Therapy For Hairy Cell Leukemia Research Articles

Новая коронавирусная инфекция COVID-19 у пациентов с волосатоклеточным лейкозом

Aim. To analyze the characteristics of novel coronavirus infection COVID-19 in hairy cell leukemia (HCL) patients and to assess humoral immune response in those of them who had COVID-19 and/or were vaccinated against SARS-CoV-2.
 Materials & Methods. This paper documents the retrospective analysis of the data from 118 HCL patients followed-up at the National Research Center for Hematology from March 2020 to October 2021. Within this period, 99 out of 118 patients had novel coronavirus infection COVID-19; 17 out of 99 COVID-19 patients were vaccinated against SARS-CoV-2 (3 of them prior to being infected and 14 of them after that). The rest of 19 HCL patients without COVID-19 were vaccinated against SARS-CoV-2 during the period from January to October 2021. By the time of HCL diagnosis, the patients were aged 23–74 years (median 47 years), whereas by the time of COVID-19 diagnosis, the age range was 25–82 years (median 55 years). There were 63 men and 36 women.
 Results. Severe CT 3–4 lung lesions were diagnosed in 22 (22 %) patients and detected more often (55 %) prior to therapy for advanced-stage HCL. In patients on therapy for advanced-stage HCL and those in remission, the rate of severe lung lesions (CT 3–4) was 17 % in each group. COVID-19 therapy was administered to 49 (49 %) patients in a special hospital. Mortality in the total cohort was 6 % (n = 6) and differed in patients with advanced-stage HCL (n = 4) and those in remission (n = 2). The patients who received anti-CD20 monoclonal antibodies for < 12 months prior to COVID-19 infection, in 42 % (n = 5) of cases showed seronegativity vs. 5 % (n = 1) of patients who received the same therapy > 12 months before COVID-19 was diagnosed.
 Conclusion. The most severe COVID-19 was observed in chemotherapy-free patients with advanced-stage HCL compared to patients on therapy or in HCL remission. When anti-CD20 monoclonal antibodies were administered for < 12 months prior to COVID-19 diagnosis, the number of patients with negative anti-SARS-CoV-2-IgG immune response increased 15-fold. Mortality in novel coronavirus infection COVID-19 differed at various HCL stages (in remission and at advanced stage).

Outcome of Hairy Cell Leukemia: A Single-center Study

Abstract: BACKGROUND: Hairy cell leukemia (HCL) is a rare chronic B-cell lymphoproliferative disorder. Modern therapy with purine analogs and immunotherapy can provide long-term remission, but the risk of recurrence remains about 40%–50%. The aim of this study was to evaluate the outcome of patients with HCL who received treatment in Nanakali Hospital. PATIENTS AND METHODS: A retrospective cross-sectional study was carried out on 50 patients of HCL diagnosed from 2004 to 2022 in Nanakali Hospital in Erbil City, Kurdistan Region, Iraq. Demographics, clinical presentation, treatment data, complications, response, recurrence, and survival data were collected from medical records. The results were presented with descriptive statistics. Variables were compared by Chi-square analysis. RESULTS: The mean age was 52.64 ± 12.37 years, and 84% were male. The most common presenting symptoms were splenomegaly (18%) and fatigue (14%). The majority (69.6%) received cladribine; the response rate was 73.9%, with a complete remission (67.4%). 47.8% had recurrent disease. The most common adverse effects were febrile neutropenia (58.7%) and Grade III and IV hematologic toxicity (41.3%). The results were significantly associated with ANC pretreatment (P = 0.019), comorbidity (P = 0.001), and treatment response (P = 0.004). Cladribine–rituximab combination resulted in complete remission (100%). Ten-year overall survival was 70%. CONCLUSIONS: The results were broadly consistent with literature reports, demonstrating the efficacy and safety of cladribine with/without rituximab as first-line therapy for HCL but with a 30% mortality of concern. Further studies should identify modifiable factors that affect poor prognosis in subgroups to guide improvements in risk management of HCL.

