Hairy cell leukemia (HCL) is among the most treatable chronic B-cell malignancies, and many patients remain in remission for years after a single course of treatment. Relapse still occurs, and a small proportion of patients have aggressive disease, unusual molecular features, or contraindications to purine analogues (Troussard et al., 2026).
Adding rituximab to cladribine now deepens first-line responses, and BRAF inhibitors have made chemotherapy-free treatment possible in relapsed or refractory disease. The effect of deeper measurable residual disease responses on long-term outcomes remains unresolved, as do treatment sequencing and the management of HCL variant and splenic diffuse red pulp lymphoma.
Presentation and Classification
HCL is a rare mature B-cell malignancy, accounting for less than 2% of leukemias. It is four to five times more common in men, with a median age at diagnosis of about 60 years. It involves the marrow, blood, and spleen, causing splenomegaly, anemia, neutropenia, thrombocytopenia, and monocytopenia. Presentation is with fatigue, recurrent infections, or splenic symptoms, and a growing share of cases are found incidentally.
HCL impairs both the number and function of immune cells. Bacterial, viral, fungal, and opportunistic infections occur, including disseminated mycobacterial disease, which can be life-threatening. The course is generally indolent, with worse outcomes in high disease burden, adverse molecular features, or early relapse.
The term has historically covered several lymphoid malignancies with circulating cells bearing cytoplasmic projections. The fifth edition of the WHO classification lists:
- classic HCL
- splenic marginal zone lymphoma
- splenic lymphoma with prominent nucleolus
- splenic diffuse red pulp lymphoma
Splenic lymphoma with prominent nucleolus includes cases formerly called HCL variant and some CD5-negative B-cell prolymphocytic leukemia. The ICC keeps HCL variant as its own entity for its clinical significance. The distinction determines treatment. Classic HCL responds well to purine analogues and usually carries BRAF V600E. HCL variant is usually BRAF V600E-negative and follows a more aggressive course.
Diagnostic Workup
Diagnosis integrates blood morphology, flow cytometry, marrow histology, and molecular testing. Most patients have at least one cytopenia, and monocytopenia is characteristic of active classic HCL. Circulating hairy cells can be scarce, so blood morphology alone is insufficient. Marrow reticulin fibrosis often produces a dry tap, and trephine biopsy typically shows widely spaced lymphoid cells in a fried-egg pattern.
Classic HCL expresses CD19, CD20, and CD22 together with CD11c, CD25, CD103, and CD123. The HCL immunophenotypic score, based on the last four markers, is usually 3 or 4. In a large immunohistochemical study, Annexin A1 was positive in 97% of classic cases and absent in the other chronic B-cell lymphoproliferative disorders evaluated. Rare exceptions occur, and the marker is most useful for separating classic HCL from HCL-like malignancies.
BRAF V600E is present in about 90%-100% of classic cases, depending on population and method, and constitutively activates the MAPK pathway. A negative result doesn’t exclude classic HCL. Rare cases carry other BRAF mutations, deletions, or MAPK-pathway alterations that can change sensitivity to BRAF inhibitors: one patient with a BRAF K601T mutation did not respond to vemurafenib, and another with a BRAF deletion responded to dabrafenib plus trametinib. Comprehensive molecular testing is needed when the clinical and immunophenotypic picture fits HCL but BRAF V600E is negative.
Molecular Biology and Microenvironment
BRAF V600E is the principal driver of classic HCL but doesn’t explain the full disease. CDKN1B, KLF2, and KMT2C are among the more frequently altered genes, and TP53 mutations occur in fewer than 5% of classic cases. Introducing BRAF V600E into hematopoietic stem cells doesn’t consistently reproduce the HCL phenotype, which indicates that additional events or cellular interactions are required.
HCL cells depend on the marrow and splenic microenvironment. Adhesion molecules and chemokine receptors, notably CXCR4, anchor malignant cells to stroma, promoting survival and reducing treatment sensitivity. Bone marrow stromal cells reduced apoptosis induced by BRAF inhibitors in experimental studies, which could explain why targeted treatment doesn’t always eradicate residual disease. B-cell receptor signaling (including BTK), NF-κB, and AKT/mTOR are also activated, supporting the use of BTK inhibitors and other targeted agents in relapse.
Risk Stratification
No molecular risk classification is established to guide initial treatment. Worse outcomes are associated with substantial splenomegaly, leukocytosis, high circulating hairy cell counts, elevated beta-2 microglobulin and lactate dehydrogenase, and unmutated immunoglobulin heavy-chain variable region genes.
The IGHV4-34 subgroup carries higher disease burden, shorter survival, and poorer responses to standard therapy. Many of these patients lack BRAF V600E and share biology with HCL variant. TP53 alterations are uncommon in classic HCL, more frequent in HCL variant, and adverse. TP53 testing is recommended in patients resistant to purine analogues. Most proposed prognostic factors haven’t been independently validated, so interpretation should be individualized.
