limited settings where advanced tests are not readily available. Misclassification may result in non-selective chemotherapy exposure and increased toxicity. Reporting such cases is important to highlight diagnostic challenges in resource-limited countries. A 51-year-old male presented with abdominal discomfort, weight loss, and fatigue. Examination revealed splenomegaly. Initial evaluation suggested lymphoplasmacytic lymphoma, and the patient received multi-agent chemotherapy (R-CHOP), which was complicated by severe cytopenias. Splenectomy was performed, yielding a spleen weighing 2216 g. Histopathology and immunophenotyping confirmed hairy cell leukemia. Molecular testing for BRAF V600E (the gold standard for diagnosis) was unavailable due to financial and infrastructural restrictions. Treatment was switched to single-agent cladribine, resulting in marked clinical improvement and a significant reduction in chemotherapy adverse effects. Follow-up imaging and blood work revealed that the patient was in complete remission. In our case, we emphasize the diagnostic challenges of HCL in low-resource environments and clarify how the empirical administration of R-CHOP chemotherapy led to unnecessary toxicity and suboptimal outcomes. Splenectomy played a crucial diagnostic role when bone marrow tests were directional but not conclusive. We provide an extensive review of differential diagnoses, immunophenotypic hallmarks, what lies beyond the BRAF V600E mutation, and therapeutic approaches. Early recognition of HCL is crucial to avoid delayed optimal therapy and to enhance patient outcomes. This case emphasizes the critical role of morphology and immunophenotyping in confirming HCL, especially in resource-limited countries.
2026-06-12 | Real-world treatment and outcomes in hairy cell leukemia: a multicenter retrospective cohort including BRAF inhibitor therapy.
Hairy cell leukemia (HCL) is a rare B-cell malignancy traditionally treated with purine analogue-based regimens. Although BRAF inhibitors are established in relapsed or refractory disease, their role as first-line therapy remains incompletely defined. We conducted a multicenter retrospective study evaluating real-world treatment of adults with classic HCL. A total of 110 patients were included. First-line therapies were cladribine (64%), cladribine plus rituximab (11%), rituximab (9%), and vemurafenib-based regimens (9%). Overall, response rate to first-line therapy was 80% (complete response rate of 65%). Median overall survival was 24.4 years. Patients treated first-line with vemurafenib-based regimens achieved an overall response rate of 80%, similar to purine analogue-based therapy. Hospitalization rates were similar across treatment groups. Vemurafenib-based therapy and rituximab monotherapy were preferentially used in older patients with greater baseline anemia. This study provides early insight into BRAF inhibitor use in HCL, highlighting encouraging responses in a limited number of patients.
2026-06-08 | Weekly Cladribine Followed by Rituximab for the Treatment of Hairy Cell Leukemia.
Hairy cell leukemia (HCL) is an uncommon hematopoietic stem cell disease known to have an underlying somatic BRAFV600E driver mutation. Currently, the most accepted treatment is five or seven consecutive days of outpatient infusion of cladribine (e.g., continuous infusion), despite frequent antibiotic use and hospitalization with this regimen. As a result, a few investigators have adopted weekly infusion of cladribine with similar or improved results and fewer side effects. We conducted a retrospective, single-institution cohort study of 36 treatment-naïve patients with HCL treated at the University of Colorado Hospital. Eighteen patients received intermittent weekly cladribine (intermittent cladribine [IC]) for 5-7 doses and 18 received standard daily cladribine (continuous cladribine [CC]) over 5-7 days. We report clinical cohort characteristics, response rates, progression-free survival, overall survival, toxicity, hospitalization rates, and measurable residual disease monitoring in select patients using peripheral blood quantitative BRAFV600E PCR. We report here our experience with 18 patients with newly diagnosed BRAF-mutated HCL treated with weekly cladribine at a single institution compared to 18 HCL patients who received continuous infusions. Baseline hematologic parameters and overall survival were comparable between groups (p = 0.1135), but there was a higher rate of complete remission for patients treated with IC (94.4% vs. 61.1%) with significantly improved progression-free survival (p < 0.0001). We observed comparable rates of neutropenia, neutropenic fever, antibiotic use, and G-CSF administration. There were fewer hospitalizations for patients treated with IC (4/18) compared to patients treated with CC (6/18). Rituximab exposure differed between groups, with 72% of patients in the IC cohort receiving rituximab compared with 27.2% in the CC cohort (although treatment status was documented for only 66.7% of patients in the CC cohort). Peripheral blood BRAFV600E allele burden significantly declined and correlated with clinical remission, but this was only performed in select patients who were treated in recent years. In this retrospective analysis, IC dosed weekly was associated with improved progression-free survival and higher rates of complete remission compared to CC with comparable toxicity and fewer hospitalizations. These findings suggest a potential clinical benefit from this regimen. However, interpretation of these findings is limited by the non-randomized design and differences in rituximab exposure between groups, which may have contributed to the observed outcomes and limited definitive conclusions. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2026-05-27 | DUSP1 is a Key Driver of Disease Persistence and Potential Therapeutic Target in Hairy Cell Leukemia.