Vemurafenib and Obinutuzumab as Frontline Therapy for Hairy Cell Leukemia

BackgroundHairy cell leukemia (HCL) is characterized by the underlying genetic lesion of BRAFV600E and responsiveness to BRAF inhibitors. We assessed the safety and activity of the BRAF inhibitor vemurafenib combined with obinutuzumab in patients with previously untreated HCL.MethodsWe conducted a single-arm, multicenter clinical study of vemurafenib plus obinutuzumab. Vemurafenib 960 mg twice daily was administered for four cycles, and obinutuzumab was administered in cycles 2 to 4. The primary end point was complete remission (CR). Secondary end points included assessment of safety, minimal residual disease (MRD), and BRAF allele burden according to digital droplet polymerase chain reaction (ddPCR).ResultsThirty patients were enrolled in the study, and 27 patients completed all four cycles of treatments and achieved CR (90%; 95% confidence interval [CI], 73 to 98). Three patients discontinued the study early because of adverse events and were not evaluable for response. Of the 27 patients who achieved CR, 26 patients (96%; 95% CI, 81 to 99) achieved MRD negativity. BRAFV600E allele was undetectable by ddPCR in all 21 evaluable patients. At a median follow-up of 34.9 months (95% CI, 29.6 to 36.9), no patient experienced disease relapse. The most common vemurafenib-related adverse events were rash and arthralgia. Febrile neutropenia occurred in two patients, and blood or platelet transfusions were required in two patients.ConclusionsCombined time-limited vemurafenib and obinutuzumab achieved CR in more than 90% of patients with previously untreated HCL. In this small study, acquired vemurafenib resistance or dose-limiting toxicity was not observed. Patients were not observed long enough to reveal secondary malignancies. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT03410875.)

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

Hodgkin Lymphoma and Hairy Cell Leukemia Arising from Chronic Lymphocytic Leukemia: Case Reports and Literature Review

Richter’s syndrome represents the progression of chronic lymphocytic leukemia (CLL) to more aggressive diseases, most frequently diffuse large B-cell lymphoma, while Hodgkin’s lymphoma (HL) and hairy cell leukemia (HCL) are rarely described. The first case involved a 67-year-old man with a diagnosis of a high-risk stage-II CLL treated with rituximab and ibrutinib, developed a HL nodular sclerosis variant after three months of therapy for CLL. After achieving a complete remission for HL and ibrutinib cessation because of drug-related cardiotoxicity, the patient relapsed after five months off-therapy and died due to disease progression after two cycles of brentuximab-vedotin. The second case involved an 83-year-old female with a diagnosis of stage-IV CLL treated with rituximab plus bendamustine who developed a HCL eight years later. Pentostatin was unsuccessfully employed as upfront HCL therapy, and the patient was then switched to rituximab while in remission for CLL. In conclusion, Richter’s transformation risk rate might be higher in patients treated with novel targeted therapies, and multiparametric flow cytometry and lymph node biopsy at relapse could help in early identifying small clones. The treatment of predominant neoplasia is mandatory, and disease-specific drugs are administered; however, clinical efficacy might be lower in these patients.

In Vitro Sensitivity to Venetoclax and Microenvironment Protection in Hairy Cell Leukemia.

Current standard treatment of patients with hairy cell leukemia (HCL), a chronic B-cell neoplasia of low incidence that affects the elderly, is based on the administration of purine analogs such as cladribine. This chemotherapy approach shows satisfactory responses, but the disease relapses, often repeatedly. Venetoclax (ABT-199) is a Bcl-2 inhibitor currently approved for the treatment of chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) in adult patients ineligible for intensive chemotherapy. Given that HCL cells express Bcl-2, our aim was to evaluate venetoclax as a potential therapy for HCL. We found that clinically relevant concentrations of venetoclax (0.1 and 1 µM) induced primary HCL cell apoptosis in vitro as measured by flow cytometry using Annexin V staining. As microenvironment induces resistance to venetoclax in CLL, we also evaluated its effect in HCL by testing the following stimuli: activated T lymphocytes, stromal cells, TLR-9 agonist CpG, and TLR-2 agonist PAM3. We found decreased levels of venetoclax-induced cytotoxicity in HCL cells exposed for 48 h to any of these stimuli, suggesting that leukemic B cells from HCL patients are sensitive to venetoclax, but this sensitivity can be overcome by signals from the microenvironment. We propose that the combination of venetoclax with drugs that target the microenvironment might improve its efficacy in HCL.

Loss of interferon antibodies during prolonged continuous interferon-alpha 2a therapy in hairy cell leukemia.

Although highly active in hairy cell leukemia (HCL), interferons (IFN) are not curative in this disease; current data indicate that prolonged IFN therapy will be necessary to control disease in the majority of patients. We previously observed acquired IFN resistance in association with neutralizing IFN-alpha 2a antibodies in small numbers of patients with HCL. This finding suggests that the requisite long-term therapy may be compromised if there is an increasing incidence over time of neutralizing antibodies. We performed a follow-up study of IFN antibodies in our patients receiving continuous IFN therapy. All 16 patients who were previously antibody negative remained so. Surprisingly, all nine patients who previously had non-neutralizing IFN antibodies became antibody negative after a median of 14.5 months. Moreover, 3 of 10 patients who had neutralizing antibodies became antibody negative and five had only non-neutralizing antibodies a median of 10 months from the time neutralizing antibody had first been detected. Only two patients had persisting neutralizing antibodies. Inhibition of neopterin synthesis, inhibition of generation of 2', 5' oligoadenylate synthetase activity, and inability to detect IFN in serum after subcutaneous injection of IFN-alpha 2a was observed only in the one patient tested with neutralizing IFN antibodies confirming that these antibodies have functional significance in vivo. We conclude that, although neutralizing IFN antibodies inhibit the effectiveness of IFN in vivo, these antibodies are produced only transiently during long-term therapy. The long-term effectiveness of this drug will not likely be affected in most patients by neutralizing antibody.

