Selecting appropriate therapy for hairy cell leukemia: current state and future prospects based on molecularly defined characterization

KEYWORDS:

• Hairy cell leukemia
• genomic subtype
• purine analog
• anti-CD20 agent
• BRAF V600E inhibitor
• moxetumomab pasudotox

1. Clinico-epidemiologic data and genomic alterations in HCL

Hairy cell leukemia (HCL) represents a heterogeneous group of mature, indolent B-cell lymphoproliferative disorders accounting for approximately 2% of all leukemias [1,2]. The median age of patients at diagnosis is 63, with HCL displaying a male predominance (M/F ratio 4:1). Caucasians are affected more than other ethnic groups. Annual incidence is approximately 3/1,000,000 worldwide [1]. Almost invariably, clinical presentation is dominated by splenomegaly and cytopenias, eventually leading to early satiety, fatigue, frequent infections, and/or increased bleeding risk. Pancytopenia is present in nearly half of patients, while 40% display a combination of two different cytopenias [1,2]. Bone marrow failure with or without fibrosis and hypersplenism are important mechanisms underlying cytopenias [2]. In recent years, massive splenomegaly has become less prevalent, perhaps owing to earlier diagnosis.

Post-germinal center memory B-cells and/or splenic marginal zone B-cells are believed to be the cells of origin of HCL [3,4]. Two clinico-laboratory subtypes have long been identified – the more common, classic HCL, and the less common, HCL variant (HCLv). Today, several molecular subtypes are recognized, each displaying a distinct clinical course and ability to respond to therapy [5]. Flow cytometry and bone marrow immunohistochemistry are used to establish the HCL diagnosis and help differentiate between the existing subtypes. B-cells in HCL express strongly CD22, CD20, CD103, and CD11c. Classic HCL B-cells are also positive for CD25, tartrate-resistant acid phosphatase (TRAP), annexin 1A, and CD72 [1]. In addition, at least 85% of classic HCL cases express BRAF V600E mutation. Approximately 80% patients with classic HCL achieve complete clinico-laboratory remissions with single-agent purine analog therapy [3]. HCLv, on the other hand, lacks expression of CD25, TRAP, annexin 1A, and BRAF V600E mutation. This subtype is clinically more aggressive and less sensitive to purine analogs [1,3]. Typically, these patients present with monoclonal lymphocytosis and less severe cytopenias than classic HCL patients. Some investigators believe that HCLv is more prevalent than previously thought, and affects nearly 40% of HCL as opposed to the previously estimated 10–20% [6].

More recently, a molecularly distinct variant of HCL expressing an unmutated immunoglobulin rearrangement (IGHV4-34+) has been described in the literature [7,8]. This variant has a similar immunophenotype to either HCL or HCLv, but characteristically lacks the BRAF V600E mutation. Even patients with ‘bright’ CD25 expression display clinical features similar to HCLv, including malignant lymphocytosis, massive splenomegaly, nodal disease, and a poorer response to purine analogs [1,8]. In one series, unmutated IGHV4-34 was detected in 10% of classic HCL and 40% of patients with HCLv [8]. Furthermore, nearly half of the patients with IGHV4–34+ HCL and HCLv harbor MAP2K1 (MEK) mutations [9,10]. New genetic and molecular alterations are constantly being discovered in HCL and could become drug targets in the near future [4].

2. Indications for treatment and response evaluation

Symptomatic splenomegaly and increased frequency of infections are indications for treatment of HCL. Treatment should also be considered when hemoglobin drops below 10 g/dL; platelet count falls below 100,000 × 10⁶/L; or absolute neutrophil count reaches 1 × 10⁶/L [1,4]. Malignant lymphocytosis of more than 5–20 × 10⁶/L and enlarging lymphadenopathies are indications for treatment in patients with HCLv and rare patients with classic HCL following splenectomy as they typically lack cytopenias [1].

Before labeling a patient with relapsed disease, clinicians must know that prolonged cytopenias often represent side effects of purine analog therapy. A bone marrow exam might not reflect treatment response and still show significant HCL involvement at 4–12 weeks after treatment. Therefore, optimal timing for restaging bone marrow exams is between 16 and 24 weeks after therapy completion [1]. A complete response is defined by resolution of symptoms, splenomegaly, cytopenias, and elimination of hairy cells from peripheral blood and bone marrow [11]. While minimal residual disease (MRD) is not uncommonly detected via flow cytometry of blood and bone marrow specimens, its association with a shorter disease-free survival remains to be proven [12].

3. Expert opinion

Cladribine (2-chlorodeoxyadenosine) is our preferred first-line agent as it leads to complete hematologic responses in approximately 80% patients after only one treatment course [1,4,13,14]. At our center, we rarely use pentostatin (2-deoxycoformycin) as it requires more than one cycle of therapy. We favor treating HCL patients within several weeks of diagnosis as they are at risk for splenic rupture, irreversible liver damage, potentially fatal infections, and marrow failure. We employ expectant management only in the frail old patients and in those with severe comorbidities. We advocate interferon-alpha only in the setting of pregnancy or a prolonged/latent infection.

