Hairy Cell Leukemia: Where Are We in 2023?

PURPOSE OF REVIEW: This article summarizes the current state of knowledge of hairy cell leukemia (HCL) regarding presentation, diagnosis, therapy, and monitoring, including perspectives on emergent therapies. RECENT FINDINGS: Over the past decade, there has been enormous progress in the understanding of the biology of HCL which has led to the development of novel therapeutic strategies. The maturation of data regarding existing management strategies has also lent considerable insight into therapeutic outcomes and prognosis of patients treated with chemo- or chemoimmunotherapy. Purine nucleoside analogs remain the cornerstone of treatment, and the addition of rituximab has deepened and prolonged responses in the upfront and relapsed setting. Targeted therapies now have a more defined role in the management of HCL, with BRAF inhibitors now having a potential in the first-line setting in selected cases as well as in relapse. Next-generation sequencing for the identification of targetable mutations, evaluation of measurable residual disease, and risk stratification continue to be areas of active investigation. Recent advances in HCL have led to more effective therapeutics in the upfront and relapsed setting. Future efforts will focus on identifying patients with high-risk disease who require intensified regimens. Multicenter collaborations are the key to improving overall survival and quality of life in this rare disease.

Consensus opinion from an international group of experts on measurable residual disease in hairy cell leukemia.

A significant body of literature has been generated related to the detection of measurable residual disease (MRD) at the time of achieving complete remission (CR) in patients with hairy cell leukemia (HCL). However, due to the indolent nature of the disease as well as reports suggesting long-term survival in patients treated with a single course of a nucleoside analog albeit without evidence of cure, the merits of detection of MRD and attempts to eradicate it have been debated. Studies utilizing novel strategies in the relapse setting have demonstrated the utility of achieving CR with undetectable MRD (uMRD) in prolonging the duration of remission. Several assays including immunohistochemical analysis of bone marrow specimens, multi-parameter flow cytometry and molecular assays to detect the mutant BRAF V600E gene or the consensus primer for the immunoglobulin heavy chain gene (IGH) rearrangement have been utilized with few comparative studies. Here we provide a consensus report on the available data, the potential merits of MRD assessment in the front-line and relapse settings and recommendations on future role of MRD assessment in HCL.

Development of a distributed international patient data registry for hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare lymphoproliferative disorder, comprising only 2% of all leukemias. The Hairy Cell Leukemia Foundation (HCLF) has developed a patient data registry to enable investigators to better study the clinical features, treatment outcomes, and complications of patients with HCL. This system utilizes a centralized registry architecture. Patients are enrolled at HCL Centers of Excellence (COE) or via a web-based portal. All data are de-identified, which reduces regulatory burden and increases opportunities for data access and re-use. To date, 579 patients have been enrolled in the registry. Efforts are underway to engage additional COE's to expand access to patients across the globe. This international PDR will enable researchers to study outcomes in HCL in ways not previously possible due to the rarity of the disease and will serve as a platform for future prospective research.

Patient-driven research: Initial results from a prospective health-related quality of life study performed at the request of patients living with hairy cell leukemia.

A diagnosis of leukemia can have a profound effect on patients' health-related quality of life (HRQoL), however this has not been measured prospectively in patients with hairy cell leukemia (HCL). At the request of patients living with HCL who had identified this gap in knowledge about the disease, we conducted a longitudinal study of HRQoL among patients enrolled in the HCL Patient Data Registry (PDR). From September 1, 2018 to September 1, 2020, 165 patients were enrolled in the study and completed the baseline survey. The Functional Assessment of Cancer Therapy - Leukemia (FACT-Leu) was used to measure patients' HRQoL. Results show that newly diagnosed HCL patients reported the lowest HRQoL, followed by patients in relapse and those on "watch and wait." Factors associated with higher (better) FACT-Leu total scores in the multivariable analysis included older age, higher social support, and greater physical activity. These same factors were associated with lower levels of fatigue. In rare diseases where it is difficult to perform large prospective studies, patient/researcher collaborations are critical for the identification of studies that are of importance to patients and their families in order to maximize the benefits of the research and improve the lives of patients living with HCL.

Cost-effectiveness and value of information analyses of Bruton's tyrosine kinase inhibitors in the treatment of relapsed or refractory mantle cell lymphoma in the United States.

