HAIRY CELL LEUKEMIA / ONCOATLAS

Disease classification

Decision principle: Confirm classic HCL versus HCL-like entities before selecting treatment. BRAF V600E often distinguishes classic HCL; BRAF wild-type disease warrants integrated morphology, immunophenotyping and molecular review.

Classic hairy-cell leukemia

Classic HCLBRAF V600E

Indolent mature B-cell neoplasm with characteristic cytopenias, monocytopenia, marrow fibrosis and splenic involvement. >95% of cases harbor BRAF V600E in the 2026 consensus. Patients without symptoms or significant cytopenias may undergo observation.

[R01] [R02]

HCL variant / SBLPN

Distinct entityBRAF WT often

Historically termed HCL-variant. WHO-HAEM5 recognizes splenic B-cell lymphoma/leukemia with prominent nucleoli (SBLPN); the ICC retains HCL-variant terminology. Commonly lacks BRAF V600E, often has leukocytosis, and generally responds less well to purine analogue monotherapy.

[R01] [R02]

Related mimics: SDRPL and SMZL

Differential diagnosis

Splenic diffuse red pulp small B-cell lymphoma and splenic marginal zone lymphoma may resemble HCL morphologically. Distinguish using flow panel, Annexin A1, marrow pattern, and molecular findings; do not transplant classic-HCL outcomes to these entities.

[R01] [R02]

When to treat

ObservationSymptom-directed

Observation is appropriate for selected asymptomatic patients with stable counts. Common triggers include symptoms, progressive cytopenias (Hb <11 g/dL, platelets <100 ×10⁹/L, ANC <1 ×10⁹/L), recurrent infection or symptomatic splenomegaly. Thresholds require clinical judgment.

[R01] [R09]

HAIRY CELL LEUKEMIA / ONCOATLAS

Diagnostic pathway

1 · RecognizeCBC, blood smear (hairy cells), monocytopenia, splenomegaly, infections

2 · Confirm lineage and phenotypeFlow: CD19/CD20/CD22 and HCL score (CD11c, CD25, CD103, CD123)

3 · Characterize tissueBone marrow core, reticulin/fibrosis, Annexin A1, morphology; dry tap possible

4 · Molecularly classifyBRAF V600E sensitive molecular assay ± VE1 IHC; if negative, consider MAP2K1, TP53 and extended genomic testing

5 · Establish management contextSymptoms, Hb/platelets/ANC, infections, prior treatment, organ function and goals

Classic HCL phenotype

Typically CD11c+, CD25+, CD103+, CD123+, Annexin A1+, CD20 bright. The four-marker HCL score is usually 3–4; individual marker exceptions are possible.

[R01] [R02]

Variant phenotype

Usually CD11c+/CD103+ with absent or weak CD25, CD123 and Annexin A1; BRAF V600E is generally absent. Interpretation must combine pathology and molecular data.

[R01] [R02]

HAIRY CELL LEUKEMIA / ONCOATLAS

Molecular & diagnostic biomarkers

BRAF V600E

Classic HCL (>95% per consensus); activates MAPK signaling. Predicts biological rationale for BRAF inhibitors (vemurafenib, dabrafenib); require mutation confirmation.

[R01] [R04] [R05]

MAP2K1 / MEK1

Enriched in BRAF-wild-type HCL-like disease and HCLv/SBLPN; potential MEK inhibitor sensitivity, supported mainly by case-level data, not a validated standard selection rule.

[R01]

IGHV4-34 / unmutated IGHV

Associated with inferior outcomes or biologically atypical BRAF-wild-type cases; not independently sufficient to select first-line treatment.

[R01] [R02]

TP53 mutation / dysfunction

More relevant in HCLv/SBLPN and resistant disease; in a small HCLv CDAR study, TP53 mutations correlated with shorter PFS and OS.

[R07] [R02]

CD11c · CD25 · CD103 · CD123

Four-marker immunophenotypic HCL scoring system. Diagnostic rather than validated drug-response biomarker.

[R01] [R02]

Annexin A1

Usually expressed in classic HCL and generally absent in HCL-like mimics; interpret in full pathological context.

[R01] [R02]

CD20

Rituximab and obinutuzumab target CD20; expression supports targeting but no validated quantitative CD20 response cutoff.