Classic hairy cell leukemia (HCL) is a rare indolent B cell lymphoproliferative disorder characterized by the driver mutation BRAF V600E. Standard treatment with purine analogs (i.e. cladribine) induces long-term remissions, but up to 25% of patients relapse early. Even when targeting BRAF V600E, residual HCL cells frequently persist in the bone marrow (BM). To unravel additional biologic alterations contributing to HCL disease persistence, we performed single-cell RNA sequencing in sorted primary HCL cells from long-term versus short-term cladribine responders (LT-R versus ST-R: >10 versus ≤3 years PFS) at diagnosis and in ST-R at diagnosis versus relapses. We identified a distinct HCL subcluster characterized by elevated DUSP1, FOS, and JUND expression, which was detected in all patients and persisted or even expanded at relapses. Cancer pathway analysis suggested enhanced tumor microenvironment dependency as reflected by suppression of the p38-MAP kinase pathway. In the absence of a suitable BRAF V600E-mutated HCL cell line, we validated HAIR-M cells (BRAF D594E) as a bona fide experimental HCL model. The activating BRAF D594E mutation mimics V600E-induced downstream signals that can efficiently be targeted by BRAF inhibitors (BRAFi). HAIR-M co-culture with BM stromal cells (BMSC) strongly induced DUSP1 that was accompanied by protection from BRAFi-induced HAIR-M apoptosis. The functional importance of DUSP1 was corroborated by demonstrating that BMSC-induced protection from cell death could be overcome through DUSP1 inhibition. Our results might set the stage for future clinical testing of DUSP1 inhibition to eliminate minimal residual disease (MRD) and prevent disease relapse in HCL.
2026-04-14 | Updated consensus guidelines for the diagnosis and management of patients with HCL and HCL variant.
Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase-activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor-based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.
cell therapies
2025-03-24 | Hairy Cell Leukemia: A Differential Diagnosis of Hepatitis B-Associated Aplastic Anemia and Syphilis.
Aplastic anemia occurs with an incidence of 2-5: 1 million people worldwide. However, the frequency of newly diagnosed cases of bone marrow aplasia is greater, and some of these patients present to emergency departments initially. Description of Case: We present the case of a middle-aged man with pancytopenia. In this case, aplastic anemia associated with hepatitis B and syphilis was only the initial diagnosis. An indolent hematologic malignancy-hairy cell leukemia-was diagnosed as the real cause of the bone marrow failure in a clinic of hematology. Conclusions: This clinical case allows us to make a conclusion, albeit not definitively, about the contribution of hepatitis B and syphilis to the clinical manifestation of hairy cell leukemia. A detailed and consistent diagnostic plan is also required in patients presenting with pancytopenia. Failure to diagnose a hepatitis B infection in a patient with malignant hematologic disease would lead to fatal therapeutic errors.
2025-02-11 | Atypical Hairy Cell Leukemia-The Current Status and Future Directions.
Hairy cell leukemia (HCL) is a rare, chronic lymphoid leukemia characterized by circulating lymphocytes with pale, hair-like cytoplasmic projections, pancytopenia, marked monocytopenia, and splenomegaly. Classic HCL displays distinct morphological, immunophenotypical, and genetic features. Classic HCL cells exhibit central nuclei, abundant cytoplasm with hair-like projections, and expression of CD20, CD22, CD11c, CD103, CD25, CD123, TBX21, annexin A1 (ANXA1), FMC7, CD200, and weak cyclin D1 (CCND1). While the vast majority of classic HCL cases harbor the BRAF V600E somatic mutation, rare examples have been reported without splenomegaly, with bulky lymphadenopathy, or with an atypical morphology, immunophenotype or genotype. This review analyzes the atypical clinical, morphologic, immunophenotypic, and genetic presentations associated with classic HCL. PubMed, Web of Science, and Google Scholar were searched for articles of hairy cell leukemia, including atypical morphology, atypical immunophenotype, atypical genotype, and rare symptoms. Publications from October 2004 to December 2024 were reviewed, with additional relevant studies obtained by reviewing references from selected articles.
2024-11-13 | Hairy Cell Leukemia Following Acute Myeloid Leukemia, Concomitant or Secondary?
