Guidelines Summary
The following organizations have released guidelines for the management of hairy cell leukemia (HCL):
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National Comprehensive Cancer Network (NCCN) [15]
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European Society for Medical Oncology (ESMO) [16]
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Hairy Cell Leukemia Foundation (HCLF) [17]
In 2021, the Hairy Cell Leukemia Foundation (HCLF) released updated guidelines for the diagnosis and management with classic HCL during the COVID-19 pandemic. [40]
Diagnosis
According to NCCN guidelines, an essential aspect of HCL diagnosis is the finding of characteristic hairy cells on morphologic examination of peripheral blood or bone marrow, and characteristic infiltrate with increased reticulin in bone marrow biopsy samples. In addition, adequate immunophenotyping is essential for establishing the diagnosis and distinguishing between classic HCL and HCL variant. [15] Immunohistochemistry (IHC) or flow cytometry must be done for CD19, CD20, CD5, CD10, CD11c, CD22, CD25, CD103, CD123, cyclin D1, and CD200.
The typical immunophenotype for classic HCL is CD5-, CD10-, CD11c+, CD20+ (bright), CD22+, CD25+, CD103+, CD123+, cyclin D1+, annexin A1+, and CD200+ (bright); monocytopenia is characteristic. In contrast, the HCL variant is typically CD25-, CD123-, annexin A1-, and negative for BRAF V600E mutations. [15]
Under certain circumstances, the following tests may also be useful:
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Molecular analysis to detect IGHV4-34 rearrangement
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IHC or molecular analysis for BRAF V600E mutation, in cases that do not have the classic HCL immunophenotype.
ESMO and HCLF recommendations concur with the above NCCN recommendations. [16, 17]
Prognostic Factors
Although no international prognostic system for risk stratification of HCL has been developed, ESMO guidelines consider the following clinical variables to indicate an adverse prognosis [16] :
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Severe cytopenias (hemoglobin [Hgb] < 10 g/dL, platelets < 100 × 10 9/L, neutrophils < 1 ×10 9/L )
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Lymphadenopathy
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Presence of TP53 mutations and lack of somatic mutations in the IGVH genes
In addition, the ESMO guidelines note that patients who achieve a complete response (CR) have a significantly longer disease-free survival than those who achieve a partial response. [16]
Treatment
NCCN guidelines recommend observation in the absence of the following clinical signs [15] :
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Systematic symptoms
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Splenic discomfort
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Recurrent infection
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Hgb < 12g/dL
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Platelets < 100,000/μL
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Absolute neutrophil count (ANC) < 1000/μL
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Progressive lymphocytosis or lymphadenopathy
If clinical indications are present, initial first-line treatments are the purine analogues cladribine or pentostatin. For patients unable to tolerate purine analogues, combined vemurafenib and obinutuzumab is recommended. [15]
ESMO concurs with the NCCN recommendations, but includes an additional recommendation of interferon alfa for pregnant patients or those with very severe neutropenia. [16]
The updated HCLF guidelines note that because treatment with a purine analogue–based regimen may be associated with prolonged granulocytopenia, which increases risk for a severe course of COVID-19, off-label treatment may be considered in patients with HCL who have pancytopenia and an active uncontrolled infection.In conjunction with appropriate antibiotics or antifungal or antiviral agents, the HCLF suggests the following [40] :
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A BRAF inhibitor (eg, vemurafenib), in patients with classic HCL that harbors a BRAF V600E mutation
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The combination of a BRAF inhibitor with either a monoclonal anti-CD20 antibody (eg, rituximab) or a MEK inhibitor (eg, trametinib) can further increase the rate of durable remissions without inducing severe myelosuppression
NCCN defines CR to treatment as the following [15] :
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Near normalization of peripheral blood counts
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Absence of HCL cells on both bone marrow biopsy and peripheral blood samples
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Regression of splenomegaly by physical exam
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Hgb >11g/dL (without transfusion)
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Platelets >100,000/μL
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ANC >1500/μL
For patients who do not achieve CR or who relapse less than 24 months after achieving CR, NCCN prefers the following treatment options [15] :
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Enrollment in appropriate clinical trial
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Alternate purine analogue with rituximab
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Vemurafenib with or without rituximab
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Rituximab monotherapy, if the patient is unable to receive purine analogues
For patients who relapse more than 24 months after achieving CR, NCCN recommends the following treatment options [15] :
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Re-treat with the initial purine analogue plus rituximab
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Alternate purine analogue plus rituximab
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Rituximab monotherapy, if the patient is unable to receive purine analogues
For progressing disease that is not responsive to purine analogue therapy, NCCN prefers the following [15] :
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Enrollment in a clinical trial
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Vemurafenib with or without rituximab
Overall, ESMO guidelines are in agreement with NCCN, but include the following additional recommendations for treatment of refractory disease [16] :
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Splenectomy may be indicated in patients with symptomatic splenomegaly (>10 cm below the costal margin) and low-level bone marrow infiltration
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Allogeneic hematopoietic stem cell transplantation
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Fludarabine with rituximab
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Bendamustine with rituximab
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Blood film at × 400 magnification. This image demonstrates a lymphocytosis and an absence of any other type of blood cell (pancytopenia). The characteristic cytoplasmic projections are already visible. Photographed by U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Blood film at × 1000 magnification. This image demonstrates lymphocytes with characteristic cytoplasmic projections. Photographed by U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Blood film at × 1000 magnification. This image demonstrates tartrate-resistant acid phosphatase (TRAP) activity of lymphocytes. Photographed by U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