IBCL-341: Inhibitor of B-RAFV600E Mutation in Hairy Cell Leukemia

Context: The use of standard therapy (ST) in hairy cell leukemia (HCL) is often impossible at the time of deep neutropenia (DN) or the development of infectious complications (IC). HCL patients who do not respond to ST present a special therapeutic problem. Objective: Vemurafenib has been used to treat resistant HCL since 2012. Vemurafenib does not have a myelotoxic effect and so can be used in therapy of HCL with DN, as well as in early relapse after ST or as a primary refractory course of HCL (RR). Design: The applicability of vemurafenib in patients with HCL with DN, including patients with IC and RR. Setting: Study setting can be used in hematological inpatient (including intensive care department) and outpatient departments. Patients: Vemurafenib was used in 27 patients with HCL (m: f = 2.4; median age 57 years (24–78 years): six RR patients and 21 patients with DN, including 7 patients with severe infectious manifestations in the intensive care department, including 1 patient on extracorporeal membrane oxygenation. Intervention: Vemurafenib was used in a dose of 240 mg 1–2 times a day. In 26 patients, vemurafenib was used for 3 months or more. Main Outcomes Measures: The response to therapy was evaluated by control of neutrophil count, size of the spleen, and resolution of the IC. Results: In patients with DN, the response was achieved in 95%, followed by 1 course of ST with cladribine. In 1 patient, within 1 month of vemurafenib therapy, the effect was not obtained. Among RR patients, 67% achieved remission of the disease after a course of therapy with vemurafenib for 3 months, followed by a ST of cladribine and maintenance therapy with rituximab or obinutuzumab. There were no complications with the use of vemurafenib. Short agranulocytosis within three days after the course of cladribine was observed in only two patients. Conclusion: Therapy of HCL patients with DN, IC, and RR is a complex therapeutic problem. In cases with proven BRAFV600E mutation, vemurafenib can be effectively used not only in RR patients but as an effective preliminary therapy in patients with DN and IN before a ST with purine analogues.

CLL-358: First-Line Treatment of Hairy Cell Leukemia with Cladribine Followed by Rituximab Consolidation Significantly Improves Leukemia-Free Survival

Context Purine analogue therapy remains the standard of care in hairy cell leukemia (HCL) management. Despite high remission rates, many patients subsequently relapse and require re-treatments. Objective The aim of this study is to compare the effectiveness and safety of cladribine vs. cladribine followed by rituximab consolidation as first-line therapy of HCL. Design This is a retrospective study including all consecutive patients with classical HCL treated and followed at the American University of Beirut Medical Center (AUBMC) between 2000 and 2019. Methods We identified 29 HCL patients, with a median age of 50.5 (range: 30–71) years. Patients were divided into two cohorts based on treatment received: cohort A (N=14) received cladribine 5.6 mg/m2 intravenously (IV) for 7 days as a single agent, and cohort B (N=15) received the same dose of cladribine followed by rituximab 375 mg/m2 IV weekly for eight doses. Rituximab consolidation was given after a median time of 33 days (17–60 days) from cladribine completion. Complete remission rates were 64% and 100% in cohorts A and B, respectively. In cohort A, seven (50%) patients relapsed after a median duration of 48 months (range: 1–209 months), requiring second-line treatment with cladribine followed by rituximab. In cohort B, no relapses occurred. After a median follow up of 67 months (range: 1–227 months), the 5-year disease-free survival was significantly better in group B (100%) compared to group A (58%) (HR=0.16, 95% CI: 0.032–0.84, p=0.03). There was no significant difference in overall survival between the two groups. Grade 3/4 adverse events were observed in 92%% and 80% of patients in cohorts A and B, respectively, mainly neutropenia (78.5% vs 66.6%) and febrile neutropenia (71% vs. 40%). One patient in cohort B who received rituximab consolidation too early (day 17) died from febrile neutropenia and septic shock. Conclusion Consolidation rituximab after cladribine in frontline treatment of classical HCL showed high response rate of 100% and translated into a significant improvement in disease-free survival. Cladribine followed by rituximab consolidation may be considered as standard first-line therapy of HCL.