A 62-year-old man diagnosed with acute myeloid leukemia (AML) showed limited responses to two courses of azacitidine (AZA)+Venetoclax (VEN) therapy. Twenty days after being transferred to our hospital, flow cytometry with broad antigen coverage and mutation analysis confirmed the presence of a second malignancy, hairy cell leukemia (HCL). Following haploidentical combined umbilical cord blood transplantation, the patient achieved complete remission (CR) for both AML and HCL. This CR has been maintained for the past 14 months. Patients with dual hematologic malignancies may not respond well to conventional therapy regimens. Early initiation of hematopoietic stem cell transplantation is beneficial for improving prognosis and extending overall survival.
1998-01-29 | Clonal populations of T-cells in patients with B-cell malignancies.
Patients with B-cell malignancies are often immunosuppressed and have defective T-cell function in vitro. In addition they frequently have unusual T-cell populations in the peripheral blood including an increase in the number of activated T-cells and an inverted CD4:CD8 ratio. More recently several reports have documented the presence of large, monoclonal populations of T-cells in patients with paraproteinaemia, B-CLL and hairy cell leukemia. Such cells can reach very high levels in the peripheral blood, occasionally representing over 50% of all CD8+ T-cells. These clonally expanded cells have a characteristic morphology and phenotype in that they are often large, granular cells with natural killer cells markers. Their properties have not been studied in detail but they appear to suppress immunoglobulin production and kill cell targets in an MHC-unrestricted manner. The relationship of clonal T-cells to the B-cell tumour is unclear. They may be directly interacting with the malignant clone or alternatively be nonspecifically activated secondary to a disruption of the immune homeostasis by tumour cells. If they indeed represent an attempt by the immune response to control the malignant cells it is possible that they may be utilised in future attempts at immunotherapy.
1991-11-06 | Immunotherapy of cancer with lymphokines and lymphokine-activated killer cells.
Our expanding knowledge of the immune system has provided a basis of rationality for immunotherapy. Some non-specific immunotherapy has achieved the status of standard treatment: interferon in hairy cell leukemia and chronic myelogenous leukemia, BCG in bladder cancer, and levamisole in colon cancer adjuvant therapy. Tumor infiltrating lymphocytes, moreover, offer a level of specificity heretofore unknown. Combined with the newly available synthetic cytokines that regulate the normal immune system there is the potential for a major breakthrough in biotherapeutics. Problems remain. We have yet to identify tumor antigens with the precision necessary for effective immunotherapy. Indeed, we have no assurance that tumors will regularly synthesize new antigens. In the broad spectrum of immune deficiency syndromes, we have yet to see an increase in the common epithelial tumors that account for the great bulk of human cancer. This suggests that we still have a great deal more to learn.
proteins
2025-11-03 | Clinically approved immunotoxins targeting hematological cancers: "the best of both worlds".
Hematological malignancies contribute significantly to the overall cancer burden. Certain subtypes, such as hairy cell leukemia (HCL), are chronic and characterized by residual disease after first-line therapy, while others, such as blastic plasmacytoid dendritic cell neoplasm (BPDCN), are aggressive and associated with poor prognosis. Although cornerstone interventions such as radiation and chemotherapy are efficiently used to treat some malignant blood neoplasms, these treatments are often limited by resistance, relapse, lack of enduring disease-free survival/complete remission, and systemic toxicity. Immunotoxins were developed to improve tumor targeting and have evolved into recombinant immunotoxins (RITs). These novel bioengineered chimeras genetically combine potent cytotoxins with targeted binding domains. In this review, we analyze three FDA-approved RITs, namely, moxetumomab pasudotox, tagraxofusp, and denileukin diftitox, that utilize bacterial toxins from Pseudomonas and Corynebacterium diphtheriae to treat refractory/relapsed (R/R) HCL, BPDCN, and adult R/R cutaneous T-cell lymphoma (CTCL), respectively. We reviewed their comprehensive safety profiles, describe complications associated with these fusion proteins, and, finally, discuss potential risk management strategies that may enhance their clinical outcomes. Overall, RITs have demonstrated efficacy, and researchers continue to extend these findings to other indications.
2025-06-05 | Successful treatment of hairy cell leukaemia with pegylated interferon-alpha-2A.
Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. Interferon-alpha (IFN-alpha) was the first successfully used drug in HCL; its favourable effect has been known since the early 1980s. However, currently the first-line treatment of the disease consists of purine nucleoside analogs. The aim of our study was to assess the efficacy of pegylated IFN-alpha in HCL patients treated with this drug at a single university center. We report the treatment characteristics and outcome of seven classical HCL patients treated with pegylated IFN-alpha at the Department of Internal Medicine and Oncology, Semmelweis University. As a result of pegylated interferon-alpha treatment, 3 of 7 patients (3/7) achieved an unconfirmed complete remission, 3 of 7 patients (3/7) achieved partial remission. One patient had stable disease while receiving pegylated IFN-alpha. Only mild adverse effects and no infectious complications were observed during our treatment. Our clinical data support that pegylated IFN-alpha in monotherapy is effective and safe even in elderly and frail HCL patients. It may also be a preferred therapeutic option in patients with profound immunosuppression and in patients with severe active infections.