[R03] [R04] [R06]

CD22

Expression supports investigational anti-CD22 CAR T and historically moxetumomab; the latter was commercially discontinued in the U.S.

[R10] [R12]

MRD (flow, IHC, BRAF ddPCR)

Undetectable measurable residual disease strongly associated with durable remission in studies; its use as a mandatory treatment-trigger or universal endpoint remains unsettled.

[R03] [R04] [R07]

CXCR4, BTK / BCR signaling, ROR1

Microenvironmental retention and B-cell signaling pathways; ROR1 is investigational. None is a validated routine selection biomarker for HCL therapy.

[R02] [R08]

HAIRY CELL LEUKEMIA / ONCOATLAS

Treatment pathways

Classic HCL · asymptomatic

Observation

Surveillance with clinical and blood-count monitoring rather than immediate therapy. Treat only when appropriate clinical criteria emerge.

[R01] [R09]

Classic HCL · treatment required

First line

Cladribine or pentostatin backbone; concurrent cladribine + rituximab can achieve deeper MRD-negative remissions in fit patients. Infection risk, organ function and access influence selection.

[R01] [R03] [R09]

Classic HCL · active infection / PNA unsuitable

Individualized

Stabilize infection first; expert-selected BRAF V600E-directed therapy can be used in select patients to improve counts without additional purine-analogue immunosuppression. It is not a universal default.

[R01] [R09]

Classic HCL · relapse

Relapse

Reassess treatment indication, prior remission duration and BRAF status. Later relapse may be suitable for PNA ± rituximab retreatment; earlier or multiply relapsed BRAF-mutant disease can be approached with BRAF + anti-CD20 or BRAF + MEK combinations.

[R01] [R04] [R05]

HCLv / SBLPN · treatment required

Variant disease

Avoid assuming classic HCL responsiveness. Concurrent cladribine + rituximab has prospective phase II evidence. TP53 and MRD may refine prognosis; personalized expert management is essential.

[R01] [R07]

BRAF wild type / resistant relapse

Selected / investigational

Consider molecular profiling, specialized hematology referral and clinical trials. BTK inhibition has phase II activity; MEK inhibitors for MAP2K1-mutated disease, venetoclax and cellular therapy remain investigational or highly individualized.

[R01] [R08] [R10] [R11]

HAIRY CELL LEUKEMIA / ONCOATLAS

Positive clinical trial evidence

Concurrent cladribine + rituximab

Classic HCL · first line

Randomized phase II, n=68: at 6 months, MRD-negative CR 97% vs 24% with cladribine alone before delayed rituximab. CR 100% vs 88% (not statistically significant). Longer follow-up supported MRD durability; OS superiority not established.

[R03]

Vemurafenib + obinutuzumab

Classic HCL · previously untreated

Single-arm study, n=30: 90% CR (27/30); 26/27 complete responders were MRD negative. Median follow-up 34.9 months, no relapses reported. Promising but not randomized standard first-line treatment.

[R06]

Vemurafenib + rituximab

Classic HCL · relapsed / refractory

Single-arm phase II, n=30: 87% CR; 17/26 (65%) of complete responders MRD negative. At median 37-month follow-up, PFS 78%. BRAF V600E-linked strategy.

[R04]

Dabrafenib + trametinib

BRAF V600E classic HCL · relapsed / refractory

Phase II, n=55: 89.0% ORR, 65.5% CR; 24-month PFS 94.4%. Grade ≥3 adverse events and pyrexia need consideration. No randomized head-to-head superiority established.

[R05]

Cladribine + rituximab in HCLv

HCL variant / SBLPN

Prospective phase II, n=20: 95% CR, 80% MRD negative at 6 months; 5-year PFS 63.3%, OS 73.9%. TP53 alterations associated with worse outcomes.

[R07]

Ibrutinib

Classic HCL and HCLv · relapsed / refractory

Phase II, n=37: ORR at 32 weeks 24%, at 48 weeks 36%; best ORR 54% after longer follow-up. Phase II activity, not a biomarker-validated preferred regimen.

[R08]

ORR = overall response rate; CR = complete response; PFS = progression-free survival; OS = overall survival; MRD = measurable residual disease. Cross-trial percentages must not be compared as evidence of superiority.

