Treatment Of Hairy Cell Leukemia Research Articles

Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40–18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.

Chinese guideline for diagnosis and treatment of hairy cell leukemia (2023)

Chinese guideline for diagnosis and treatment of hairy cell leukemia (2023)

CLL-237 Efficacy of Cladribine Combine With Rituximab versus Cladribine Alone in the Treatment of Hairy Cell Leukemia: A Retrospective Single-Center Study

CLL-237 Efficacy of Cladribine Combine With Rituximab versus Cladribine Alone in the Treatment of Hairy Cell Leukemia: A Retrospective Single-Center Study

BRAF(V600E) mutation together with loss of Trp53 or pTEN drives the origination of hairy cell leukemia from B-lymphocytes

Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations to drive HCL ontogeny. To resolve this issue, here we surveyed human HCL genomic sequencing data. Together with previous reports, we speculated that the tumor suppressor TP53, P27, or PTEN restrict the oncogenicity of BRAF(V600E) in B-lymphocytes, and therefore that their loss-of-function facilitates BRAF(V600E)-driven HCL ontogeny. Using genetically modified mouse models, we demonstrate that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induces chronic lymphoma with pathological features of human HCL. To further understand the cellular programs essential for HCL ontogeny, we profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that they had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, illustrating why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations required for HCL ontogeny, revealed the B cell origin of hairy cells and investigated the molecular basis underlying the unique pathological features of the disease, with important implications for HCL research and treatment.

Phenolic compounds as potential adenosine deaminase inhibitors: molecular docking and dynamics simulation coupled with MM-GBSA calculations.

Adenosine deaminase (ADA) is a Zn2+-containing enzyme that catalyzes the irreversible deamination of adenosine to inosine or deoxyadenosine to deoxyinosine. In addition to this enzymatic function, ADA mediates cell-to-cell interactions involved in lymphocyte co-stimulation or endothelial activation. ADA is implicated in cardiovascular pathologies such as atherosclerosis and certain types of cancers, including lymphoma and leukemia. To date, only two drugs (pentostatin and cladribine) have been approved for the treatment of hairy cell leukemia. In search of natural ADA inhibitors, we demonstrated the binding of selected phenolic compounds to the active site of ADA using molecular docking and molecular dynamics simulation. Our results show that phenolic compounds (chlorogenic acid, quercetin, and hyperoside) stabilized the ADA complex by forming persistent interactions with the catalytically essential Zn2+ ion. Furthermore, MM-GBSA ligand binding affinity calculations revealed that hyperoside had a comparable binding energy score (ΔG = -46.56 ± 8.26kcal/mol) to that of the cocrystal ligand in the ADA crystal structure (PDB ID: 1O5R) (ΔG = -51.97 ± 4.70kcal/mol). Similarly, chlorogenic acid exhibited a binding energy score (ΔG = -18.76 ± 4.60kcal/mol) comparable to those of the two approved ADA inhibitor drugs pentostatin (ΔG = -14.54 ± 2.25kcal/mol) and cladribine (ΔG = - 25.52 ± 4.10kcal/mol) while quercetin was found to have modest binding affinity (ΔG = - 8.85 ± 7.32kcal/mol). This study provides insights into the possible inhibitory potential of these phenolic compounds against ADA.

Outcomes of intravenous and subcutaneous cladribine administration in patients with hairy cell leukemia: A systematic review and meta-analysis.

