scholarly journals Vemurafenib Has Potent Antitumor Activity in Patients with Relapsed/Refractory BRAF Mutant Hairy Cell Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 24-24
Author(s):  
Jae H Park ◽  
Stephen S. Chung ◽  
Young Rock Chung ◽  
Helen Won ◽  
Eunhee Kim ◽  
...  
Keyword(s):  
Map Kinase ◽  
Hairy Cell Leukemia ◽  
Response Rate ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Purine Analogs ◽  
Promising Therapeutic Target ◽  
Map Kinase Pathway ◽  
Braf Mutant

Abstract Background: Although treatment with purine analogs is associated with a high response rate, hairy cell leukemia (HCL) remains incurable with a 30-40% relapse rate. For these patients (pts) and those intolerant to purine analogs, novel therapies are needed. The major finding that BRAFV600E mutations occur in 98% of HCL suggests BRAF as a promising therapeutic target. We therefore designed a phase II trial to (1) determine the clinical efficacy of the BRAF inhibitor vemurafenib in pts with relapsed/ refractory HCL and (2) identify biologic determinants of response and resistance to vemurafenib in HCL. Patients and Methods: Pts 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 pts received vemurafenib 960mg twice daily for 3 months. Bone marrow (BM) evaluations were performed after 3 months to assess response. Pts with partial (PR) or complete response (CR) with detectable minimal residual disease (MRD) were allowed to receive vemurafenib for up to 3 additional months. The primary endpoint of the study was overall response rate (ORR: CR + PR). Using a Simon’s mini-max two-stage design, if at least 4 of the 19 pts (≥20%) achieve ORR in the first stage, an additional 17 patients will be accrued to the second stage. If 11 or more pts achieve ORR out of the 36 pts, the study would be considered worthy of further investigation. Serial peripheral blood and/or BM samples were collected during the study for quantitative BRAF mutant allele burden, serum cytokine, multiparameter flow cytometry, and targeted next-generation sequencing analysis of a 350-gene panel to detect potential predictors of resistance and identify genes collaborating with BRAF mutations in HCL. Results: 22 pts have been enrolled and 20 pts received treatment. The median age was 61 years (range 44-77), and the median number of prior treatments was 3.5 (range 1-7). 20 pts are evaluable for toxicity and 17 patients for disease response with a median follow up of 10 months (range 2-19). The most common adverse events were rash (40%, Gr1-2), arthralgia (30%, Gr1-2), photosensitivity (20%, Gr1), and pruritis (15%, Gr1). Three pts developed squamous cell carcinoma (SCC), all of whom had previous history of SCC. All patients were able to complete the intended treatment (3 cycles: 11 pts, >3 cycles: 6 pts). All 17 evaluable pts achieved complete hematologic recovery with an overall response rate (ORR) of 100%. 6 pts achieved CR (4 MRD- and 2 MRD+) and 11 pts achieved PR with very minimal disease (Figure 1). Responses were rapid with reduction of circulating hairy cells within 24 hours and normalization of sCD25 within 2-3 weeks (Figure 2). This correlated with dephosphorylation of ERK at 1 month. Several additional inflammatory cytokines correlated with the leukemic cell burden identifying novel tumor markers in HCL including sTNF-R2, sIL-1R2, and sIL4R. Genetic analysis identified a median of 3 (range 0-5) somatic mutations co-existing with the BRAFV600E mutation in HCL including recurrent mutations in MLL2 and CREBBP (Figure 2). Several of these alterations were present as minor clones identifying a clonal architecture in HCL which was not previously appreciated. One pt was found to have de novo resistance to vemurafenib. Genetic analysis identified that this pt’s pretreatment HCL cells harbored a previously undescribed missense mutation in IRS1 (IRS1P1201S) in addition to BRAFV600E mutation. Given prior knowledge that IRS1 (Insulin Receptor Substrate 1) activates both MAP kinase and PI3K-AKT signaling, we compared the effects of expression of wildtype and mutant IRS1 cDNAs on signaling. This revealed robust activation of PI3K-AKT signaling induced by IRS1P1201S-mutant cells relative to wildtype. Conclusions: While longer follow-up is needed to assess the durability of the response, our results indicate that vemurafenib has potent antitumor activity in pts with relapsed/refractory BRAF mutant HCL. These data confirm the MAP kinase pathway as a rational promising therapeutic target in HCL and identify activation of signaling pathways parallel to the MAP kinase pathway as a first mechanism of RAF inhibitor resistance in a hematological malignancy. Subsequent studies will be required to prove that inhibition of B-raf may be the best initial therapy in HCL pts who require treatment. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Park: Genentech: Research Funding. Off Label Use: Vemurafenib in hairy cell leukemia. Rosen:Novartis: Consultancy.

Antigenic Variation of Hairy Cell Leukemia Defines a CD25 Negative Variant with a Uniform Immunophenotype and Distinct Clinicopathologic Features.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1102-1102
Author(s):  
Henry Y. Dong
Keyword(s):  
Flow Cytometry ◽  
Hairy Cell Leukemia ◽  
Standard Therapy ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Overall Response