Atypical features of cutaneous adverse drug reactions during therapy for hairy cell leukemia

Atypical features of cutaneous adverse drug reactions during therapy for hairy cell leukemia

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

BackgroundPurine 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.ResultsIn 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.ConclusionsPNA 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.

Randomized phase II study of cladribine with simultaneous or delayed rituximab in patients with untreated hairy cell leukemia.

7003 Background: Single-agent purine analog therapy, usually cladribine, has been the standard 1st-line therapy of hairy cell leukemia (HCL) for ~30 years. Relapse is attributed to minimal residual disease (MRD) persisting despite complete remission (CR). Rituximab can clear MRD, but there are no long-term data for how frequently and for how long this happens, or even how frequently MRD remains after cladribine. We therefore conducted a randomized phase II trial of 1st-line cladribine with concurrent vs delayed rituximab. Methods: The primary endpoint was to determine if 8 weekly doses of rituximab (375 mg/m2 iv) begun the same day as 5 daily doses of cladribine (0.15 mg/kg iv) reduce HCL MRD 6 months later compared to cladribine alone. Secondary endpoints included testing delayed rituximab, 8 weekly doses beginning if/when MRD is detected in blood (or if HCL-related cytopenias persist preventing consideration of CR) ≥ 6 months after cladribine. Both groups could receive a 2nd course of rituximab if the same situation recurred ≥ 6 months after starting the 1st course of rituximab. MRD was assessed in blood (PB) and bone marrow (BM) using flow cytometry (FC), consensus PCR, and immunohistochemistry. Results: Sixty-eight patients were randomized 1:1 to concurrent vs delayed arms. At 6 months after cladribine, 97% concurrent vs 24% delayed (p &lt; 0.0001) patients were MRD-free by all tests. 100% concurrent vs 41% delayed patients were MRD-free by all tests except BMA FC (p &lt; 0.0001). At a median follow-up of 87.3 months, delayed rituximab was required by 1 concurrent patient vs 27 courses in 21 delayed patients. MRD-free survival after 1st rituximab was not reached for 34 patients after concurrent rituximab, with 32 still MRD-free after a median of 72 months (94% MRD-free survival), compared to median MRD-free survival 60.1 months after delayed rituximab, with 10 (48%) of 21 remaining MRD-free (p &lt; 0.0001, hazard ratio for concurrent rituximab 0.09). Conclusions: Achievement of MRD-free CR after 1st line cladribine for HCL is greatly enhanced by concurrent rituximab. Use of delayed rather than concurrent rituximab could achieve MRD-free CR but durability was clearly inferior to concurrent rituximab. Longer follow-up will determine if MRD-free survival leads to cures of HCL, increased CR duration, and/or less need for additional therapy. Clinical trial information: NCT00923013.

Infection at the Time of Initial Therapy for Hairy Cell Leukemia Is Associated with Inferior Time to Next Treatment

