Long-term outcomes in patients with relapsed or refractory hairy cell leukemia treated with vemurafenib monotherapy.

Vemurafenib, an oral BRAF inhibitor, has demonstrated high response rates in relapsed/refractory (R/R) hairy cell leukemia (HCL). However, little is known about long-term outcomes and response to retreatment. Herein, we report the results of 36 patients with R/R HCL treated with vemurafenib from the United States arm of the phase 2 clinical trial (NCT01711632). The best overall response rate was 86%, including 33% complete response (CR) and 53% partial response (PR). After a median follow-up of 40 months, 21 of 31 responders (68%) experienced relapse with a median relapse-free survival (RFS) of 19 months (range, 12.5-53.9 months). There was no significant difference in the RFS for patients with CR vs PR. Fourteen of 21 (67%) relapsed patients were retreated with vemurafenib, with 86% achieving complete hematologic response. Two patients acquired resistance to vemurafenib with the emergence of new KRAS and CDKN2A mutations, respectively. Six of 12 (50%) responders to vemurafenib retreatment experienced another relapse with a median RFS of 12.7 months. Overall survival (OS) was 82% at 4 years, with a significantly shorter OS in patients who relapsed within 1 year of initial treatment with vemurafenib. Higher cumulative doses or a longer duration of treatment did not lengthen the durability of response. All adverse events in the retreatment cohort were grade 1/2 except for 1 case of a grade 3 rash and 1 grade 3 fever/pneumonia. Our data suggest that vemurafenib retreatment is a safe and effective option for patients with R/R HCL.

Long-term outcomes of elderly hairy cell leukemia patients treated with cladribine.

Hairy cell leukemia (HCL) is a rare hematologic disorder characterized by pancytopenia and splenomegaly for which a single course of cladribine is highly effective in inducing complete remissions. However, there is limited real-world data on outcomes and complications among geriatric patients with HCL treated with cladribine. We conducted a retrospective review of all patients 70 years or older within the Scripps Clinic HCL Database at the time of first treatment with cladribine. Of the 45 patients meeting inclusion criteria, 32 (71%) achieved CR and 4 (9%) achieved PR. Of the 9 remaining patients, 7 achieved normalization of peripheral blood counts after a single course of cladribine (complete hematologic response, CHR) and 2 had no response. The median duration of response for all responders was 119 months. Nine (20%) patients relapsed with a median time to first relapse of 28 months. Ten patients subsequently developed 12 primary malignancies with an excess frequency (observed-to-expected ratio) of 0.85 (95% confidence interval, 0.48-1.49). Median overall survival for the entire cohort was 166 months from time of HCL diagnosis and 119 months from time of first cladribine administration. Forty patient deaths were observed; the standardized mortality ratio (observed-to-expected ratio) was 1.42 (95% confidence interval, 1.03-1.96), representing a statistically significant increase in the risk of death (P = .03). This study supports the high rate of complete and durable responses following a single course of cladribine in geriatric patients.

An observational study of hospitalized COVID-19 patients with cancer in San Diego county.

Aim: To delineate clinical correlates of COVID-19 infection severity in hospitalized patients with malignancy. Methods: The authors conducted a retrospective review of all hospitalized patients with a hematologic and/or solid tumor malignancy presenting to the authors' institution between 1 March 2020 and 5 January 2021, with a laboratory confirmed diagnosis of COVID-19. Univariate and multivariate logistic regression analyses were used to determine associations between specific severity outcomes and clinical characteristics. Results: Among 2771 hospitalized patients with COVID-19, 246 (8.88%) met inclusion criteria. Patients who were actively receiving treatment had an increased rate of death following admission (odds ratio [OR]: 2.7). After adjusting for significant covariates, the odds ratio increased to 4.4. Patients with cancer involvement of the lungs had a trend toward increased odds of death after adjusting for covariates (OR: 2.3). Conclusions: Among COVID-19 positive hospitalized cancer patients, systemic anti-cancer therapy was associated with significantly increased odds of mortality.

Plain language summary Though cancer is a biologically heterogenous disease with a wide spectrum of clinical features and behavior, accumulating evidence suggests that cancer patients are at greater susceptibility to COVID-19 infection and more likely to experience morbidity and mortality from COVID-19 infection than non-cancer patients. In this study, the authors reviewed the clinical characteristics of patients with a diagnosis of cancer hospitalized with COVID-19 to assess potential correlates of COVID-19 severity in this population. Notably, analysis of the hospital data revealed a statistically significant increased incidence of mortality in cancer patients who were receiving systemic anti-cancer treatment, including chemotherapy, immunotherapy or targeted therapy, than in those not on therapy. Likewise, there was a trend toward increased mortality in those with either primary or metastatic tumor involvement of the lung compared with those without lung involvement.