e19546 Background: Hairy cell leukaemia (HCL) is a rare, chronic B cell cancer that involves the bone marrow, peripheral blood, and spleen. Cladribine (2CdA) monotherapy is used as a first line treatment for HCL. 2CdA can be administered intravenously (IV) or subcutaneously (SC). The aim of our study is to compare the safety and efficacy of these two routes of administration of 2CdA as a first line treatment of HCL. Methods: We conducted a systematic literature search across multiple databases and Google up to February 2023. We included studies that reported outcomes for either intravenous (IV) or subcutaneous (SC) cladribine (2CdA) therapy, as well as those that directly compared the two routes. Our primary efficacy outcomes were overall response rate (ORR) and complete response rate (CRR), and our primary safety outcome was adverse effects (AEs). We used OpenMetaAnalyst to pool data using the Hedges-Olkin Random effects model and conducted subgroup analysis for HCL type (classical vs classic and variant both). We calculated odds ratios (ORs) for studies involving a head-to-head comparison between the two routes and used the Higgins I2 statistic to assess heterogeneity. Results: We identified a total of 25 studies (15 trials, 10 cohorts) with a patient population of 2669. The median age of the patients was 53.5 years. The pooled ORR and CRR for IV and SC 2CdA therapy were 96%, 82%, 88% and 67% respectively. The incidence of neutropenia (82% vs 61%) and infections (13% vs 16%) was greater for SC 2CdA than IV 2CdA. Five studies provided a direct comparison between SC and IV routes but three were excluded from the analysis due to unavailability of desired outcomes. Studies involving a direct comparison between the 2 routes of administration showed that the odds of achieving CRR were 86.6% greater with IV than SC 2CdA but these results were not significant. The proportion of adverse events was comparable for IV and SC routes. Subgroup analysis for HCL type did not resolve heterogeneity for ORR and CRR. It did, however, result in greater ORR for classic (92%) and mixed (92%) HCL treated with SC 2CdA. Conclusions: Compared to SC 2CdA, IV 2CdA is safer and more effective as a first-line treatment of HCL. However, future high-power randomized control trials that directly compare IV and SC routes are needed to confirm this evidence. [Table: see text]

Identifying the mechanistic differences between hypomethylating agents for the treatment of peripheral T cell lymphoma

Introduction: Peripheral T-cell lymphomas (PTCL) are a rare and heterogeneous group of malignancies that share a unifying feature of epigenetic dysregulation. Recent evidence suggests that PTCL, unlike other forms of cancer or even lymphoma, exhibits a marked vulnerability to hypomethylating agents (HMAs) alone and especially in combination with HDAC inhibitors. HMAs like azacitidine (AZA) and decitabine (DAC) have been shown to reverse transcriptional repression secondary to hypermethylation. Cladribine (CLAD) is FDA-approved for the treatment of hairy cell leukemia and is postulated to inhibit both DNA and histone methylation. Here, we sought to define the mechanistic differences between different DNA HMAs in order to inform a rationale on the optimal combinations that might exploit the epigenetic vulnerabilities of PTCL. Methods: Cell viability, caspase activity assay, and western blotting (WB) were performed on a panel of T-cell lymphoma cell lines to identify the effects of AZA/DAC/CLAD on cell survival, apoptosis, and DNA methyltransferase (DNMT) levels. Liquid chromatography-based mass spectrometry (LC-MS) was done to quantify 5-methyl cytosine (5-mC) levels. Results: Cell viability analysis confirmed that the dose and time-dependent sensitivity of the six PTCL cell lines differed following exposure to AZA/DAC/CLAD, where CLAD showed the lowest IC50 value (0.1–1 µM) across all cell lines, followed by AZA (IC50: 1–10 µM), and DAC had the least effect on cell viability (IC50: >100 µM, except T-ALL). A differential threshold of caspase activation was observed across the PTCL cell lines where CLAD showed the most superior caspase activity leading to the highest apoptotic potential. However, WB analysis showed that after 24 hours of treatment, DNMT1 and DNMT3A protein levels were significantly depleted at low concentrations of DAC (<0.01 µM) compared to AZA whereas CLAD did not affect the DNMT1 and DNMT3A levels. LC-MS-based quantification of 5-mC showed a similar relationship in methylation, with initial changes observed at doses >0.01 μM of DAC and >0.1 μM of AZA/CLAD. Taking the short half-life of AZA/DAC into account, cell viability assays with daily addition of AZA/DAC showed increased cell cytotoxicity for AZA/DAC treated samples, which was comparable to CLAD. Ongoing analyses of gene expression and metabolism of the universal methyl donor S-adenosylmethionine (SAM) will help to understand the mechanistic difference between these HMAs. Conclusions: These data suggest that the HMAs have a distinct mechanism of action for hypomethylation. While AZA/DAC induces hypomethylation by depletion of DNMTs, CLAD acts in a DNMT depletion-independent pathway. A mechanistic understanding of AZA/DAC/CLAD will inform how best to use them in clinic as well as assist in the strategic development of biological correlates to further support their therapeutic application. The research was funded by: Translational Orphan Blood Cancer Research Initiative Fund and RO1 # FD-R-006814-01. Keywords: Genomics, Epigenomics, and Other -Omics, Molecular Targeted Therapies No conflicts of interests pertinent to the abstract.