Introduction: Hairy Cell Leukemia (HCL) is a rare, chronic hematological malignancy that makes up approximately 2% of all leukemias. HCL patients are at a markedly increased risk for infection related to a combination of disease-related and treatment-related immunosuppression which has been well described in the literature. However, the significance of infection prior to initiation of HCL therapy and its impact on the subsequent selection of HCL treatment, or outcomes, is not well described. Using the HCL patient data registry, we report here the impact of antecedent infection on the treatment patterns and outcomes of HCL patients.Methods: We evaluated adult (≥18 years) patients with HCL who had information regarding antecedent infections and subsequent HCL treatment during 1984-2018. The primary endpoint was progression-free survival (PFS-1). Secondary endpoint included time to next treatment (TTNT). PFS-1 was measured from the date of first HCL treatment to date of progression/death or last follow-up. TTNT was defined as the time from first HCL treatment to initiation of second HCL treatment. The study population was stratified into 3 groups based on the presence or absence of antecedent infections: no infection prior to first HCL treatment (no infection group), infection within 30 days prior to first HCL treatment (infection1 group) and infection >30 days prior to first HCL treatment (infection2 group). Fisher's exact test or Kruskal-Wallis test was used to compare the characteristics among the no infection and infection groups and the Cox proportional hazard model was used to evaluate the association with PFS-1 and TTNT.Results: A total of 205 HCL patients who had information regarding antecedent infections and subsequent HCL treatment were eligible for the study. Among these, 144 (70%) belonged to the no infection group, while 26 patients (13%) belonged to infection1 group and 35 (17%) to infection2 group. Patient characteristics are shown in Table 1 with a breakdown between the three groups. The majority of the patients were Caucasian with a male preponderance and had classic HCL.The patients in the infection1 group had a lower median WBC (K/uL) (1.9 vs 3.1 vs 2.9), particularly the absolute neutrophil count (K/uL) (0.4 vs 0.7 vs 0.8) and significantly lower median hemoglobin (gm%) (10.1 vs 12.2 vs 12.4) relative to the no infection and infection2 groups, respectively (p=0.01). Similarly, a greater proportion of patients in the infection1 group had significant comorbidities (including pulmonary, gastrointestinal and hepatic disease) relative to no infection and infection2 groups as shown in Table 1. The majority of patients received purine nucleoside analogs as their first HCL treatment (no infection group=92%, infection1 group=85%, infection2 group=94%).The median PFS-1 (in years) was better in the no infection group compared to the infection1 group but was not statistically significant (17.0 [95% CI=7.9-not reached (NR)] vs 8.8 [95% CI=4.2-NR], respectively, p=0.98, Figure 1). However, the median TTNT (in years) was significantly longer for HCL patients with no infection versus the infection1 group (6.3 [95% CI=5.4-7.8] vs 3.6 [95% CI=0.7-NR], respectively, p=0.001, Figure 1). On subgroup analysis, relative to the no infection group, median PFS-1 (in years) was not significantly different in infection1 group treated with Pentostatin (10.7 [95% CI=3.53-NR] vs NR [95% CI=1.38-NR], respectively, p=0.43), however, the median PFS-1 (in years) was shorter in the infection1 group treated with Cladribine (17.0 [95% CI=7.67-NR] vs 4.0 [95% CI=2.00-NR], respectively), although not reaching statistical significance (p=0.09) probably due to small sample size.Conclusion: In this large series of HCL patients who received treatment, we show that the patients who had infections at the time of HCL treatment have a significantly shorter TTNT. The reasons for this are unclear but may indicate that patients were unable to receive treatment in a timely manner because of the infection, or were unable to complete treatment because of complications. The significant difference in hemoglobin between the infection1 and other groups indicates the possibility that these patients had more advanced HCL at the time of diagnosis. These findings indicate the potential long term negative impact of infections in patients who need treatment for HCL and reinforce the need for careful management in this setting. [Display omitted] DisclosuresLozanski:Beckman: Research Funding; Coulter: Research Funding; Stem Line: Research Funding; Genentech: Research Funding; Novartis: Research Funding; BI: Research Funding. Andritsos:HCLF: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy.

Impact of Rituximab in the Clinical Outcomes of Hairy Cell Leukemia: A Single-Institution Analysis

Background: Hairy cell leukemia (HCL) is an indolent mature B-cell disorder that comprises ~2% of all leukemias. Purine analoguess (PNAs) such as cladribine (2-CdA) remains as the standard initial treatment with high response rate, but frequent late relapses occur. The addition of rituximab (R) has shown efficacy as a single agent and in combination in the first- and second-line settings. In this single-institution study, we show the impact of rituximab (R) in the outcomes of HCL.Methods: An IRB-approved retrospective analysis was performed using patients diagnosed with HCL or HCL-variant (HCLv) who were seen at Moffitt Cancer Center between January 2000 and February 2018. Clinical and pathologic data at diagnosis as well as treatment history and clinical outcome data were collected. Primary endpoints were overall (OS) and progression-free survival (PFS). Secondary endpoints included overall response rate (ORR) defined as complete response + partial response (CR + PR). Statistical comparisons and survival analyses were performed using SPSSTM Statistics and GraphPad PrismTM.Results: We identified 136 patients but 104 cases had available treatment data and follow up (96 HCL, 8 HCLv). The median follow-up was 79 months. The median age was 57 years (27 - 89) with a male:female ratio of 3.7:1 . Regarding symptoms present at diagnosis, most patients presented with cytopenias and splenomegaly (70% and 34%, respectively), with weight loss and recurrent infections present in 11% and 13%, respectively. The 5 and 10 year OS was 97% and 91%, respectively, with 2 deaths reported secondary to HCL. The median PFS for all patients receiving first-line therapy was 93 months. Several clinical and pathologic factors present at diagnosis were independently associated with worse PFS, including recurrent infections (HR 3.11, p = 0.01), weight loss (HR 2.67, p = 0.019), diagnosis of HCL-v (HR 3.22, p = 0.015), Hgb < 12 gm/dL (HR 2.41, p = 0.054), and abnormal cytogenetics (HR 13.6, p = 0.01). There were 18 patients in the treated population with known BRAF mutation status (11 positive, 7 negative) which did not correlate with PFS. Patients who achieved a CR after 1st line therapy had significantly longer PFS compared to those who achieved a PR (median PFS 103 vs 39 months, p = 0.001). Most patients received 2-CdA or 2-CdA+R (79 and 13, respectively) as first line with a higher CR rate in the 2-CdA+R group (100% vs 73%) and a higher median PFS for [not reached (NR) and 82 months, respectively, p= 0.09] with only 1 relapse in the 2-CdA+R group. In the 2nd line setting, 2-CdA+R (n=9) was also associated with a higher CR rate than 2-CdA alone (n=15, 89% vs 80%) with only 1 relapse in the 2-CdA+R group at 97 months. The median PFS for 2nd line 2-CdA+R vs 2-CdA was 97 and 43 months, respectively (p=0.31).Conclusions: In this study, we report a large, single-institution dataset of HCL and HCLv patients with long-term follow-up. The addition of rituximab improved the PFS in patients with HCL in the first-line and relapse settings and should be considered as a reasonable addition in the therapy for HCL even in the absence of randomized trials. DisclosuresChavez:Humanigen: Consultancy; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Speakers Bureau.