2025-04-29 | B Cell Activating Factor Induces Drug Resistance in Hairy Cell Leukemia Variant.
Background: Chemoresistance is an existing challenge faced in the treatment of the hairy cell leukemia variant (HCL-v). Classical hairy cell leukemia (HCL-c) is very sensitive to the standard of care with purine nucleoside analogs (PNAs) cladribine (cDa) and pentostatin. However, almost half of these patients eventually become less sensitive to chemotherapy and relapse. HCL-variant (HCL-v) is a biologically distinct entity from HCL-c that is not sensitive to frontline PNA therapy, and this treatment is not recommended for these patients. To address these treatment challenges, we investigated the role of B-cell activating factor (BAFF) in promoting HCL-v cell chemoresistance. Methods: Flow cytometry and quantitative PCR were used to measure the levels of BAFF and its receptors. To determine BAFF activated pathways in HCL-c and HCL-v, the Bonna-12 HCL-c cell line or HCL-v patient-derived cancer cells were stimulated with recombinat BAFF and activation of common BAFF-activated pathways, including the nonclassical nuclear factor kappa B (NF-κB) pathway, the Extracellular Signal-Regulated Kinase (Erk) and phosphatidylinositol-3 (PI-3) kinase (PI3K)/AKT serine/threonine kinase (AKT) pathways were measured by western blotting. To test whether BAFF signaling promotes chemoresistance in HCL-v, we stimulated patient-derived HCL-v cells with BAFF and performed RNA sequencing. Lastly, to confirm the functional implications of BAFF signaling in HCL-v, we treated patient-derived HCL-v cells with exogenous BAFF before treatment with cladribine. Results: We found that HCL-v patient-derived cancer cells express receptors of BAFF at varying degrees and express relatively lower levels of membrane-bound BAFF ligand expression. BAFF stimulation of these cells resulted in substantial activation of the nonclassical NF-κB pathway, which is known to promote anti-apoptotic and pro-survival effects in B-cell cancers. Conversely, in the Bonna-12 cell line, we observed constitutive activation of the nonclassical NF-κB pathway. Through RNA sequencing, we found that BAFF upregulates a myriad of genes that are known to promote chemoresistance in various cancers, including IL1, CXCL1/2, CXCL5, CXCL8, TRAF3, and PTGS2. Lastly, we found that BAFF protects these cells from cladribine-induced cell death in vitro. Conclusions: We conclude that BAFF provides chemo-protection in HCL-v cells by activating nonclassical NF-κB signaling, which results in the upregulation of multiple pro-survival or anti-apoptotic genes. Our results highlight an important role of BAFF in HCL-v resistance to chemotherapy and suggest that the BAFF blockade may enhance the chemosensitivity to PNAs in drug-resistant HCL-v patients.
2025-04-21 | Abstract 6102: BAFF ligand CAR-T cells for hairy cell leukemia variant treatment
Abstract Hairy cell leukemia variant (HCL-v) is a rare B-cell malignancy that is biologically distinct from the classical form (HCL-c) and presents unique treatment challenges. The characteristic genetic or molecular markers of classical HCL include CD11c, CD25, CD103, CD123, the BRAFV600E point mutation, and tartrate resistant acid phosphatase (TRAP) expression. However, HCLv cells have a low immunologic score and don’t carry the BRAFV600E mutation or express TRAP. Treatment with the purine nucleoside analogs (PNAs) is effective in a majority of HCLc patients, who can look forward to a normal lifespan. However, HCLv patients are resistant to this treatment, which likely contributes to the significantly shorter prognosis of 6-9 years, in addition to the relative lack of druggable targets. To address poor clinical outcomes for HCL-v patients, we aimed to test a novel cellular therapy for HCL-v. We recently developed a third generation BAFF-ligand chimeric antigen receptor (CAR-T) cell product. B-cell activating factor (BAFF) is a critical factor that promotes B-cell maturation and survival. BAFF binds to three receptors, including BAFF-Receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), and B-cell maturation antigen (BCMA). Because of the pro-survival signaling that BAFF enhances upon binding to its receptors, B-cell cancers tend to exploit this signaling, and serum BAFF levels are often elevated. In a panel of HCLv cell lines and patient-derived splenocytes, we found that HCLv cells have high expression levels of all three receptors. In co-culture assays with fluorescently labeled HCLv patient samples and cell lines, CAR-T cells express significantly elevated markers of degranulation (CD107a) and activation (CD69) and secrete elevated levels of pro-inflammatory cytokines and lytic enzymes relative to control T-cells. BAFF CAR-T cells also display significantly increased cancer cell killing relative to control T-cells. This enhanced cancer cell killing was also observed in an autologous model, where CAR-T cells were generated from a de-identified HCLv patient and co-cultured with the patients’ own cancer cells. Similar findings were seen in multiple novel in vivo HCL xenograft models, in which BAFF CAR-T cell treatment (intratumor or intravenous) resulted in decreased tumor burden without significant toxicities.While we have seen success in our in vivo models, we also aim to generate a novel patient-derived xenograft model of HCLv to more accurately model the disease, both for more CAR-T cell translational studies and for more basic investigations into HCLv mechanisms. An additional future direction is to explore whether our BAFF CAR-T cells, which bind three receptors can mitigate antigen escape, the process by which tumor cells downregulate a target to avoid killing. To do so, we will perform single and double receptor knockouts of BAFF-R, TACI, and BCMA and assess if cell killing is intact with in vitro co-culture assays. Citation Format: Claire Elizabeth Fritz, Derek P. Wong, Akshaya Radhakrishnan, Philip Rock, Richard Burack, Reshmi Parameswaran. BAFF ligand CAR-T cells for hairy cell leukemia variant treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6102.