Enhanced Pentostatin Production in Actinomadura sp. by Combining ARTP Mutagenesis, Ribosome Engineering and Subsequent Fermentation Optimization

The special structure of pentostatin causes it to possess a wide spectrum of biological and pharmacological properties, and it has been extensively employed to treat malignant tumors and is the first-line treatment for hairy cell leukemia. Pentostatin is mainly distributed in several actinomycetes and fungi species. However, its low titer in microbes is not able to meet medical needs. Here, we report a strain improvement strategy based on combined atmospheric and room-temperature plasma (ARTP) mutagenesis and ribosome engineering screening, as well as fermentation optimization, for enhanced pentostatin production. The original strain, Actinomadura sp. ATCC 39365, was treated with ARTP and screened by ribosome engineering to obtain one stable pentostatin high-yield mutant Actinomadura sp. S-15, which produced 86.35 mg/L pentostatin, representing a 33.79% increase compared to Actinomadura sp. ATCC 39365. qRT-PCR analysis revealed that pentostatin biosynthesis-related gene expression was significantly upregulated in Actinomadura sp. S-15. Then, to further enhance pentostatin production, the fermentation medium was optimized in flask culture and the pentostatin production of Actinomadura sp. S-15 reached 152.06 mg/L, which is the highest pentostatin production reported so far. These results demonstrate the effectiveness of combined ARTP mutation, ribosome engineering screening, and medium optimization for the enhancement of pentostatin production, and provide a methodology enabling the sustainable production of pentostatin on an industrial scale.

The protective role of the microenvironment in hairy cell leukemia treatment: Facts and perspectives.

Hairy cell leukemia (HCL) is an incurable, rare lymphoproliferative hematological malignancy of mature B cAlthough first line therapy with purine analogues leads to positive results, almost half of HCL patients relapse after 5-10 years, and standard treatment may not be an option due to intolerance or refractoriness. Proliferation and survival of HCL cells is regulated by surrounding accessory cells and soluble signals present in the tumor microenvironment, which actively contributes to disease progression. In vitro studies show that different therapeutic approaches tested in HCL impact the tumor microenvironment, and that this milieu offers a protection affecting treatment efficacy. Herein we explore the effects of the tumor microenvironment to different approved and experimental therapeutic options for HCL. Dissecting the complex interactions between leukemia cells and their milieu will be essential to develop new targeted therapies for HCL patients.

BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2

In classical hairy cell leukemia (HCL), standard treatments including purine analogs achieve a durable response (up to 90%), but lead to severe immunosuppression and long-lasting depletion of CD4 + T lymphocytes. The BRAF inhibitor vemurafenib is effective in HCL, but its use in first-line treatment is restricted to select clinical situations (e.g. active infection). Its impact on immune function or response to vaccines in HCL is unclear. We treated four HCL patients with vemurafenib during the COVID-19 pandemic and monitored immune reconstitution and response to SARS-CoV-2 immunization. All patients responded to HCL treatment with normalization of peripheral blood counts. No severe infections occurred. As an indication of limited immunosuppression by vemurafenib, stable CD4 + and CD8 + T lymphocyte counts and immunoglobulin levels were observed. Three out of four patients received SARS-CoV-2 vaccination (Pfizer-BioNTech) during treatment with vemurafenib. IgG antibody levels against the spike-protein of SARS-CoV-2 were detected (40–818 AE/ml). Our data suggest that vemurafenib has limited effects on cellular and humoral immune function in HCL, which allows for successful SARS-CoV-2 vaccination. These data support the use of BRAF inhibitors during the current pandemic where continued immune response is necessary for minimizing the COVID-19-related risk of non-vaccinated patients.