SIL2R ratio as early marker for response in hairy cell leukemia and the prognostic relevance of IL28B genotype to interferon-α therapy.

Interferon-α (IFNα) was the first effective drug therapy for hairy cell leukemia (HCL). Nowadays, it is used as an alternative treatment in selected patients. Due to unlimited treatment time, monitoring and early prediction of response are important. Moreover, IFNα is used in the therapy of chronic hepatitis C, where a single nucleotide polymorphism of interleukin-28B gene (IL28B) correlates with therapy response. The role of this polymorphism in therapy response of IFNα-treated patients with HCL is unknown. Thirty-seven HCL patients treated between 1978 and 2014 were included in this study. Treatment strategy and response parameters (blood cell counts, soluble interleukin-2 receptor (sIL2R), and bone marrow examination) have been assessed. Relative decrease of sIL2R was correlated with outcome parameters. Response parameters of IFNα-treated patients were correlated with IL28B polymorphism. Twenty-one patients were analyzed for the correlation of sIL2R ratio and outcome. After 1 and 3months of therapy (IFNα or cladribine (CDA)), the median sIL2R level showed a relative decrease of 79 and 91%. These decreases significantly correlate with time to complete remission (CR, p=0.029 and p=0.018). Correlation analyses of IL28B genotype with outcome parameters are not significant. Six patients (16%) were diagnosed with secondary malignancies, and one death was registered (median follow-up time 14years). IFNα is a safe, effective, and well-tolerated long-term treatment in HCL. Relative decreases of sIL2R levels correlate with time to CR and are useful as early predictor for response. There is no significant correlation between IL28B polymorphism and treatment response to IFNα. Graphical abstract.

