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:
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.
2026-04-24 | 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.
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.
2026-04-24 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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