When to Treat
About 10% of patients can be observed, sometimes for several years. Treatment is generally recommended for symptomatic disease, progressive cytopenias, or clinically significant splenomegaly. Common thresholds are hemoglobin below 11 g/dL, platelets below 100,000/µL, or absolute neutrophil count below 1,000/µL. Observational evidence supports the safety of surveillance in selected patients with stable counts and no symptoms, which matters because treatment-related immunosuppression can be substantial.
First-Line Treatment
Cladribine and pentostatin have been the foundation of HCL treatment for decades. Both produce high response rates and prolonged remissions, and no randomized trial has shown one to be superior. Both cause myelosuppression and prolonged immune suppression.
Cladribine Plus Rituximab
A phase II study of 139 patients (untreated and relapsed classic HCL and HCL variant) tested cladribine followed by rituximab. The complete response rate was 97%, 77% had undetectable MRD, and 10-year event-free survival and overall survival were 86.7% and 91.1%.
A randomized phase II study compared concurrent cladribine and rituximab with cladribine followed by delayed rituximab. At six months, CR rates were 100% versus 88%, and undetectable MRD was 97% versus 24%. At a median follow-up of 96 months, 94% of the concurrent group remained MRD-negative, versus 12% of the delayed group. Early rituximab therefore deepens and sustains molecular remission.
Concurrent cladribine plus rituximab is preferred for symptomatic patients fit for chemoimmunotherapy. This is an expert recommendation based on phase II data, and selection still has to weigh infection risk, comorbidities, and the chance of a long remission with purine analogue monotherapy.
Chemotherapy-Free Option
In a phase II study of vemurafenib plus obinutuzumab in 30 untreated patients, 27 achieved CR, and 26 of them had undetectable MRD by flow cytometry and immunohistochemistry. At a median follow-up of about 35 months, progression-free survival and overall survival were both 97%. The study was small and lacked a randomized comparator, and the combination isn’t recommended as routine first-line therapy.
Active Infection and Purine Analogue Contraindications
Purine analogues can deepen immune suppression before counts recover, so active infection should be controlled first. In selected BRAF V600E-mutated patients, short-term vemurafenib can bridge this period because it raises neutrophil counts relatively quickly. Interferon is an alternative in older or frail patients. Significant renal impairment, at specified clearance thresholds, is a contraindication to purine analogues. Treatment is individualized by molecular status, organ function, infection severity, and anticipated toxicity.
Relapsed Disease
Relapse doesn’t always require immediate treatment. Patients are reassessed to confirm recurrence and check whether treatment criteria are met. Remission duration then guides the choice.
After a remission longer than about two to five years, retreatment with cladribine plus rituximab is favored. Small studies report high CR rates and durable control, particularly in patients with prior purine analogue monotherapy and no rituximab exposure. Cumulative immunosuppression and infection risk limit repeated courses. After earlier relapse or inadequate initial response, treatment shifts to a different mechanism, with vemurafenib plus rituximab favored in BRAF V600E-positive disease.
BRAF and MEK Inhibitors
Vemurafenib monotherapy produces rapid responses but frequent relapse after discontinuation. In 36 patients with relapsed or refractory disease, the overall response rate was 86%, about two-thirds of responders relapsed, and median relapse-free survival was 19 months.
Vemurafenib Plus Rituximab
In a phase II trial of 30 relapsed or refractory patients, CR was 87%, and 65% of complete responders had undetectable MRD. Real-world data from 54 patients showed CR in 86% of evaluable patients and two-year PFS of 90%. The course is short and chemotherapy-free. Monitoring is needed for dermatologic toxicity, photosensitivity, arthralgia, and ocular complications.
Dabrafenib Plus Trametinib
Combined BRAF and MEK inhibition produced an overall response rate of 89%, CR in 65.5%, and two-year PFS of about 94%. Few patients reached undetectable MRD. Grade 3 or higher adverse events occurred in 63.6%, including pyrexia, pneumonia, hyperglycemia, and neutropenia, so tolerability may be limiting in patients with substantial comorbidities.
After Multiple Relapses
Repeated purine analogue exposure loses appeal as remissions shorten and toxicity accumulates. From third-line treatment onward, BTK or BCL-2 inhibition is favored, with or without rituximab, particularly when BRAF-directed options are unsuitable or exhausted.
In a phase II study of 37 patients with classic HCL or HCL variant, ibrutinib produced an overall response rate of 54% at any time during follow-up, with three-year PFS of 73% and overall survival of 85%. Zanubrutinib has shown activity in a small relapsed or refractory cohort. Response rates appear lower than with several BRAF-directed combinations, though small populations and study differences limit comparison.