Diverse Mechanisms of Vemurafenib Resistance in BRAF-Mutant Hairy Cell Leukemia

▪Background: We previously reported potent anti-tumor activity of the oral BRAF inhibitor vemurafenib in patients with relapsed or refractory BRAF mutant hairy cell leukemia (HCL) (Park et al. ASH 2014). According to the study design, patients whose disease relapsed following the initial treatment were allowed to be re-treated with vemurafenib. Here we report the clinical outcome of patients who were retreated with vemurafenib at relapse following initial treatment, as well as the result of genomic analysis that provided an insight into mechanisms of resistance to BRAF inhibition in HCL.Patients and Methods: Patients with BRAF mutant HCL who were refractory or resistant to purine analogs, or who had ≥2 relapses with an indication for treatment (ANC ≤1.0, HGB ≤10, or PLT ≤100K) were enrolled. Eligible patients received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Patients with partial (PR) or complete response (CR) with detectable minimal residual disease were allowed to receive vemurafenib for up to 3 additional months. After a maximum of 6 months of therapy, patients were observed with monthly CBC. At disease relapse with peripheral blood (PB) counts low enough to meet the initial eligibility criteria, re-treatment with vemurafenib was allowed until disease progression or unacceptable toxicity. Serial PB and/or BM samples were collected for targeted next-generation sequencing analysis of a 300-gene panel to detect contributors to resistance and genes collaborating with BRAF mutations in HCL.Results: 26 patients have been enrolled. 2 patients discontinued treatment before response assessment: 1 patient due to primary refractory disease to vemurafenib and 1 patient due to grade 3 photosensitivity. 24 patients completed at least 3 months of treatment, and therefore are available for efficacy evaluations. Of the 24 evaluable patients, all patients achieved response (10 CR and 14 PR) with the overall response rate of 100% when assessed after 3 months of vemurafenib.With the median follow up of 11.7 months (range, 1.3 - 25.4 months), 7 patients experienced disease relapse (3 previous CR and 4 PR). Of the 7 relapse patients, 6 met re-treatment criteria and restarted vemurafenib. 4 of the 6 patients regained response (all PR) with complete hematologic recovery and remain on therapy. 2 patients discontinued re-treatment before response assessment: 1 patient due to grade 2 photosensitivity and fatigue, and 1 patient due to resistant disease with refractory cytopenia and a rapid increase in splenomegaly.Targeted genomic analysis in 20 patients pre-vemurafenib revealed at least 1 somatic alteration coexisting with the BRAF V600E mutation in every patient, including deletion of 7q in more than half of patients and recurrent mutations in MLL3 and MED12 (Figure). Genomic analysis of the patient with de novo resistance to vemurafenib identified a missense mutation in IRS1 (Insulin Receptor Substrate 1; IRS1 P1201S) in addition to the BRAF V600E mutation. Functional characterization of the IRS1 P1201S mutation in vitro revealed potent induction of MAP kinase and PI3K-AKT signaling by the IRS1 mutant relative to wildtype, consistent with prior knowledge that IRS1 activates both MAP kinase and PI3K-AKT signaling. These data suggest that bypass activation of ERK and parallel activation of the AKT pathway contributed to de novo vemurafenib resistance.In the patient with acquired resistance to vemurafenib, genetic analysis of pretreatment, remission and relapse PB mononuclear cells revealed emergence of 2 separate, activating subclonal KRAS mutations at relapse. The mutations in KRAS were not seen at pretreatment or at remission. Activating RAS mutations are well known mediators of vemurafenib resistance in BRAF V600E-mutant malignancies, and, in this case, the detection of KRAS mutations coincided with clinical relapse and insensitivity to vemurafenib.Conclusions: Despite high response rates after a short course of vemurafenib in most patients, we observed de novo and acquired resistance to vemurafenib. Serial genomic analysis revealed ERK-dependent and independent mechanisms of BRAF inhibitor resistance in HCL. Our data provide the first insights into genetic mechanisms of RAF inhibitor resistance in HCL and suggest combinatorial therapeutic strategies that may have a role in the therapy of HCL. [Display omitted] DisclosuresPark:Amgen: Consultancy; Juno Therapeutics: Other: Advisory Board, Research Funding; Genentech: Research Funding. Off Label Use: Vemurafenib in HCL. Stone:Agios: Consultancy; AROG: Consultancy; Juno: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Celator: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Roche/Genetech: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Novartis: Research Funding. Rai:Nash Family Foundation: Research Funding; Karches Family Foundation: Research Funding; Nancy Marks Family Foundation: Research Funding; Leon Levy Foundation: Research Funding. Altman:Seattle Genetics: Other: Advisory board; Ariad: Other: Advisory board; Spectrum: Other: Advisory board; Novartis: Other: Advisory board; BMS: Other: Advisory board; Astellas: Other: Advisory board; assistance with abstract preparation. Levine:Foundation Medicine: Consultancy; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Loxo Oncology: Membership on an entity's Board of Directors or advisory committees.

Targeted Therapy for Hairy Cell Leukemia

The BRAF V600E mutation is present in tumor cells of hairy cell leukemia (HCL) and is a disease-defining biomarker (NEJM JW Oncol Hemtol Aug 2011 and N Engl J Med 2011; 364:2305). Now, two independent phase II trials, conducted in the U.S. and Italy, have tested the clinical activity of vemurafenib in previously treated HCL …