2024-11-28 | Cell therapy for a rare disease- hairy cell leukemia variant.
Hairy cell leukemia variant (HCL-v) is a rare malignancy of clonal mature B-cells that follows a chronic disease course. HCL-v patients are often resistant to purine nucleoside analogs, which are the first-line therapy. To address the shortcomings of current therapy for HCL-v, we investigated the activity of a BAFF ligand-based CAR-T cell which binds to all three BAFF receptors, BAFF-receptor, TACI, and BCMA. Here, we demonstrate that HCLv patient-derived cells highly express all three BAFF receptors and that BAFF CAR-T cells induce significant cytotoxicity in vitro against both cell lines and HCL-v patient cells. This cytotoxicity corresponds with significant CAR-T cell activation, degranulation, and release of pro-inflammatory cytokines after co-incubation with HCLv cells. Furthermore, we successfully generated BAFF CAR-T cells directly from an HCLv patient and observed direct autologous killing against patient tumor cells in vitro. These HCLv patient-derived CAR-T cells were also effective in killing the Hair-M cell line and tumor cells derived from a different HCLv patient. Lastly, we also developed two mouse xenograft models for HCL, a subcutaneous Bonna-12 model and intravenous Hair-M xenograft model. We observed decreases in tumor burden and prolonged overall survival without significant toxicity. In conclusion, here we show that BAFF CAR-T cells exert anti-tumor effects in vitro and in vivo against multiple cell lines and patient-derived HCL-v samples and may be a successful therapeutic strategy for HCLv patients.
antibodies
2026-04-24 | Successful treatment of hairy cell leukemia with TP53 abnormality using cladribine combined with low-dose rituximab: a case report and literature review.
Hairy cell leukemia (HCL) is a rare mature B-cell malignancy characterized by the BRAF V600E mutation. TP53 abnormalities in HCL are associated with poor response to standard therapies and a higher risk of relapse. We report an elderly male patient diagnosed with classical HCL (BRAF V600E-positive) who also presented with a TP53 deletion detected by fluorescence in situ hybridization (FISH) and bone marrow fibrosis. The patient was treated with one cycle of cladribine combined with low-dose rituximab (100 mg). The treatment was well tolerated. At the 7-month follow up, the patient achieved complete molecular remission, characterized by normalized blood counts, recovery of bone marrow morphology, disappearance of the TP53 deletion by FISH, negative minimal residual disease by flow cytometry, and reversal of bone marrow fibrosis from MF-2 to MF-0. This case suggests that the combination of cladribine and low-dose rituximab may be an effective therapeutic strategy for classical HCL with TP53 abnormality, enabling deep molecular response and reversal of associated bone marrow fibrosis. Further prospective studies are warranted to validate these findings.
2025-10-08 | Phase 2 trial of rituximab with either pentostatin or bendamustine for multiply relapsed or refractory hairy cell leukemia.