Incidence, Description, and Timing of Serious or Opportunistic Infections in Patients with Hairy Cell Leukemia Treated with Purine Nucleoside Analogues

Background: Hairy cell leukemia (HCL) is an uncommon B-cell malignancy characterized by pancytopenia on presentation. While the purine nucleoside analogues (PNAs) cladribine and pentostatin have resulted in long overall survival, infections remain a major cause of mortality. PNAs are known to be immunosuppressive, and in combination with the inherent infection risk of HCL, patients are vulnerable to serious and/or opportunistic infections throughout the disease course. Furthermore, there is prolonged CD4+ lymphopenia post-PNA treatment for 1-3 years. We thus conducted a comprehensive retrospective review at an academic center to (1) describe the incidence and types of infections seen in HCL and (2) determine how treatment with pentostatin versus cladribine may affect infection risk. Methods: We reviewed charts of all HCL patients that were seen at The Ohio State University between January 1 2012 and June 30 2020. Patients with less than 1 year of follow up were excluded. We defined our infections of interest as (1) serious i.e. requiring hospitalization or (2) opportunistic i.e. organisms commonly seen in immunosuppression. These patients’ baseline demographics, disease characteristics, bone marrow biopsies, and treatment histories were abstracted from medical records. Time to infection was calculated from the start of HCL treatment to the onset of infections, treating death without infection as a competing risk. The cumulative incidence of infection was estimated, and the associations with patient characteristics were evaluated using Fine and Gray sub-distribution hazard models accounting for competing risks. Overall survival was calculated from diagnosis to date of death or last contact. Kaplan-Meier method was used to estimate the survival functions and corresponding 95% confidence intervals. Results: Our study included 149 patients with a median follow up time of 6.9 years (range 1.3 - 48.8) and a 10-year estimated overall survival of 99% (95% CI: 93 - 100%). Median age at diagnosis was 51 years (range 22 - 80) and most patients (n = 117, 78.5%) were male. A total of 138 (92.6%) had classical HCL and 11 (7.4%) had variant HCL. There was a total of 70 incidents of infection, with 52 patients (35%) experiencing at least one infection and 18 (12%) with a second infection. Forty-six infections (66%) were serious and 24 (34%) were opportunistic. Most infections were likely to be seen 2 months prior to (n = 10, 14%) or 2 months after (n=14, 20%) initial treatment. The cumulative incidence of infection increased during the 50 days after starting treatment (Figure 1). Based on infection site, clinical presentation, and/or laboratory findings, 36 infections (51%) were classified as bacterial, 14 (20%) were viral, 8 (11%) were fungal, and 1 was concurrent viral and bacterial. Eleven (16%) infections did not have a confirmed organism. Sixty-seven (96%) infection cases had resolved; the outcomes in 2 cases were unknown, and 1 case resulted in death. Organisms were confirmed in 38 cases and are listed in Table 1. We examined baseline factors that could be associated with increased risk of infection, including sex, age at diagnosis, variant histology, total number of HCL treatment courses, prior infection, and a palpable spleen at diagnosis: none of these were associated with increased risk. Using cladribine as a reference, no treatment agents (including newer, non-PNA therapies) were associated with lower or higher infection risk. Examining the PNAs specifically, treatment with pentostatin versus cladribine was not associated with a significant difference in infection incidence (HR 1.12, 95% CI: 0.48 - 2.63). Conclusions: In our large institutional cohort of patients with HCL, a considerable fraction (35%) of patients experienced serious or opportunistic infections. The majority of these were in the 2 months before or after initial treatment. We did not identify any demographic or disease factors associated with infection, although this is limited by the small sample size. Notably, treatment with either cladribine or pentostatin was not associated with a significant difference in infection incidence. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Retrospective Analysis of Residual Hairy Cell Leukemia Measured By IHC or Flow Cytometry and Frontline Treatment with Pentostatin on Time to Next Treatment