Series of Hairy Cell Leukemia Patients with Co-Existent Plasma Cell Disorders

Despite a reported increased incidence of secondary hematologic malignancies and plasma cell disorders in the literature, the specific co-existence of hairy cell leukemia (HCL) and monoclonal gammopathies of unknown significance (MGUS) or plasma cell multiple myeloma (MM) has been based on a few case reports. In the following report, we compile clinico-pathologic data on a series of hairy cell leukemia patients with myeloma precursor diseases using immunohistochemistry, molecular polymerase chain reaction (PCR) and multi-parametric flow cytometry (MFC) techniques with an aim to deep sequence these parallel lymphoid processes in the future.Between 2004 and 2014, 6 HCL patients followed at the National Institutes of Health were identified with associated plasma cell disorders, based on presence of increased clonal plasmacytosis in bone marrow and abnormal serum and/or urine protein electrophoresis/immunofixation. Immunohistochemical (IHC) staining for CD20, TRAP, CD138, cyclin D1, kappa and lambda light chains was performed on bone marrow biopsies. MFC using a panel of B-cell antibodies and PCR clonality studies targeting immunoglobulin heavy and light chain loci were performed prior to treatment to confirm the presence of malignant lymphoid clonal processes.Among the 6 hairy cell leukemia patients with associated plasma cell disorders, there were 5 males and one female. Median age was 67 (range, 47-74). Patients prior to treatment showed bone marrow involvement by HCL with 5-90% infiltration. Hairy cells in all patients tested were TRAP positive, Cyclin D1 was positive in 5, and BRAF V600E was detected in 5 of 5 patients tested. All patients were diagnosed as classic HCL, although 1 patient had an additional population consistent with HCL variant. In addition, 3/6 patients (50%) showed mild increase in marrow plasma cells (5-10%) and the other 3 patients (50%) had over 10% of plasma cells in the core biopsy. The mean plasma cell percentage was 10% (3-25%), mean monoclonal protein concentration was 1.3 g/dL, and isotypes included: 4 IgG, 1 IgA, and 1 free kappa only. 3 patients were classified as MGUS and 3 as smoldering MM (SMM). Interestingly, three out of 6 (50%) patients had positive cyclin D1 expression by IHC in both plasma cells and hairy cells. Several patients had evidence of multiple clonal rearrangements by PCR studies. In addition, two patients demonstrated evidence of monoclonal B-cell lymphocytosis (MBL) on MFC. So far, 3 patients achieved complete remission without minimal residual disease (MRD) using moxetumomab pasudotox in one multiply relapsed case, and first line cladribine plus rituximab in 2 newly diagnosed HCL cases, without significant progression to MM. No patients demonstrated end organ damage due to MGUS/SMM after a median follow-up of 4.6 (range 0.9-10.1) years.By using serum studies, IHC staining, PCR and MFC tools, we identified a group of HCL patients with evidence of additional precursor malignant lymphoid disease states, including MGUS/SMM and MBL. Underlying mechanisms of these parallel malignant processes may include global lymphoid dysregulation through common lymphocyte ancestry pathways; or, it could be due to post-immune HCL therapy exposure, or a combination. Currently, we are conducting deep sequencing of these samples with the aim to uncover mechanisms of pathogenesis. Treatments capable of eliminating HCL MRD, including addition of rituximab to first-line cladribine, or single-agent moxetumomab pasudotox for multiply relapsed HCL, might be advantageous for patients who may need treatment for MM in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Rituximab therapy for hairy cell leukemia: a retrospective study of 41 cases.

The purine analogs (PAs) cladribine and pentostatin have transformed the prognosis of hairy cell leukemia (HCL). However, some patients still relapse after PAs, or fail to reach an optimal response, and new agents are needed to further improve treatment outcome. We retrospectively studied 41 HCL patients from 10 centers in France and Belgium, who received 49 treatment courses with the anti-CD20 monoclonal antibody rituximab. Most of the patients were treated at relapse (84% of cases) and rituximab was combined to a PA in 41% of cases. Overall, response rate is 90% including 71% complete hematologic responses (CHRs). Frontline treatment, combination therapy, and absolute neutrophil count were associated with response in multivariate analysis. Three-year relapse-free and overall survivals are 68 and 90%, respectively. When combined to a PA, rituximab yields a 100% response rate, even beyond frontline therapy. In contrast, response rate is only 82% (59% CHR) when rituximab is used alone. In this latter setting, relapse rate is 56% and median time to relapse is 17.5months. All eight patients who were treated two times with the antibody responded again to re-treatment. We confirm the high efficacy of the combination rituximab + PA. However, when rituximab is used as monotherapy, response rate is lower and the high relapse rate is a concern. Prospective clinical trials are needed to confirm the superiority of the combination rituximab + PA over PA alone, both as frontline therapy and at relapse.

Disseminated ulcerating lupus panniculitis emerging under interferon therapy of hairy cell leukemia: Treatment‐ or disease‐related?

We report a 43-year-old woman, who underwent therapy with interferon-α for hairy cell leukemia. During interferon-α therapy she developed multiple subcutaneous swellings, accompanied by fever and fatigue. A skin biopsy revealed lobular, T-cell lymphocytic panniculitis. In conjunction with the clinical and immunological findings, the diagnosis of lupus panniculitis was made and interferon-α therapy stopped. Initially, she responded well to oral prednisone and hydroxychloroquine, but after several months she became resistant to it. Her condition worsened, she developed skin ulcers in the inflamed regions. Only with the leukemia-targeted therapy using cladribine and rituximab her skin condition could be controlled, suggesting hairy cell leukemia as an additional trigger of the lupus panniculitis. Our report is the first one to show induction of lupus panniculitis under interferon therapy of hairy cell leukemia and its presumable sustentation by the latter.