BACKGROUND: Ibrutinib, acalabrutinib, and zanubrutinib have shown improvements in efficacy and safety over conventional chemoimmunotherapy in refractory or relapsed mantle cell lymphoma (R/R MCL). OBJECTIVE: To evaluate the comparative cost-effectiveness of the Bruton's tyrosine kinase inhibitors (BTKIs) and estimate the expected value of (partial) perfect information (EV[P]PI) in terms of net health benefits (NHBs) and net monetary benefits (NMBs) forgone. METHODS: Using a two-state Markov model (progression-free; progression or death), we estimated in base-case and probabilistic sensitivity analyses (PSAs) the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) of, respectively, progression-free survival (PFS) life-years (PFLYs) and PFS quality-adjusted LY (PFQALY) gained (g) against 3-year and 5-year time horizons. A willingness-to-pay threshold of $150,000/PFQALY was used to assess the probability of being cost-effective in the PSA. EVPI was calculated from the respective NHBs and NMBs. RESULTS: Compared with ibrutinib, acalabrutinib yielded a 3-year ICER of $90,571 (PSA = $88,588)/PFLYg and ICUR of $117,098 ($110,063)/PFQALYg, whereas zanubrutinib yielded a 3-year ICER of $58,422 ($58,907)/PFLYg and ICUR of $73,027 ($73,634)/PFQALYg. The corresponding 5-year estimates were ICER of $73,918 ($74,189)/PFLYg and ICUR of $90,512 ($90,844)/PFQALYg for acalabrutinib and ICER of $48,641 ($48,732)/PFLYg and ICUR of $61,612 ($63,727)/PFQALYg for zanubrutinib. Compared with zanubrutinib, treatment with acalabrutinib yielded a 3-year ICER of $144,633 ($134,964)/PFLYg and ICUR of $197,227 ($166,109)/PFQALYg; the corresponding 5-year estimates were $117,579 ($118,161)/PFLYg and $136,144 ($136,818)/PFQALYg. The EVPI/patient was an NHB of 0.036 PFQALYs and NMB of $3,602 forgone, resulting in a population EVPI of $134,766,957 forgone. The EVPPIs/patient for effectiveness were NHB of 0.015 PFQALYs and NMB of $1,479, with corresponding values of 0.032 and $3,187 for costs and 0.015 and $1,519 for health-related quality of life forgone. CONCLUSIONS: This early cost-effectiveness analysis based on phase I/II clinical trials of BTKIs in R/R MCL suggests an additional PFS benefit for second-generation BTKIs compared with ibrutinib. However, the relative uncertainty due to the lack of direct trial evidence may lead to an opportunity cost or lost health benefits if the current evidence is adopted to compare between these products. Additional evidence is needed to address the relative efficacy of the BTKIs. DISCLOSURES: A. McBride serves on speakers bureaus for Coherus BioSciences and Merck. He is now at Bristol-Myers Squibb in a position unrelated to this study. I. Abraham is joint equity owner in Matrix45. By company policy, owners and employees are prohibited from owning equity in client and sponsor organizations (except through mutual funds or other independently administered collective investment instruments), contracting independently with client and sponsor organizations, or receiving compensation independently from such organizations. Matrix45 provides similar services to biopharmaceutical, diagnostics, and medical device companies on a nonexclusivity basis. Of relevance to this article, Matrix45 has not provided any services to this study. I. Abraham is the quantitative methods editor of JAMA Dermatology and deputy editor-in-chief of the Journal of Medical Economics. The remaining authors have no relevant financial or nonfinancial interests to disclose.

Hairy cell leukemia and COVID-19 adaptation of treatment guidelines.

Standard treatment options in classic HCL (cHCL) result in high response rates and near normal life expectancy. However, the disease itself and the recommended standard treatment are associated with profound and prolonged immunosuppression, increasing susceptibility to infections and the risk for a severe course of COVID-19. The Hairy Cell Leukemia Foundation (HCLF) has recently convened experts and discussed different clinical strategies for the management of these patients. The new recommendations adapt the 2017 consensus for the diagnosis and management with cHCL to the current COVID-19 pandemic. They underline the option of active surveillance in patients with low but stable blood counts, consider the use of targeted and non-immunosuppressive agents as first-line treatment for cHCL, and give recommendations on preventive measures against COVID-19.

Phase 2 study of ibrutinib in classic and variant hairy cell leukemia.

