Introduction:

Discussion:

The description of hairy cell leukemia as a specific clinical entity was published 50 years ago. The clinical outcome for patients was hampered by ineffective chemotherapy, and splenectomy was the major therapeutic approach to improve peripheral blood counts. The median survival after diagnosis was 4 years. The use of α-interferon in 1984 and using it for HCL in 1986 led to significant improvements in patient outcomes ⁶. Following this, the development of purine nucleoside analogs turned hairy cell leukemia (HCL) into a highly manageable form of leukemia.⁷ Today, patients with the classic form of this rare leukemia can expect a nearly normal lifespan.⁸ However, accurate diagnosis is crucial because other conditions that resemble HCL do not respond to these treatments.⁷ In classic HCL, Leukemic cells express CD22, CD20, CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A (Anxa1), and BRAF V600E mutation. HCL variations that do not have CD25, Anxa1, TRAP, and BRAF V600E, are more aggressive and less purine analog-sensitive.⁹

BRAF is a serine/threonine kinase with a regulatory role in the mitogen-activated protein kinase (MAPK) signaling pathway. A mutation in the RAF gene, especially in BRAF protein, leads to an increased stimulation of this cascade. This causes uncontrolled cell division and development of malignancy. BRAF V600E mutation is present in almost all classic HCL patients.¹⁰ This mutation is not found in HCL-variant (HCL-v) or IGHV4-34 variants of HCL ¹¹. These findings solidify the BRAF V600E mutation as a molecular hallmark of classic HCL. In BRAF V600E–negative HCL cases, two novel mutations in exon 11 of the BRAF gene have been identified ¹², prompting recommendations to screen exon 11 in such cases. Additionally, the BRAF mutation has been detected in hematopoietic stem cells of patients with HCL ¹³.

The treatment of BRAF-negative HCL can be more challenging compared to BRAF V600E–positive classic HCL. These cases often do not respond to BRAF inhibitors like vemurafenib which have shown good efficacy in treating relapsing diseases¹⁴ . The purine analogs pentostatin (2'-deoxycoformycin, 2'-DCF) and cladribine (2-chlorodeoxyadenosine, 2-CdA) are naturally targeted to lymphocytes and are cytotoxic to both resting and dividing cells. Both drugs induce durable complete remissions (CR) in the overwhelming majority of patients with HCL¹⁵ but the BRAF negative HCLs have shown poor sensitivity to these agents.¹⁶ However, several therapeutic options are available for managing BRAF-negative HCL :

• Rituximab, either alone or in combination with purine analogs, has shown efficacy in BRAF-negative HCL, particularly in relapsed or refractory cases¹⁷.
• While Vemurafenib and BRAF Inhibitors are not effective in BRAF-negative HCL, some cases with alternative BRAF mutations (e.g., in exon 11) may still benefit from targeted therapy. Screening for non-V600E BRAF mutations is recommended in these cases.¹⁸
• Moxetumomab Pasudotox is an anti-CD22 immunotoxin that has been approved for relapsed or refractory HCL, including BRAF-negative cases. It has shown promising results in achieving durable responses.¹⁹
• For refractory or difficult-to-treat cases, participation in clinical trials exploring novel agents, such as BTK inhibitors or MEK inhibitors, may be considered.²⁰
• In rare cases where systemic therapy is not feasible, splenectomy may be considered to alleviate symptoms related to splenomegaly a report has shown that Splenectomy followed by administration of rituximab is useful to treat a patient with hairy cell leukemia-variant.²¹
• There is Support for cladribine plus rituximab comes from small prospective studies that report complete remission rates (CR) of at least 90 percent in HCLv.²² The favorable response of some cases of BRAF-negative HCL to Cladribine may be attributed to its mechanism of action. Cladribine incorporates into DNA, causing strand breaks and apoptosis, regardless of BRAF mutation status.²³ Cladribine's selective cytotoxicity targets malignant B-cells by interfering with DNA replication and repair, and it also depletes CD4+ T-cells, which may alter the tumor microenvironment. These explain the observed efficacy in some BRAF-negative cases.²⁴

In this instance, we suspected HCL due to the lack of response to standard chemotherapy regimens for CLL.  The diagnosis of hairy cell leukemia (HCL) was established through the identification of LCA, CD20, CD25, and CD103 in bone marrow samples. Additionally, testing for the BRAF V600E mutation yielded negative results, complicating the treatment.

Prior to the availability of BRAF testing results, treatment with Cladribine was initiated due to the diagnosis of HCL and the patient's unstable condition. Given its favorable response in the patient, we opted to pursue the continued use of purine nucleoside analogs (Cladribine), which typically exhibit significant efficacy in classic HCL and limited effectiveness in BRAF-negative variants. This approach unexpectedly resulted in complete remission for the patient. Studies have indicated efficacy of Rituximab and Cladribine combination therapy in HCLvs, therefore prior usage of Rituximab in this patient may have helped unforeseen in this situation.

Covid-19 and HCL: Although the specific cause-and-effect link between SARS-CoV-2 infection and HCL is unknown, COVID-19 is known to produce transient hematologic abnormalities. Anemia, leukopenia, lymphopenia, thrombocytopenia, and anemia can worsen pre-existing cytopenia in patients with hematologic diseases. In this patient, virus-induced cytopenia may have caused severe and persistent pancytopenia before a formal diagnosis, complicating clinical assessment and perhaps delaying HCL diagnosis.⁷ EPICOVIDEHA registry data suggests that HCL patients with COVID-19 may have severe illness courses and blood count changes. So assessing hematologic data in this group of patients, recent infection must be considered.²⁵

Conclusion:

HCL should be considered a differential diagnosis in patients suspected of having CLL that is resistant to standard therapy. Certain BRAF-negative hairy cell leukemias have demonstrated favorable responses to therapy with purine nucleoside analogs (Cladribine), warranting consideration as a therapeutic strategy. Additional investigations and randomized controlled trials are necessary to establish suitable treatment protocols for HCL variations.

Ethics and Consent:

We confirm that the study complies with current ethical standards. No names or personal information is mentioned in the article. Informed consent was obtained from the patient for the use of his clinical data in this publication, and the study was conducted in accordance with the Declaration of Helsinki.