Nonetheless, prolonged myelosuppression and multiple immune defects have been attributed to purine analogs [3]. While NK cells, monocytes, and neutrophils recover relatively quickly after responses are achieved with these agents, significant CD4⁺ T-cell count reductions can last more than 3 years [3,15]. Increased incidence of second solid and hematologic cancers in HCL patients treated with purine analogs has been documented in several large retrospective epidemiologic studies [2,13,16,17]. Stem cell damage and resulting acquired immune defects due to these agents may play a role in subsequent carcinogenesis [2]. These important findings must be carefully considered before entertaining retreatment with a purine analog.

Rituximab is a chimeric murine/human monoclonal antibody that kills CD20⁺ HCL cells via apoptosis and antibody-dependent cytotoxicity. This agent can be used either concurrently or 4 weeks after administration of a purine analog, with similar clinical results. A total of eight weekly rituximab cycles are utilized in this setting. Five-year disease-free survival and overall survival (OS) in HCL were 94.8% and 96.8%, respectively [1]. Preliminary data suggest that adding rituximab to cladribine improves the durability of responses in HCL due to probable MRD eradication [18–20] and represents the preferred first-line approach at our center. We prefer sequential use of rituximab as our experience shows that cytopenias tend to be more prolonged and severe with concurrent use. Rituximab in combination with the nucleoside analog bendamustine was also shown to be effective in both first- and second-line therapy, with absent MRD in a small HCL patent series and case reports [1]. The humanized type II anti-CD20 monoclonal antibody obinutuzumab has also shown efficacy in combination with nucleoside analogs [21]. Obtaining hepatitis B serology before starting an anti-CD20 antibody (and offering hepatitis B prophylaxis to the patients at risk for reactivation) is paramount. We recommend the 23-valent polysaccharide pneumococcal pneumonia vaccination 2 weeks prior to the first-line therapy and every 5 years thereafter. Ideally, COVID-19 vaccination series would also be completed prior to cladribine-rituximab, in an attempt to prevent a severe COVID-19 infection.

Cladribine with sequential rituximab is our preferred first-line combination in patients with HCLv or HCL with IGHV4-34 + . We treat these patients as soon as the diagnosis is confirmed as they represent subsets with suboptimal response to conventional therapy and worse clinical outcomes [9,10].

The CD22 antigen is frequently expressed in HCL cells and represents an effective therapeutic target. In 2018, the U.S. FDA approved the anti-CD22 recombinant antibody–drug conjugate moxetumomab pasudotox for relapsed HCL as it showed a complete hematologic response rate of 80%, with an MRD negativity rate of 33.8%, in this setting [4,13]. Nonetheless, infusion reactions are not uncommon, and the treated patients bear a 5% and 7.5% risk for capillary leak syndrome and thrombotic microangiopathy, respectively [4].

Activation of BRAF V600E pathway is important for proliferation and survival of hairy cells. BRAF V600E mutation is present in nearly 85% patients with classic HCL subtype, but not in HCLv or IGHV4-34+ HCL. Patients harboring this mutation are candidates for vemurafenib, dabrafenib, or encorafenib [1,4]. Of these agents, the most studied is vemurafenib leading to response rates of 96–100%, including 35–42% complete responses in relapsed or refractory HCL [22]. Persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment with vemurafenib suggests bypass reactivation of MEK and ERK as a resistance mechanism in these patients [22]. As a result, dabrafenib in combination with the MEK inhibitor trametinib is currently being studied in clinical trials [1]. Importantly, BRAF unmutated patients such as HCLv and IGHV4-34+ HCL may also respond to MEK inhibitors as they frequently harbor MAP2K1 (MEK) mutations [4,9,10,23].

Furthermore, the combination vemurafenib-rituximab was shown to be highly effective in relapsed/refractory HCL patients [24]. Vemurafenib for 16 weeks in combination with obinutuzumab starting at week 5 was also evaluated in 11 treatment-naïve HCL patients enrolled in a phase II clinical trial [25]. The ORR in nine patients who had completed the treatment was 100%, with MRD-negativity in all patients at 10 months. Combination of a BRAF inhibitor with an anti-CD20 antibody might become the first time-limited, chemotherapy-free treatment option in HCL, potentially matching the clinical efficacy of cladribine-rituximab. However, larger trials are needed to confirm these findings.

B-cell receptor downstream signaling via Bruton’s tyrosine kinase (BTK) is important for growth, survival, and ‘homing’ of malignant B-cells. BTK inhibitors may become valuable therapeutic options for BRAF-unmutated HCL patients [26,27]. A phase II study of ibrutinib in 37 patients with classic HCL and HCLv showed a response rate of 54% at 42 months [26]. Furthermore, there is interest in studying Bcl2 inhibitors and chimeric antigen receptor-engineered (CAR) T-cell targeting CD22 antigen in relapsed/refractory diseases, including HCLv and IGHV4-34+ HCL. Future HCL treatments might include multi-agent constructs, new molecularly based treatments, and use nanotechnology for drug delivery. Therefore, participation of patients with relapsed/refractory HCL in clinical trials with these promising agents or combinations, where available, is strongly encouraged.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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