HAIRY CELL LEUKEMIA / ONCOATLAS

Active research & evidence gaps

CD22-directed CAR T

Phase I / investigational

Phase I anti-CD22 CAR T study NCT04815356 in relapsed/refractory classic or variant HCL. Investigational; safety and efficacy are being defined. No established routine role.

[R10] [R11]

BRAF wild-type / MAP2K1-directed therapy

Trial option

MEK inhibition, including binimetinib studies, is under investigation. MAP2K1 alone does not create a validated routine MEK-treatment indication in HCL.

[R01] [R11]

Alternative targeted approaches

Emerging

BTK inhibitors, BCL2 inhibition, emerging RAF agents and combinations may be relevant in multiply treated cases or trials. Biomarker selection and long-term efficacy remain unsettled.

[R01] [R08] [R11]

CD22 immunotoxin historical context

Commercially discontinued (U.S.)

Moxetumomab pasudotox previously showed clinical activity and was FDA-approved, but U.S. sales ended in August 2023. Do not list as readily available current standard treatment.

[R12]

HAIRY CELL LEUKEMIA / ONCOATLAS

Safety, testing & interpretation

Purine analogue and anti-CD20 safety

Cladribine/pentostatin can cause neutropenia, prolonged T-cell suppression and infection. Rituximab/obinutuzumab introduce infusion and immune risks; consider infection management and HBV screening per applicable protocols.

[R01] [R09]

BRAF / MEK targeted therapy

Monitor skin effects, photosensitivity, fever, ocular/cardiac toxicities, liver abnormalities and drug interactions according to the regimen; adverse-event profile differs by inhibitor.

[R04] [R05] [R06]

Response assessment

Blood counts, spleen findings, marrow morphology and MRD by expert flow/IHC or BRAF-based molecular assays when appropriate. MRD definitions and timepoints vary across trials.

[R01] [R03] [R06]

Precision-oncology guardrails

No single assay is sufficient to diagnose HCL; a BRAF-negative result does not automatically prove variant disease. Drugs discussed here may be off-label or investigational depending on jurisdiction.

[R01] [R02]

HAIRY CELL LEUKEMIA / ONCOATLAS

Original references & guidelines

R01
2026 consensus
Grever et al. Updated consensus guidelines for diagnosis and management of HCL and HCL variant. Blood. 2026;148:31–42.
Original scientific / authoritative source ↗
R02
2026 review
Troussard X, Maître E, Paillassa J. Hairy Cell Leukemia: 2026 Update. Am J Hematol. 2026.
Original scientific / authoritative source ↗
R03
Concurrent CDAR
Chihara D et al. Randomized phase II first-line cladribine with concurrent or delayed rituximab. J Clin Oncol. 2020.
Original scientific / authoritative source ↗
R04
BRAF + CD20 (relapse)
Tiacci E et al. Vemurafenib plus rituximab in refractory/relapsed hairy-cell leukemia. N Engl J Med. 2021.
Original scientific / authoritative source ↗
R05
BRAF + MEK
Kreitman RJ et al. Dabrafenib plus trametinib in relapsed/refractory BRAF V600E-positive HCL. Blood. 2023.
Original scientific / authoritative source ↗
R06
Chemo-free first line
Park JH et al. Vemurafenib and obinutuzumab as frontline therapy for HCL. NEJM Evid. 2024.
Original scientific / authoritative source ↗
R07
HCL-variant CDAR
Kreitman RJ et al. Long-term follow-up of phase II concurrent cladribine/rituximab in HCL variant. Blood. 2021.
Original scientific / authoritative source ↗
R08
BTK inhibition
Rogers KA et al. Phase 2 study of ibrutinib in classic and variant hairy cell leukemia. Blood. 2021.
Original scientific / authoritative source ↗
R09
NCI HCL treatment
National Cancer Institute. Hairy Cell Leukemia Treatment (PDQ), health-professional summary.
Original scientific / authoritative source ↗
R10
CD22 CAR-T trial
ClinicalTrials.gov, NCT04815356. Phase I anti-CD22 CAR T-cells in relapsed/refractory HCL and HCL-variant.
Original scientific / authoritative source ↗
R11
Trials listing
National Cancer Institute. Current treatment clinical trials for HCL; trial availability changes.
Original scientific / authoritative source ↗
R12
Historical CD22 drug
NCI: moxetumomab pasudotox U.S. commercial discontinuation in August 2023.
Original scientific / authoritative source ↗