Introduction: Pentostatin (pent) and cladribine (2CdA) are purine analogs used as frontline therapy for Hairy Cell Leukemia (HCL). Both agents can induce long-term remissions, but neither is considered curative. A better understanding of the factors that predict time to next therapy (TTNT) is needed to improve prognostication and monitoring after frontline therapy. The presence of minimal residual disease (MRD), as measured by advanced molecular techniques such as PCR, IHC, and flow cytometry, has been associated with reduced relapse-free survival in HCL. However, there is no uniform method for detecting MRD in HCL. Furthermore, most data regarding MRD has been collected from patients treated with 2CdA and less is known about MRD status after pent. Our institution has a large cohort of HCL patients treated with pent in the frontline setting. Thus, we performed a retrospective analysis to investigate (1) the impact of persistent HCL as measured by IHC or flow cytometry on TTNT after any frontline therapy, (2) the effect of pent on TTNT, and (3) the effect of MRD status after pent on TTNT. Methods: We conducted a retrospective analysis of HCL patients treated at Ohio State University on an IRB approved protocol. Patients with less than 1 year of follow up were excluded from the analysis. Bone marrow biopsy reports were collected at diagnosis and within 1 year of starting frontline therapy. MRD was defined as the lack of detectable HCL by morphological analysis, but the presence of HCL by IHC or flow cytometry. TTNT was calculated from the first HCL treatment to the initiation of next treatment treating death as a competing risk. The associations between TTNT and patient characteristics as well as percent bone marrow HCL measured by IHC and flow cytometry following completion of first line therapy were evaluated using Fine and Gray subdistribution hazard models accounting for competing risks. Results: 149 patients met criteria for this analysis. Median age a diagnosis was 51, 78% were male, and 7.4% had variant HCL. There were no significant differences in baseline characteristics for patients treated with pent or 2CdA. Univariable analysis of baseline characteristics found that a palpable spleen at diagnosis (HR 2.65, 95% CI 1.51-4.63, p=0.001) and variant HCL (HR 2.62, 95% CI 1.36-5.05, p=0.004) had significantly shorter TTNT. Patients who received pent (n=39, median number of infusions 14) as frontline treatment had significantly longer (HR 0.40, 95% CI 0.20-0.79, p=0.008) TTNT compared to 2CdA (n=72, Figure 1). By our definition of MRD, there were 47 total patients whose MRD status could be accurately determined. Univariable analysis showed MRD positivity after frontline treatment, regardless of agent, trended towards a shorter TTNT but was not statistically significant (HR 2.5, 95% CI 0.75-8.28, p=0.13). This was also true following treatment with pent (n=25, HR 5.83, 95% CI 0.53-64.43, p=0.15) whereas no trend was seen after 2CdA (n=15, HR 1.05, 95% CI 0.09-11.7, p=0.97). Univariable analysis of all patients, regardless of frontline treatment, showed that IHC ranges of 1-5% (HR 3.16, 95% CI 1.12-8.90, p=0.029), and >5% (HR 9.75, 95% CI 4.12-23.09 p<0.001) had significantly shorter TTNT compared to IHC<1% (Figure 2). Similarly, residual HCL burden measured by flow cytometry of 1-5% (HR 4.63, 95% CI 1.95-10.99, p=0.001) and >5% (HR 12.26, 95% CI 4.27-35.24 p<0.001) had significantly shorter TTNT. Following pent, residual HCL ranges measured by IHC of 1-5% (HR 8.82, 95% CI 1.22-63.84, p=0.031) and >5% (HR 29.17, 95% CI 3.99-213.42, p=0.001) had significantly shorter TTNT compared to <1%. Residual HCL ranges of 1-5% (HR 5.79, 95% CI 1.28-26.12, p=0.022) and >5% (HR 21.2, 95% CI 3.09-145.64, p=0.002) by flow cytometry after pent also had significantly shorter TTNT. Similar results were observed following 2CdA. Conclusions: Pent and 2CdA are considered efficacious in terms of achieving complete remission in HCL. Our finding that pent was associated with a significantly longer TTNT compared to 2CdA suggests there could be additional clinical differences between these agents, but drawing definitive conclusions is difficult due to the retrospective nature of this work. Finally, our data suggest that assessment of the degree of residual HCL burden measured by either IHC or flow cytometry yields important prognostic information. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Increased risk of severe cutaneous adverse reactions when cladribine is used together with other medications with a propensity for skin reactions