Hairy cell leukemia (HCL) is a rare B-cell malignancy, and there is a need for novel treatments for patients who do not benefit from purine analogs. Ibrutinib, an oral agent targeting Bruton tyrosine kinase in the B-cell receptor signaling pathway, is highly effective in several malignancies. Its activity in HCL was unknown, so we conducted a multisite phase 2 study of oral ibrutinib in patients with either relapsed classic or variant hairy cell leukemia. The primary outcome measure was the overall response rate (ORR) at 32 weeks, and we also assessed response at 48 weeks and best response during treatment. Key secondary objectives were characterization of toxicity and determination of progression-free survival (PFS) and overall survival (OS). Thirty-seven patients were enrolled at 2 different doses (24 at 420 mg, 13 at 840 mg). The median duration of follow-up was 3.5 years (range, 0-5.9 years). The ORR at 32 weeks was 24%, which increased to 36% at 48 weeks. The best ORR was 54%. The estimated 36-month PFS was 73% and OS was 85%. The most frequent adverse events were diarrhea (59%), fatigue (54%), myalgia (54%), and nausea (51%). Hematologic adverse events were common: anemia (43%), thrombocytopenia (41%), and neutropenia (35%). Ibrutinib can be safely administered to patients with HCL with objective responses and results in prolonged disease control. Although the initial primary outcome objective of the study was not met, the observation of objective responses in heavily pretreated patients coupled with a favorable PFS suggests that ibrutinib may be beneficial in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01841723.

Current and Emerging Therapeutic Options for Hairy Cell Leukemia Variant.

Hairy cell leukemia variant (HCL-v) is a rare B-cell lymphoproliferative disorder with distinct immunophenotypic and molecular characteristics when compared to classical hairy cell leukemia (HCL-c). In contrast to the enormous progress in therapeutic options for HCL-c, HCL-v remains a therapeutic challenge due to inferior outcomes with standard chemoimmunotherapy and BCR signaling pathway inhibitors, and due to the fact that HCL-v has limited molecular therapeutic targets. In addition, because of the rarity of the disease, there is a paucity of later phase studies or multicenter trials to guide treatment decisions. In this article, we briefly review the diagnostic criteria and clinical characteristics of HCL-v and present a comprehensive overview of current therapeutic options in HCL-v.

A Phase 1b Study to Evaluate the Safety and Efficacy of Durvalumab in Combination With Tremelimumab or Danvatirsen in Patients With Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

BACKGROUND: Despite recent advances, outcomes in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) remain poor. Immune checkpoint inhibitors have shown limited efficacy in this setting, but combinations with novel agents may enhance benefit. Combination therapy with durvalumab, an anti-programmed death ligand 1 (PD-L1) antibody, and danvatirsen (AZD9150; an antisense oligonucleotide inhibiting signal transducer and activator of transcription 3 [STAT3]) or tremelimumab (an anti-cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] antibody) may augment endogenous antitumor activity. PATIENTS AND METHODS: In this phase 1b dose escalation and dose expansion study, we evaluated durvalumab 20 mg/kg every 4 weeks plus either tremelimumab 1 mg/kg every 4 weeks or danvatirsen 2 or 3 mg/kg (administered on days 1, 3, 5, 8, 15, and 22, then every week). Treatment continued until disease progression. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. RESULTS: As of April 4, 2019, 32 patients were enrolled and treated, receiving a median of 2 prior lines of systemic therapy. Treatment-related adverse events occurred in 21 patients (65.6%), most commonly alanine aminotransferase/aspartate aminotransferase increased (grade 1-3), anemia (grade 1-3), and fatigue (grade 1). The overall objective response rate was 6.3%, with 2 partial responses. Median time to response was 11.0 weeks (range, 7.7-14.3 weeks). Median progression-free survival was 7.4 weeks (range, 0.1-31.4 weeks), and median overall survival was 28.0 weeks (range, 1.9-115.4 weeks). CONCLUSION: The primary endpoint was met, with durvalumab plus tremelimumab/danvatirsen generally well tolerated in patients with relapsed/refractory DLBCL; however, antitumor activity was limited.

Prognostic significance of translocations in the presence of mutated IGHV and of cytogenetic complexity at diagnosis of chronic lymphocytic leukemia.