The primary objective in multiply relapsed hairy cell leukemia and variant (HCL/HCLv) was to determine whether pentostatin-rituximab (DCFR) and bendamustine-rituximab (BR) each achieve an overall response rate (ORR) exceeding that historically achieved by rituximab alone (∼40%) in favor of 65%. Prospective data were unreported for either regimen. Fifty-six patients received 6 28-day cycles of rituximab (375 mg/m2, days 1 and 15) with either bendamustine (90 mg/m2, days 1 and 2) or pentostatin (4 mg/m2, days 1 and 15). Eligibility required ≥2 purine analogs, or 1 purine analog plus rituximab for response of <1 year to the initial purine analog. Although patients were assigned to either regimen through randomization to increase homogeneity of the 2 treatment groups, the DCFR arm had fewer previous purine analogs (P = .021) and lower baseline marrow HCL/HCLv infiltration (P = .013). ORRs for DCFR and BR were 93% (95% confidence intervals [CI], 83-102) and 86%, (95% CI, 73-99), respectively, exceeding 40% (P< .0001) for each group. Rates for complete remission (CR) and minimal residual disease-free CR and median progression-free survival (141 vs 50 months; HR, 0.63; 95% CI, 0.32-1.25) numerically favored DCFR, but that arm was significantly enriched with less previous purine analogs and marrow infiltration, each of which was associated post hoc with better response. Post hoc subgroup analysis, particularly for 41 patients with classic HCL, suggested any superiority of DCFR vs BR might apply to patients with more favorable disease. DCFR and BR were highly effective in multiply relapsed HCL/HCLv. Possible DCFR superiority was hypothesis-generating, given uneven baseline risks and trial design. This trial was registered at www.clinicaltrials.gov as #NCT01059786.
2025-09-26 | Bacterial Protein Toxins as Anticancer Agents: Clinical Potential of Pseudomonas and Anthrax Toxins.
Protein toxins are biologically active polypeptides produced by a variety of organisms, including bacteria, plants, fungi, and animals. These molecules exert potent and specific toxic effects on target cells and are primarily associated with pathogenicity and defense mechanisms of the organisms. In the past few decades, significant progress has been made in understanding their structure, mechanisms of action, and regulation. Among these, bacterial protein toxins have emerged as valuable tools particularly in the development of targeted therapies. A notable example is Botulinum toxin, originally known for its neurotoxic effects, which was approved as a therapeutic agent in 1989 for strabismus treatment, paving way for repurposing bacterial toxins for clinical use. This review provides an overview of the different classes of bacterial toxin-based therapeutics, with a particular focus on Pseudomonas exotoxin A (PE) from Pseudomonas aeruginosa and anthrax toxin from Bacillus anthracis. The modular architecture and potent cytotoxicity of these A-B type toxins have enabled their successful adaptation into targeted cancer therapies. The clinical approval of the PE-based immunotoxin, moxetumomab pasudotox, for the treatment of hairy cell leukemia, underscores the potential of this strategy. This review also discusses current challenges and outlines future directions for the advancement of bacterial toxin-based therapeutics.
2024-12-17 | The role of the JunD-RhoH axis in the pathogenesis of hairy cell leukemia and its ability to identify existing therapeutics that could be repurposed to treat relapsed or refractory disease.
Hairy cell leukemia (HCL) is an indolent malignancy of mature B-lymphocytes. While existing front-line therapies achieve excellent initial results, a significant number of patients relapse and become increasingly treatment resistant. A major molecular driver of HCL is aberrant interlocking expression of the transcription factor JunD and the intracellular signaling molecule RhoH. Here we discuss the molecular basis of how the JunD-RhoH axis contributes to HCL pathogenesis. We also discuss how leveraging the JunD-RhoH axis identifies CD23, CD38, CD66a, CD115, CD269, integrin β7, and MET as new potential therapeutic targets. Critically, preclinical studies have already demonstrated that targeting CD38 with isatuximab effectively treats preexisiting HCL. Isatuximab and therapeutics directed against each of the other six new HCL targets are currently in clinical use to treat other disorders. Consequently, leveraging the JunD-RhoH axis has identified a battery of therapies that could be repurposed as new means of treating relapsed or refractory HCL.
2024-11-04 | Tumour assessment of ROR1 levels in various adult leukaemia and lymphoma types.
Receptor tyrosine kinase-like orphan receptor 1 (ROR1) is a tumour target currently used for the development of novel therapeutic modalities, such as antibody-drug conjugates, chimeric antigen receptor T-cell therapies, and others. Success of these new drugs depends on the selection of relevant indications based on ROR1 tumour prevalence, staining heterogeneity, and subcellular localization, among other parameters. We investigated ROR1 immunophenotype using validated antibody clones for immunohistochemistry (IHC) and flow cytometry (FC), analyzing 292 tumour specimens from 7 haematological malignancies and triple negative breast cancer (TNBC) as a reference solid tumour indication. ROR1 prevalence varied significantly across distinct tumour types, showing 100% of ROR1 positivity in all chronic lymphocytic leukaemia (n = 48) and hairy cell leukaemia (n = 14) specimens analyzed via FC with ranges between 1.1-99.8% and 0.8-62.1%, respectively. Samples analysed via IHC showed ROR1 membrane/cytoplasmic positivity in 44% of mantle cell lymphoma tumour samples (n = 27; H-score range: 10-285 in positive cases); 30% in TNBC (n = 46; H-score range: 1-200); 15% in diffuse large B-cell lymphoma (n = 45; H-score: 40-250); and 11% in follicular lymphoma (n = 34; H-score: 2-300). Finally, all acute myeloid leukaemia (n = 52) and most T-cell non-Hodgkin lymphoma (n = 31/32) tested samples were negative for ROR1 via IHC. In conclusion, ROR1 shows a heterogeneous tumour cell expression profile across multiple leukaemias and lymphomas, making it a tumour target that would require different patient selection strategies to develop novel therapeutic modalities.
small molecules
2026-07-08 | Hairy cell leukemia in a 51-year-old Syrian male: a case report.