Consensus guidelines for the diagnosis and management of patients with classic hairy cell leukemia.

Hairy cell leukemia is an uncommon hematologic malignancy characterized by pancytopenia and marked susceptibility to infection. Tremendous progress in the management of patients with this disease has resulted in high response rates and improved survival, yet relapse and an appropriate approach to re-treatment present continuing areas for research. The disease and its effective treatment are associated with immunosuppression. Because more patients are being treated with alternative programs, comparison of results will require general agreement on definitions of response, relapse, and methods of determining minimal residual disease. The development of internationally accepted, reproducible criteria is of paramount importance in evaluating and comparing clinical trials to provide optimal care. Despite the success achieved in managing these patients, continued participation in available clinical trials in the first-line and particularly in the relapse setting is highly recommended. The Hairy Cell Leukemia Foundation convened an international conference to provide common definitions and structure to guide current management. There is substantial opportunity for continued research in this disease. In addition to the importance of optimizing the prevention and management of the serious risk of infection, organized evaluations of minimal residual disease and treatment at relapse offer ample opportunities for clinical research. Finally, a scholarly evaluation of quality of life in the increasing number of survivors of this now manageable chronic illness merits further study. The development of consensus guidelines for this disease offers a framework for continued enhancement of the outcome for patients.

Targeting Mutant BRAF in Relapsed or Refractory Hairy-Cell Leukemia.

BACKGROUND: BRAF V600E is the genetic lesion underlying hairy-cell leukemia. We assessed the safety and activity of the oral BRAF inhibitor vemurafenib in patients with hairy-cell leukemia that had relapsed after treatment with a purine analogue or who had disease that was refractory to purine analogues. METHODS: We conducted two phase 2, single-group, multicenter studies of vemurafenib (at a dose of 960 mg twice daily)--one in Italy and one in the United States. The therapy was administered for a median of 16 weeks in the Italian study and 18 weeks in the U.S. study. Primary end points were the complete response rate (in the Italian trial) and the overall response rate (in the U.S. trial). Enrollment was completed (28 patients) in the Italian trial in April 2013 and is still open (26 of 36 planned patients) in the U.S. trial. RESULTS: The overall response rates were 96% (25 of 26 patients who could be evaluated) after a median of 8 weeks in the Italian study and 100% (24 of 24) after a median of 12 weeks in the U.S. study. The rates of complete response were 35% (9 of 26 patients) and 42% (10 of 24) in the two trials, respectively. In the Italian trial, after a median follow-up of 23 months, the median relapse-free survival was 19 months among patients with a complete response and 6 months among those with a partial response; the median treatment-free survival was 25 months and 18 months, respectively. In the U.S. trial, at 1 year, the progression-free survival rate was 73% and the overall survival rate was 91%. Drug-related adverse events were usually of grade 1 or 2, and the events most frequently leading to dose reductions were rash and arthralgia or arthritis. Secondary cutaneous tumors (treated with simple excision) developed in 7 of 50 patients. The frequent persistence of phosphorylated ERK-positive leukemic cells in bone marrow at the end of treatment suggests bypass reactivation of MEK and ERK as a resistance mechanism. CONCLUSIONS: A short oral course of vemurafenib was highly effective in patients with relapsed or refractory hairy-cell leukemia. (Funded by the Associazione Italiana per la Ricerca sul Cancro and others; EudraCT number, 2011-005487-13; ClinicalTrials.gov number NCT01711632.).

Treatment outcomes and secondary cancer incidence in young patients with hairy cell leukaemia.

Repeated therapy of hairy cell leukaemia (HCL) with treatments that have potential long-term toxicities has raised concerns regarding increased risk for younger patients. We compared clinical outcomes and disease complications in 63 patients with HCL aged ≤40 years at diagnosis with 268 patients >40 years treated at Memorial Sloan Kettering Cancer Center. The rate of complete remission following initial therapy was 87% and 83% (P = 0·71) and estimated 10-year overall survival was 100% and 82% (P = 0·25) in younger and older patients, respectively. Younger patients required therapy earlier and had a significantly shorter time between first and second therapy (median: 63 months vs. 145 months) (P = 0·008). Younger patients required significantly more lines of therapy during follow-up. The 10-year cumulative incidence of secondary malignancies in young and old patients was 0·205 and 0·287, respectively (P = 0·22). The incidence of secondary cancers in patients aged >40 years at diagnosis increased with the number of treatments for HCL (P = 0·018). These results highlight that young patients with HCL have shorter responses to treatment and require more lines of therapy to maintain disease control, while attaining similar long-term survival. This has implications in the design of future clinical trials given our findings that secondary malignancies increase with more chemotherapy exposure.