Cladribine is a purine analog used in first-line treatment of hairy cell leukemia and in relapsed/refractory chronic lymphocytic anemia. Although cladribine is typically associated with mild, self-limited skin reactions, there is increasing evidence that cladribine may increase the risk of severe cutaneous adverse reactions (SCAR) when combined with drugs classically associated with SCAR (e.g. allopurinol) beyond what would be expected for either drug alone, possibly due to cladribine-induced lymphopenia. We analyzed all SCAR cases reported for cladribine in Janssen’s Global Safety Database and found that 26/35 (74.3%) reported concomitant drugs known to be associated with SCAR, most commonly sulfamethoxazole/trimethoprim (SMX/TMP) and allopurinol. In addition, a review of the WHO VigiBase showed that several drugs, including penicillins, SMX/TMP, and allopurinol had a statistically significant contribution to cladribine-associated SCAR. These results lend further support that cladribine may increase the propensity of these drugs to cause SCARs.

Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

A 3-decade multicenter European experience with cladribine as upfront treatment in 384 patients with hairy cell leukemia

Cladribine is regarded as the first treatment of choice of symptomatic hairy cell leukemia (HCL): it provides high rates of response and very long duration of remission in some cases. Disease-specific patients records have been reviewed at four European centers of excellence; all patients with HCL requiring treatment who received frontline cladribine have been extrapolated. Responses have been classified according to Consensus Resolution Criteria. Three hundred and eighty-four patients have been diagnosed and followed between 1969 and 2018; all received frontline cladribine (subcutaneously or intravenously). A complete response was obtained in 72% of cases and a partial response in 22%. A continuous complete response was documented in 20% of patients at a median follow-up period of 8.5 years (range, 1-22 years). Median overall survival was reached at 25 years. Median progression-free survival was 13 years and median disease-free survival was 11 years. Cladribine is effective as frontline treatment of HCL and may determine deep disease control in a significant proportion of cases, given that more than 50% of treated patients require no further therapy. Good quality responses may be maintained for more than 20 years in up to 35% of patients.

Treatment of Classic Hairy Cell Leukemia: Targeting Minimal Residual Disease beyond Cladribine.

Simple SummaryStandard treatment with purine analogues facilitates a near normal life expectancy in the majority of patients with classic hairy cell leukemia (HCL), a rare chronic B-cell malignancy. However, nearly all patients ultimately relapse and require retreatment, while drug-induced myelotoxicity accumulates predisposing to infectious complications and, possibly, secondary malignancies. Persistence of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. New insights into disease biology initiated design and investigation of several new, chemotherapy-free, targeted drugs with encouraging efficacy in early clinical trials aimed at enhancing eradication of MRD and optimizing drug tolerability. This review provides an update on recent clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.Classic hairy cell leukemia (HCL) is a rare indolent B-cell lymphoproliferative disorder characterized by profound pancytopenia and frequent infectious complications due to progressive infiltration of the bone marrow and spleen. Lacking effective treatment options, affected patients were confronted with a dismal survival prognosis of less than 5 years when the disease was first described in 1958. Tremendous therapeutic advances were accomplished with the introduction of purine analogues such as cladribine in the 1990s, facilitating a near-normal life expectancy in most HCL patients. Nevertheless, nearly all patients eventually relapse and require successive retreatments, while drug-associated myelotoxicity may accumulate and secondary malignancies may evolve. Detection of minimal residual disease (MRD) in a substantial portion of treated patients has become a surrogate for this still limited treatment efficacy. In the last decade, novel biologic insights such as identification of the driver mutation BRAF V600E have initiated the development and clinical investigation of new, chemotherapy-free, targeted drugs in HCL treatment, with encouraging efficacy in early clinical trials aimed at boosting eradication of MRD while optimizing drug tolerability. This review summarizes current clinical trials investigating treatment strategies beyond purine analogues in HCL and discusses clinically relevant obstacles still to overcome.