Mutations of the IGH variable region in patients with chronic lymphocytic leukemia (CLL) are associated with a favorable prognosis. Cytogenetic complexity (>3 unrelated aberrations) and translocations have been associated with an unfavorable prognosis. While mutational status of IGHV is stable, cytogenetic aberrations frequently evolve. However, the relationships of these features as prognosticators at diagnosis are unknown. We examined the CpG-stimulated metaphase cytogenetic features detected within one year of diagnosis of CLL and correlated these features with outcome and other clinical features including IGHV. Of 329 untreated patients, 53 (16.1%) had a complex karyotype (16.1%), and 85 (25.8%) had a translocation. Median time to first treatment (TFT) was 47 months. In univariable analyses, significant risk factors for shorter TFT (p3.5, log-transformed WBC, unmutated IGHV, complex karyotype, translocation, and FISH for trisomy 8, del(11q) and del(17p). In multivariable analysis, there was significant effect modification of IGHV status on the relationship between translocation and TFT (p=0.002). In IGHV mutated patients, those with a translocation had over 3.5 times higher risk of starting treatment than those without a translocation (p.

Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia.

PURPOSE: Infectious complications constitute a leading cause of morbidity and mortality in chronic lymphocytic leukemia (CLL). Patients respond poorly to vaccines, particularly pneumococcal polysaccharide and influenza vaccines. In addition, patients with genetically high-risk disease are at increased risk for early disease progression and death. Lenalidomide, an oral immunomodulatory agent with demonstrated clinical activity in CLL, can potentially restore immune system dysfunction associated with CLL while improving disease outcomes. PATIENTS AND METHODS: Phase II study randomized 49 patients with genetically high-risk CLL or small lymphocytic lymphoma [SLL; defined as unmutated Ig heavy chain variable region, deletion(17p) or (11q), and/or complex abnormal karyotype], to receive lenalidomide either concurrent (arm A) or sequential to (arm B) two doses of 13-valent protein-conjugated pneumococcal vaccine (PCV13) administered 2 months apart, in patients not meeting International Workshop on Chronic Lymphocytic Leukemia treatment criteria. RESULTS: Four serotypes (3, 4, 5, 6B) achieved the additional seroprotection definition of a fourfold increase in arm A, and six serotypes (3, 4, 5, 6B, 19A, 19F) in arm B. All patients achieved the defined concentration of 0.35 µg/mL for at least one serotype tested. No significant difference was observed with the addition of lenalidomide. At median time on treatment of 3.6 years, median progression-free survival (PFS) was 5.8 years [95% confidence interval (CI), 3.1-not reached]. PFS at 1, 2, and 3 years was 85% (95% CI, 72-93), 79% (95% CI, 64-88), and 72% (95% CI, 57-83), respectively. CONCLUSIONS: Lenalidomide is efficacious with manageable toxicities as an early intervention strategy in patients with high-risk CLL, but did not enhance humoral response to PCV13 vaccine.

Adverse event rates and economic burden associated with purine nucleoside analogs in patients with hairy cell leukemia: a US population-retrospective claims analysis.

BACKGROUND: Purine nucleoside analogs (PNAs) are the recommended first-line treatment for patients with hairy cell leukemia (HCL), but they are associated with adverse events (AEs). Due to a lack of real-world evidence regarding AEs that are associated with PNAs, we used commercial data to assess AE rates, AE-related health care resource utilization (HCRU), and costs among PNA-treated patients with HCL. Adults aged ≥18 years with ≥2 claims for HCL ≥30 days apart from 1 January 2006 through 31 December 2015 were included. Included patients had ≥1 claim for HCL therapy (cladribine ± rituximab or pentostatin ± rituximab [index date: first claim date]) and continuous enrollment for a ≥ 6-month baseline and ≥ 12-month follow-up period. Patient sub-cohorts were based on the occurrence of myelosuppression and opportunistic infections (OIs). Generalized linear models were used to compare HCRU and costs. RESULTS: In total, 647 PNA-treated patients were identified (mean age: 57.1 years). Myelosuppression and OI incidence were 461 and 42 per 1000 patient-years, respectively. Adjusted results indicated that those with myelosuppression had higher rates of hospitalization (47.4% vs 12.4%; P < .0001) and incurred higher mean inpatient costs ($23,517 vs $12,729; P = .011) and total costs ($57,325 vs $34,733; P = .001) as compared with those without myelosuppression. Similarly, patients with OIs had higher rates of hospitalization (53.8% vs 30.8%; P = .025) and incurred higher mean inpatient costs ($21,494 vs $11,229; P < .0001) as compared with those without OIs. CONCLUSIONS: PNA therapy is highly effective but associated with significant toxicities that increase costs; these findings indicate a need for therapies with improved toxicity profiles and better risk stratification of patients at risk of developing myelosuppression and OIs.