BCL-2 is overexpressed in HCL cells. In six heavily pretreated patients, venetoclax produced responses in three, including two CRs with detectable residual disease, and further responses followed rituximab in selected patients. Stromal interactions reduce venetoclax-induced cell death experimentally, so future combinations may need to target microenvironment-mediated resistance as well.
HCL Variant
HCL variant presents with more pronounced lymphocytosis and splenomegaly, and circulating cells have prominent nucleoli. CD25, CD123, and Annexin A1 are frequently absent. Most cases lack BRAF V600E, which limits BRAF-directed therapy, and MAP2K1 and TP53 alterations are more common.
Cladribine plus rituximab is preferred first line. In a phase II study of 20 patients, eight untreated, CR was 90% and undetectable MRD 80%. Five-year PFS was 63.3% and overall survival 74%. Patients with TP53 mutations had significantly poorer outcomes despite deep initial responses.
Relapse options include MEK inhibitors for susceptible MAP2K1 mutations, BTK inhibitors, and bendamustine or pentostatin with rituximab. A randomized phase II study of pentostatin plus rituximab versus bendamustine plus rituximab in HCL and HCL variant found activity with both in the small HCL variant subgroup. Rarity and molecular heterogeneity prevent identification of a single preferred sequence.
Splenic Diffuse Red Pulp Lymphoma
This entity can resemble HCL, with splenomegaly, circulating villous lymphocytes, and diffuse red pulp infiltration. BRAF V600E is generally absent. Recurrent alterations include CCND3 and BCOR, with incompletely defined significance.
Asymptomatic patients can be observed. In symptomatic disease, splenectomy is an important first-line option and can control disease for a prolonged period. Patients unsuitable for surgery may receive rituximab alone or with chemotherapy. CCND3 alterations raise interest in cell-cycle inhibitors, but clinical evidence is insufficient.
Does a Deeper Response Improve Outcomes?
MRD can be assessed by multiparameter flow cytometry, immunohistochemistry, or molecular methods targeting BRAF V600E. Several studies link undetectable MRD to longer remission, including the vemurafenib plus rituximab studies. The association isn’t uniform: in the long-term cladribine followed by rituximab study, MRD status was not significantly associated with event-free or overall survival.
A deeper laboratory response has not been shown to improve outcomes that matter to patients. Routine MRD testing is most useful in trials and selected relapsed cases. In older or frail patients, normalized counts and resolution of splenomegaly may suffice without repeated marrow assessments. Standardized methods, reporting thresholds, and interpretation are needed.
Second Malignancies
Evidence suggests increased second malignancies in HCL, particularly hematologic cancers. Reported cumulative incidence ranges from about 5% to 32%, reflecting differences in follow-up and study populations. Disease-related immune dysfunction, prior treatment, and patient factors may contribute, and repeated purine analogue courses are a candidate because of prolonged immune suppression.
Observational studies can’t separate treatment effects from those of the malignancy, and a clear excess risk of acute myeloid leukemia hasn’t been established. Follow-up should cover second cancers, persistent immune dysfunction, and treatment complications alongside relapse.
Emerging Therapies
Early experience with anti-CD22 CAR T cells in four patients with HCL or HCL variant was heterogeneous: one reached an MRD-negative CR nine months after infusion, and another died of severe treatment-related complications. Bispecific antibodies, including mosunetuzumab, are under exploration. ROR1, a surface protein expressed in several B-cell malignancies including HCL, is a candidate target for antibodies, antibody-drug conjugates, and cellular therapies.
Allogeneic transplantation remains an option for highly selected, heavily pretreated patients. In a series of 22 patients with HCL or HCL variant, non-relapse mortality was 26%.
Priorities for Future Research
It is unclear whether deeper first-line responses yield long-term benefit large enough to justify added treatment exposure for all eligible patients, and the optimal sequence of BRAF-directed therapy, BTK inhibition, and BCL-2 inhibition after relapse is undefined. Progress in HCL variant and splenic diffuse red pulp lymphoma depends on multicenter collaboration. Standardized MRD assessment, broader trial participation, and real-world registries are also needed.
In a study of 165 patients, quality of life varied with disease status, with the greatest impairment in newly diagnosed patients and better outcomes in remission. Symptom burden and quality of life should be included in treatment evaluation alongside remission rates and survival.
Source: Troussard X, Maître E, Paillassa J. Hairy Cell Leukemia: 2026 Update on Diagnosis, Risk-Stratification, and Treatment. American Journal of Hematology. Published September 15, 2026. DOI: 10.1002/ajh.70441.
Adult ALL Treatment in 2026: Promising Advances and Remaining Challenges