Treatment outcomes with purine nucleoside analog alone or with rituximab for hairy cell leukemia at first relapse.

Frontline treatment of hairy cell leukemia (HCL) with a single course of the purine nucleoside analog (PNA) produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, although treatment guidelines recommend re-treatment with a PNA alone or in combination with rituximab (R), practice patterns vary and data supporting each approach are limited. We conducted a multisite outcomes analysis of patients treated for HCL between 1995 and 2018 at six US medical centers. All patients were treated with frontline PNA and subsequently required treatment with a PNA alone (PNA) or with R (+R). Of the 88 patients analyzed, 56 (63.6%) received second-line PNA and 22 (36.4%) received a PNA+R. Baseline characteristics of both groups were similar. There was no difference in median PFS [67months (95% CI 43.8 non-reached (NR)) vs. 65months (95% CI 60-NR)] or 5-year OS [98% (95% CI 0.94-1) vs. 94% (95% CI 0.83-1), p=.104] in the PNA versus PNA+R cohorts, respectively. To our knowledge, this is the largest study evaluating the role of R in treatment of relapsed HCL and suggests that there is no advantage to the addition of R to PNA therapy at the time of first re-treatment.

Experience with the Use of B-RAF Inhibitor Vemurafenib in the Treatment of Hairy Cell Leukemia

Background. The standard and effective treatment of hairy cell leukemia (HCL) involves purine analogs, interferon-а (IFN-а) administration, and splenectomy. However, primary resistant HCL and early relapses (within 2-3 years after achieving remission) remain clinical challenges. Due to myelotoxicity of cladribine and slow effect of IFN-а, these drugs can be administered neither in deep neutropenia/agranulocytosis patients (especially in case of infectious complications) nor in patients with IFN-а allergy/intolerance. Aim. To report clinical experience with vemurafenib, a B-RAF inhibitor, in HCL with BRAFV600E mutation in treatment-resistant patients with contraindications to standard therapy. Materials &amp; Methods. The study enrolled 39 HCL patients aged 24-78 years (median 55 years), 13 women and 26 men. HCL was diagnosed in accordance with the WHO 2017 criteria. Vemurafenib 240 mg was administered once or twice a day within 3 months. Three groups of patients were analyzed: those with early relapses and resistant HCL (n = 7), those with deep neutropenia/agranulocytosis (with and without infectious complications, n = 29), and those with IFN-а intolerance (n = 3). Results. In 6 (86 %) out of 7 patients from group 1 (with early relapses and resistant HCL) a complete course of treatment was carried out, which included vemurafenib with subsequent standard cladribine chemotherapy and further consolidation with rituximab. Complete remission was achieved in 5 (71 %) patients, and partial remission was achieved in 1 (14 %) patient. The 7th patient was a non- responder. In 28 (97 %) out of 29 patients from group 2 with deep neutropenia/agranulocytosis, hematologic recovery was reported which allowed for further basic treatment with cladribine. In 1 patient vemurafenib appeared to be ineffective. In 3 patients from group 3 with IFN-а intolerance, vemurafenib administration was used as a stage of treatment preceding cladribine therapy. Cladribine treatment resulted in complete remission in 2 (67 %) patients and partial remission in 1 (33 %) patient. Conclusion. In HCL with BRAFV600E mutation, low-dose vemurafenib can be effective in patients with relapsed/refrac- tory disease as well as deep neutropenia with life-threatening infectious complications. In addition to that, vemurafenib administration can be used in cases of IFN-а intolerance as a stage of treatment of HCL with BRAFV600E mutation which precedes the basic cladribine therapy.