Ruxolitinib In The Treatment Of Polycythemia Vera: An Update On Health-Related Quality Of Life And Patient-Reported Outcomes.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm (MPN) associated with significant impairment in quality of life (QoL) due to disease-related symptoms and complications. Assessment of disease burden constitutes standard monitoring of symptoms and response. Conventional treatments for MPN, such as hydroxyurea, phlebotomy, or interferon, have not shown a significant impact in QoL or patient-reported outcomes (PRO). Ruxolitinib (RUX) is a JAK2 inhibitor approved for patients intolerant or resistant to hydroxyurea (HA). We conducted a systematic review of clinical trials of RUX in patients with PV that incorporated PRO measures to evaluate the effects on PRO and QoL. Three randomized Phase 3 studies reported in four publications were relevant for analysis. Although the small number of trials and potential for treatment bias in the review, treatment with RUX was associated with improved QoL and PRO in PV patients intolerant or resistant to hydroxyurea.

Spontaneous resolution of untreated diffuse large B-cell lymphoma of maxillary bone after incisional biopsy.

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphomas which require multiagent therapy for remission induction and are associated with relapse in more than 40% of patients. Spontaneous remission of diffuse large B-cell lymphoma (DLBCL) is a rare occurrence.

Clinical and cost outcomes of pre-emptive plerixafor administration in patients with multiple myeloma undergoing stem cell mobilization.

PURPOSE: The stem cell mobilization agent plerixafor significantly improves CD34+ stem cell procurement in patients with multiple myeloma undergoing autologous stem cell transplant. We compared mobilization success rates and costs of two regimens of plerixafor administration: pre-emptive (P-PL, initiated the evening prior to the first day of stem cell collection) and standard (S-PL, initiated the evening prior to the second day of stem cell collection in the event of inadequate collection on the first day). METHODS: Patients with multiple myeloma undergoing mobilization were categorized as either P-PL or S-PL. Stem cell collection success was evaluated using logistic regression models. Associated costs were aggregated in terms of average collections per patient in each mobilization option (patient level), and escalated to a panel of 5000 patients (population level). RESULTS: 299 patients were evaluable; 241 received P-PL and 58 received S-PL. Patients receiving P-PL had higher median CD34+ count pre-collection and higher median total CD34+ cell harvest on the first collection (6.75 × 106/kg for P-PL, 1.96 × 106/kg for S-PL; P<0.01). In multivariable analyses, P-PL remained significantly associated with the ability to collect ≥2 × 106/kg CD34+ on the first day (OR = 4.05, 95% CI, 1.19-13.83, P = 0.03) and ≥5 × 106/kg CD34+ in total (OR = 3.09, 95% CI, 1.04-9.23, P = 0.04). P-PL saved $11,248 (46%) per patient compared with S-PL. CONCLUSION: P-PL significantly enhanced collection efficiency, with most patients completing collection in 1 day, resulting in substantial cost savings.

A multicenter phase 1 study of plerixafor and rituximab in patients with chronic lymphocytic leukemia.

CXCR4 directs chronic lymphocytic leukemia (CLL) trafficking within protective tissue niches, and targeting CXCR4 with plerixafor may enhance drug sensitivity. We performed a phase 1 dose escalation study of plerixafor (NCT00694590) with rituximab in 24 patients with relapsed/refractory CLL. Patients received rituximab 375 mg/m2 on days 1, 3, and 5, followed by bi-weekly rituximab plus dose-escalated plerixafor for 4 weeks. The maximum tolerated dose of plerixafor was 320 µg/kg. The most common toxicities were fatigue (13 patients, 57%), nausea (11, 48%), chills (10, 43%), and diarrhea and dyspnea (seven, 30% each). No patients developed symptomatic hyperleukocytosis or tumor lysis syndrome. A median 3.3-fold increase (range 1.2-12.4) in peripheral blood CLL was seen following the first dose of plerixafor, confirming CLL cell mobilization. The overall response rate was 38% and correlated with higher doses of plerixafor. Plerixafor is well-tolerated in patients with CLL; further tumor sensitization studies with CXCR4 antagonists are warranted.