Hairy cell leukemia (HCL), a rare B-cell lymphoproliferative disorder, originates from the splenic marginal zone B cell. However, diagnosis can be particularly challenging in resource-limited settings where advanced tests are not readily available. Misclassification may result in non-selective chemotherapy exposure and increased toxicity. Reporting such cases is important to highlight diagnostic challenges in resource-limited countries. A 51-year-old male presented with abdominal discomfort, weight loss, and fatigue. Examination revealed splenomegaly. Initial evaluation suggested lymphoplasmacytic lymphoma, and the patient received multi-agent chemotherapy (R-CHOP), which was complicated by severe cytopenias. Splenectomy was performed, yielding a spleen weighing 2216 g. Histopathology and immunophenotyping confirmed hairy cell leukemia. Molecular testing for BRAF V600E (the gold standard for diagnosis) was unavailable due to financial and infrastructural restrictions. Treatment was switched to single-agent cladribine, resulting in marked clinical improvement and a significant reduction in chemotherapy adverse effects. Follow-up imaging and blood work revealed that the patient was in complete remission. In our case, we emphasize the diagnostic challenges of HCL in low-resource environments and clarify how the empirical administration of R-CHOP chemotherapy led to unnecessary toxicity and suboptimal outcomes. Splenectomy played a crucial diagnostic role when bone marrow tests were directional but not conclusive. We provide an extensive review of differential diagnoses, immunophenotypic hallmarks, what lies beyond the BRAF V600E mutation, and therapeutic approaches. Early recognition of HCL is crucial to avoid delayed optimal therapy and to enhance patient outcomes. This case emphasizes the critical role of morphology and immunophenotyping in confirming HCL, especially in resource-limited countries.
2026-06-12 | Real-world treatment and outcomes in hairy cell leukemia: a multicenter retrospective cohort including BRAF inhibitor therapy.
Hairy cell leukemia (HCL) is a rare B-cell malignancy traditionally treated with purine analogue-based regimens. Although BRAF inhibitors are established in relapsed or refractory disease, their role as first-line therapy remains incompletely defined. We conducted a multicenter retrospective study evaluating real-world treatment of adults with classic HCL. A total of 110 patients were included. First-line therapies were cladribine (64%), cladribine plus rituximab (11%), rituximab (9%), and vemurafenib-based regimens (9%). Overall, response rate to first-line therapy was 80% (complete response rate of 65%). Median overall survival was 24.4 years. Patients treated first-line with vemurafenib-based regimens achieved an overall response rate of 80%, similar to purine analogue-based therapy. Hospitalization rates were similar across treatment groups. Vemurafenib-based therapy and rituximab monotherapy were preferentially used in older patients with greater baseline anemia. This study provides early insight into BRAF inhibitor use in HCL, highlighting encouraging responses in a limited number of patients.
2026-06-08 | Weekly Cladribine Followed by Rituximab for the Treatment of Hairy Cell Leukemia.
Hairy cell leukemia (HCL) is an uncommon hematopoietic stem cell disease known to have an underlying somatic BRAFV600E driver mutation. Currently, the most accepted treatment is five or seven consecutive days of outpatient infusion of cladribine (e.g., continuous infusion), despite frequent antibiotic use and hospitalization with this regimen. As a result, a few investigators have adopted weekly infusion of cladribine with similar or improved results and fewer side effects. We conducted a retrospective, single-institution cohort study of 36 treatment-naïve patients with HCL treated at the University of Colorado Hospital. Eighteen patients received intermittent weekly cladribine (intermittent cladribine [IC]) for 5-7 doses and 18 received standard daily cladribine (continuous cladribine [CC]) over 5-7 days. We report clinical cohort characteristics, response rates, progression-free survival, overall survival, toxicity, hospitalization rates, and measurable residual disease monitoring in select patients using peripheral blood quantitative BRAFV600E PCR. We report here our experience with 18 patients with newly diagnosed BRAF-mutated HCL treated with weekly cladribine at a single institution compared to 18 HCL patients who received continuous infusions. Baseline hematologic parameters and overall survival were comparable between groups (p = 0.1135), but there was a higher rate of complete remission for patients treated with IC (94.4% vs. 61.1%) with significantly improved progression-free survival (p < 0.0001). We observed comparable rates of neutropenia, neutropenic fever, antibiotic use, and G-CSF administration. There were fewer hospitalizations for patients treated with IC (4/18) compared to patients treated with CC (6/18). Rituximab exposure differed between groups, with 72% of patients in the IC cohort receiving rituximab compared with 27.2% in the CC cohort (although treatment status was documented for only 66.7% of patients in the CC cohort). Peripheral blood BRAFV600E allele burden significantly declined and correlated with clinical remission, but this was only performed in select patients who were treated in recent years. In this retrospective analysis, IC dosed weekly was associated with improved progression-free survival and higher rates of complete remission compared to CC with comparable toxicity and fewer hospitalizations. These findings suggest a potential clinical benefit from this regimen. However, interpretation of these findings is limited by the non-randomized design and differences in rituximab exposure between groups, which may have contributed to the observed outcomes and limited definitive conclusions. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.