Updates in hairy cell leukemia (HCL) and variant-type HCL (HCL-V): rationale for targeted treatments with a focus on ibrutinib.

Hairy cell leukemia (HCL) and HCL-like disorders such as hairy cell leukemia variant (HCL-V) and splenic diffuse red pulp lymphoma (SDRPL) are rare indolent B-cell malignancies. Purine analogs (PNAs), alone or in association with rituximab (R), are the standard of care for HCL in the first-line setting. However, PNAs are toxic and patients may become resistant to these drugs. Therefore, new therapeutic strategies are needed. Several recent in vitro studies highlighted the importance of the interactions between HCL cells and their microenvironment, in particular with bone marrow stromal cells, endothelial cells, and the extracellular matrix. In these interactions, chemokine receptors and adhesion molecules play a major role. Moreover, the importance of signaling pathways, like BRAF, BCR, and CXCR4 has been underlined. Bruton’s tyrosine kinase (BTK) is a fundamental signal transmitter of BCR and CXCR4 in HCL. Preclinical and recent clinical data showed an efficacy of ibrutinib, a BTK inhibitor (BTKi), in HCL and HCL-V. These promising results joined those of other emerging drugs like BRAF or MEK inhibitors and anti-CD22 immunotoxins.Plain Language Summary Bruton’s tyrosine kinase (BTK) inhibitors (BTKi) in hairy cell leukemia (HCL) and variant-type HCL The treatment of hairy cell leukemia (HCL) has changed significantly in recent years. In the first-line settings, treatment with purine analogs (PNAs) with or without anti-CD20 monoclonal antibodies remains the gold standard in 2022. In relapsed/refractory HCL, other drugs are needed: BRAF inhibitors: vemurafenib monotherapy with or without rituximab or dabrafenib in combination with trametinib, an MEK inhibitor (MEKi), as well as the anti-CD22 antibody drug conjugate moxetumomab pasudotox.There are arguments for the use of Bruton’s tyrosine kinase inhibitors (BTKi). Ibrutinib was recently tested in a multisite phase 2 study in 37 patients with either HCL (28 patients: 76%) or HCL-V (nine patients: 24%) including two who were previously untreated. Patients received single-agent ibrutinib at 420 mg daily (24 patients) or 840 mg daily (13 patients) until disease progression or unacceptable toxicity. The overall response rate (ORR) at 32 weeks was 24%, increasing to 36% at 48 weeks and reaching 54% at any time since starting ibrutinib. Seven patients achieved a complete response (CR) as the best response at any time on study, while 13 patients had a partial response (PR) and 10 patients had stable disease (SD). Interestingly, the response rate was not statistically different between HCL and HCL-V patients, suggesting that ibrutinib could be an option in both entities. The estimated 36-month progression-free survival (PFS) was 73% and the estimated 36-month overall survival (OS) was 85%, with no differences between HCL and HCL-V. The frequency of cardiovascular grade 1–2 adverse events (AEs) was 16% for atrial fibrillation; 3% for atrial flutter; 32% for hypertension; and 0%, 3%, and 11%, respectively, for grade ⩾ 3 AEs. Unlike in chronic lymphocytic leukemia (CLL), where the mechanism of action of ibrutinib is well known, the mechanism of action of ibrutinib in HCL appears to be unclear. No mutations were identified in patients with progressive disease, suggesting that the mechanisms of resistance could be different between HCL and CLL. The BTKi that are not yet approved are challenged by the new other targeted treatments.

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl

First Line Chemo-Free Therapy with the BRAF Inhibitor Vemurafenib Combined with Obinutuzumab Is Effective in Patients with Hcl