Clinical characteristics and long-term outcome of young hairy cell leukemia patients treated with cladribine: a single-institution series.

Hairy cell leukemia (HCL) is a rare, indolent B-cell disorder in which single courses of cladribine induce high rates of complete responses. We report on 88 young HCL patients (≤40 years of age at diagnosis) treated with cladribine from the Scripps Clinic HCL Database, of whom 83 were evaluable for response. Seventy-three patients (88%) achieved an initial complete response and 10 (12%) a partial response, with a median response duration of 57 months. Forty-eight patients (58%) relapsed, with a median time to first relapse for all responders of 54 months. Eight patients developed 11 second primary malignancies with an excess frequency of 1.60 (95% confidence interval, 0.80-2.89). Thirteen (15%) patients died with a mortality ratio compared with age-matched normals of 1.85 (95% confidence interval, 1.07-3.18). Median overall survival for all patients following the first cladribine course was 231 months, and 251 months from diagnosis. Single courses of cladribine induce high rates of complete and durable responses in the majority of young HCL patients and are therefore recommended for HCL patients regardless of age.

Detangling the Threads of Hairy Cell Leukemia, Beyond the Morphology and Into the Molecular.

Hairy cell leukemia (HCL) makes up 2% of leukemias in the United States and encompasses great molecular heterogeneity. The standard treatment paradigm involves purine nucleoside analogues in the upfront setting with high complete response rate to initial therapy but frequent relapses. There is an increasing role for BRAF inhibitors, with or without rituximab, in refractory and even in untreated patients. The response to purine analogues in HCL variant cases, otherwise classified as splenic lymphoma with prominent nucleolus in the 5th WHO edition classification, is less robust. Several antibodies, small molecular inhibitors, and combination regimens have been explored in HCL but data is frequently limited by case reports or small case series. Here we review available treatment options including their efficacy and safety profiles. We also explore investigational agents and potential future targets. The goal is to present a comprehensive therapeutic review of this rare disease entity and outline the ever increasing and novel therapeutic management options which interrupt key pathways in the pathogenesis of this malignancy.

Very long-term eradication of minimal residual disease in patients with hairy cell leukemia after a single course of cladribine.

Cladribine induces protracted remissions in patients with hairy cell leukemia (HCL). However, many long-term responders ultimately relapse. We sought to determine whether long-term complete responders subsequent to a single 7-day course of cladribine were without minimal residual disease (MRD) and potentially cured of HCL. From the 358-person Scripps Clinic cladribine database, we identified 19 patients in continuous and complete hematologic response (median age, 75 years; median time from diagnosis, 18 years; and median time from cladribine, 16 years). Nine of 19 (47%) patient samples had no evidence of residual disease; 7 of 19 (37%) samples had MRD; and 3 of 19 (16%) had morphologic evidence of HCL in hematoxylin and eosin-stained bone marrow sections. These results indicate that HCL is potentially curable after cladribine treatment. In addition, patients with MRD and even gross morphologic disease can live many years without manifesting hematologic relapses.

Beyond hairy cell: the activity of cladribine in other hematologic malignancies.

Before the contemporary development of rationally designed antineoplastic therapies, cladribine was identified as a lymphocyte-specific agent. Its profound impact on the natural history of hairy cell leukemia, with responses approaching 100% and a median duration of response of nearly a decade after only a single 7-day course, is well known and revolutionized the treatment of hairy cell leukemia. However, cladribine's impressive activity in other lymphoproliferative disorders has been generally underappreciated. Multiple single-arm phase 2 trials have demonstrated cladribine's potency across the full spectrum of lymphoid malignancies. In a limited number of phase 3 trials and cross-study analyses, cladribine compared favorably with fludarabine, another purine nucleoside analog that is more commonly used in the treatment of indolent lymphoid malignancies. Cladribine has been noted to have particular activity among lymphoid disorders with few effective therapies, specifically, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma. Recently approved novel agents may act in synergy with cladribine for these conditions and should be incorporated into future clinical studies.

In vivo targeting of B-cell lymphoma with glycan ligands of CD22.