2026-05-27 | DUSP1 is a Key Driver of Disease Persistence and Potential Therapeutic Target in Hairy Cell Leukemia.
Classic hairy cell leukemia (HCL) is a rare indolent B cell lymphoproliferative disorder characterized by the driver mutation BRAF V600E. Standard treatment with purine analogs (i.e. cladribine) induces long-term remissions, but up to 25% of patients relapse early. Even when targeting BRAF V600E, residual HCL cells frequently persist in the bone marrow (BM). To unravel additional biologic alterations contributing to HCL disease persistence, we performed single-cell RNA sequencing in sorted primary HCL cells from long-term versus short-term cladribine responders (LT-R versus ST-R: >10 versus ≤3 years PFS) at diagnosis and in ST-R at diagnosis versus relapses. We identified a distinct HCL subcluster characterized by elevated DUSP1, FOS, and JUND expression, which was detected in all patients and persisted or even expanded at relapses. Cancer pathway analysis suggested enhanced tumor microenvironment dependency as reflected by suppression of the p38-MAP kinase pathway. In the absence of a suitable BRAF V600E-mutated HCL cell line, we validated HAIR-M cells (BRAF D594E) as a bona fide experimental HCL model. The activating BRAF D594E mutation mimics V600E-induced downstream signals that can efficiently be targeted by BRAF inhibitors (BRAFi). HAIR-M co-culture with BM stromal cells (BMSC) strongly induced DUSP1 that was accompanied by protection from BRAFi-induced HAIR-M apoptosis. The functional importance of DUSP1 was corroborated by demonstrating that BMSC-induced protection from cell death could be overcome through DUSP1 inhibition. Our results might set the stage for future clinical testing of DUSP1 inhibition to eliminate minimal residual disease (MRD) and prevent disease relapse in HCL.
2026-04-14 | Updated consensus guidelines for the diagnosis and management of patients with HCL and HCL variant.
Hairy cell leukemia (HCL) and HCL variant (HCLv) are distinct, rare, and chronic splenic B-cell lymphomas/leukemias that partially overlap in clinicopathologic presentation but differ in genetic basis, prognosis, and management. HCL is caused by the BRAF-V600E kinase-activating mutation in >95% of the patients, usually has excellent responses to chemotherapy with purine analogues, and is also amenable to BRAF inhibitor-based targeted treatments. In contrast, HCLv lacks BRAFV600E mutation, requires combined therapy with purine analogues in addition to rituximab, and generally shows less durable responses. Here, an international team of hematologists, experts on these rare diseases, was convened by the Hairy Cell Leukemia Foundation to update the previous guidelines (published in 2017) by providing a summary of current methods to diagnose and manage patients with HCL and HCLv as well as a prospective on newer targeted therapies to further improve outcomes.
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Drug Discovery Landscape
7 orphan drug designations for Classic hairy cell leukemia, including 3 approved therapies.
7 orphan drug designations for Classic hairy cell leukemia, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
vemurafenib | small molecules | FDA | 2014-08-26 | — | Genentech, Inc. |
Moxetumomab pasudotox [Lumoxiti] | proteins | EMA | 2008-12-05 | — | AstraZeneca AB |
blinatumomab | proteins | FDA | 2008-05-16 | — | Amgen, Inc. |
moxetumomab pasudotox-tdfk [LUMOXITI] | proteins | FDA | 2007-11-15 | 2018-09-13 | AstraZeneca Pharmaceuticals LP |
Cladribine [Leustatin Injection] | small molecules | FDA | 1990-11-15 | 1993-02-26 | R. W. Johnson Pharmaceutical Research Institute |
Granulocyte macrophage-colony stimulating factor | proteins | FDA | 1990-05-03 | — | Schering Corporation |
pentostatin for injection [Nipent] | small molecules | FDA | 1987-09-10 | 1991-10-11 | SuperGen, Inc. |
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