Antibody-mediated cell depletion therapy has proven to provide significant clinical benefit in treatment of lymphomas and leukemias, driving the development of improved therapies with novel mechanisms of cell killing. A current clinical target for B-cell lymphoma is CD22, a B-cell-specific member of the sialic acid binding Ig-like lectin (siglec) family that recognizes alpha2-6-linked sialylated glycans as ligands. Here, we describe a novel approach for targeting B lymphoma cells with doxorubicin-loaded liposomal nanoparticles displaying high-affinity glycan ligands of CD22. The targeted liposomes are actively bound and endocytosed by CD22 on B cells, and significantly extend life in a xenograft model of human B-cell lymphoma. Moreover, they bind and kill malignant B cells from peripheral blood samples obtained from patients with hairy cell leukemia, marginal zone lymphoma, and chronic lymphocytic leukemia. The results demonstrate the potential for using a carbohydrate recognition-based approach for efficiently targeting B cells in vivo that can offer improved treatment options for patients with B-cell malignancies.

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.

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.

Primary intraocular lymphoma: a review.

Primary intraocular lymphoma (PIOL) is a rare, non-Hodgkin lymphoma considered to be a subtype of primary central nervous system lymphoma. We describe a 65-year-old woman who presented to the Hematology/Oncology Clinic at Scripps Clinic, La Jolla, California, who was diagnosed with bilateral PIOL without systemic disease. She enjoyed a 16-month remission but ultimately recurred in the brain. We reviewed the literature and present a discussion of the diagnostic criteria for PIOL and current strategies for treating PIOL in immunocompetent patients.

ABO phenotype and clinical correlates of COVID-19 severity in hospitalized patients.

AIM: This study investigates the association between ABO blood phenotype and COVID-19 severity, measured by intensive care unit admission, need for intubation, hospitalization length and death. It further explores clinical predictors of COVID-19 severity within a primarily Hispanic demographic in San Diego County. MATERIALS & METHODS: We retrospectively reviewed 942 total patients, 473 with available blood type, hospitalized at five Scripps Health hospitals with COVID-19. RESULTS: No significant association was found between ABO phenotype and COVID-19 severity on multivariate analysis, while a diagnosis of anemia and male sex was associated with all severity outcomes on exploratory analysis. CONCLUSION: Our results provide relevant clinical correlates of COVID-19 severity and help better elucidate the association between ABO phenotype and COVID-19.

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.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo.

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non-small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent.

Novel therapeutics in hairy cell leukemia.

Introduction: Hairy Cell Leukemia (HCL) is an indolent lymphoproliferative disorder resulting in a high complete response rate when treated with purine nucleoside analogs. However, at some time, nearly all patients relapse. In the relapsed setting, historically, options beyond repeat treatment with a purine nucleoside analog were limited. A number of novel agents have now been prospectively studied clinically for HCL in this setting.Areas covered: A review of the prospective data on newer agents in the relapsed setting is discussed. Emphasis is placed on overall response rates, complete response rates, minimal residual disease rates, and toxicities. The drugs vemurafenib, moxetumumab-pasudotox, bendamustine, and ibrutinib, all of which are commercially available, are reviewed in greatest detail.Expert opinion: Despite the number of prospective studies recently published on these agents in HCL, questions remain about which agents to use, when to best utilize them, how to best dose or schedule them, and the role of combination therapy. Further clinical research is required to answer these questions and to discover other drugs effective in the treatment of relapsed HCL.

Hairy cell leukemia.

Hairy cell leukemia is an indolent B-cell non-Hodgkin's lymphoma with a characteristic presentation of pancytopenia, splenomegaly, and circulating hairy cells. An immunophenotypic pattern of CD11c, CD25, and CD103 expression. TRAP staining, reticulin deposition, and morphology of bone marrow and circulating cells help establish the diagnosis. Although up to 10% of patients might not require systemic treatment, for the vast majority effective treatments are available with the purine-nucleoside analogues cladribine and pentostatin. Cladribine is considered the drug of choice in the first-line setting due to the very high complete remission rate and prolonged duration of response following a single 7-day infusion. Cladribine and pentostatin both have unique but different mechanisms of action, with a lack of cross-resistance between them, which might be exploited in the relapsed or refractory disease setting. Therapy for relapsed and refractory patients also includes novel biologic agents as well as splenectomy. Despite the effective treatment options, the prospect of cure remains elusive due to the frequent presence of MRD even in complete responders. Future studies employing combination therapies targeting the eradication of MRD will hopefully improve relapse-free survivals as well as overall survival, and might even offer the prospect of cure.