Abstract Classical hairy cell leukemia (HCL) coexpressing both CD25 and CD103 is highly responsive to the treatment with cladribine and pentostatin (complete response rate, 75–95%; overall response rate, 86–100%). HCL variant in the literature is characterized by HCL-like morphology, lack of CD25 coexpression, and variable immunophenotypes indistinguishable from those of splenic marginal zone B cell lymphoma (Matutes, et al. Leukemia2001; 15:184). Importantly, HCL variant is associated with a poor response to standard therapy. It is unclear if HCL cases lacking CD25 but otherwise phenotypically identical to classical HCL belong to HCL or HCL variant, and if the standard therapy is effective in these patients. To further delineate features of HCL and its variants, we analyzed immunophenotyping data, by flow cytometry or immunohistochemistry, or by both when feasible, in 260 consecutive patients with HCL (Dong, et al. Mod Pathol2003; 16:230A). The diagnosis was established by hairy cell morphology together with coexpression of strong CD20 and CD22, bright CD11c, and CD103. Clinical data were obtained for a subset of cases in which expression of CD25 was distinctly absent. Our results were consistent with the literature in that HCL has a consistent and unique immunophenotypic profile, which allowed detection of residual HCL by flow cytometry at levels as low as 0.1% of total cells. In addition, approximately 20% and 37% of classical HCL coexpressed CD10 and BCL-1 respectively, which may significantly confuse the diagnosis in an incomplete work-up. Interestingly, there were 43 cases (20% of all CD103+ cases) that lacked CD25 but were otherwise identical to classical HCL in their uniform phenotypic profiles. Compared with classical HCL, patients with the CD25- HCL were generally older (medium age: 59yrs vs. 79yrs; p=0.001) and frequently had leukocytosis (medium WBC: 3.0x109/L vs. 24.5x109/L; p=0.014). Among 14 patients with follow up data, 7 were treated with cladribine or pentostatin. The complete response (CR) rate was 14.3% (1/7) and the overall response rate was 57.1% (4/7). Three patients had no response. One patient who had an initial partial response (PR) to pentostatin died of the disease 10 months after the diagnosis. Of others, an additional two patients achieved CR and PR upon initial treatment with fludarabine and Rituxamab respectively. Four patients were untreated and were alive with disease (follow up, 21–41 months). One patient died of the disease in 2 years and treatment for this patient was unknown. These clinical features overlapped with those of HCL variant in the literature. However, unlike the HCL variant that has significant phenotypic heterogeneity, including lack of CD11c and CD103 in a substantial number of cases, the CD25- HCL was remarkably uniform in phenotype and can be easily identified by immunophenotyping. In conclusion, these results suggest that lack of CD25 in HCL defines a clinically distinct chronic lymphoproliferative disorder, which appears to require different clinical management.

A Randomized Study of Daily Versus Weekly Administration of 2-Chlorodeoxyadenosine in Patients with Hairy Cell Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1352-1352 ◽  
Author(s):  
Reinhard Zenhausern ◽  
Nicolas Leupin ◽  
Shu-Fang Hsu Schmitz ◽  
Max Solenthaler ◽  
Andre Tichelli ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Hairy Cell Leukemia ◽  
Bolus Injection ◽  
Response Rate ◽  
Acute Infection ◽  
Severe Neutropenia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Weekly Administration

Abstract Background: In hairy cell leukemia (HCL), one cycle of 2-chlorodeoxyadenosine (CDA) is considered a standard treatment. The treatment often results in a high frequency of severe neutropenia and neutropenic fever. Weekly administration of CDA has been reported as effective as daily administration, but with a reduction of febrile episodes and infectious complications. This trial compares the two regimens for efficacy and toxicity. Design and Methods: HCL patients (pts) were randomized to receive either the standard schedule CDA 0.14 mg/kg/day as a s.c. bolus injection on days 1–5 (Arm A) or the experimental schedule of one weekly dose of CDA 0.14 kg/day as a s.c. bolus injection on five consecutive weeks (Arm B). The primary endpoint was the average of 6 weekly white blood cell count after randomization, analyzed using ANCONA to adjust for baseline count. 100 pts were required to detect a difference between 0.8 G/L and 1.2 G/L with 5% type I errror and 80% power. Secondary endpoints were response rates, other acute hematotoxicity, acute infection rate and fever within 10 weeks, remission duration (RD), event-free survival (EFS) and overall survival. Clinical and laboratory examinations were repeated weekly during the first 6 weeks, then biweekly up to week 10, every 3 months up to 2 years and every 6 months thereafter. Response was assessed at week 10, then every 6 months up to 2 years, and every year thereafter. Results: 50 pts were enrolled to each arm. There was no significant difference between treatment arms (A vs. B) in the primary endpoint (2.2 G/L vs. 3.0 G/L), the rate of grade 3/4 leucocytopenia (94% vs. 84%) or neutropenia (90% vs. 80%), acute infection of any grade (44% vs. 40%), fever (44% vs. 38%), hospitalization (38% vs. 34%), and blood transfusion (22% vs. 30%). Response rate (CR + PR) at week 10 was 78% with 95% confidence interval (CI) (64%, 88%) vs. 68% with CI (54%, 80%) (1-sided p-value 0.13). Over all follow-up visits the best response rate was improved to 86% in both arms. The median follow-up time was 50.2 months vs. 42.3 months. The median values for RD and EFS have not been reached, and the between-arm differences were not significant. One pt in each arm died during treatment and one additional pt in arm A died during follow-up. Conclusions: Weekly application of CDA fails to show any advantage in toxicity or efficacy compared to standard approach.

scholarly journals Moxetumomab pasudotox in heavily pre-treated patients with relapsed/refractory hairy cell leukemia (HCL): long-term follow-up from the pivotal trial

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Robert J. Kreitman ◽  
◽  
Claire Dearden ◽  
Pier Luigi Zinzani ◽  
Julio Delgado ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Braf Inhibitor ◽  
Nucleoside Analogs ◽  
High Rate ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Long Term Follow Up

Abstract Background Moxetumomab pasudotox is a recombinant CD22-targeting immunotoxin. Here, we present the long-term follow-up analysis of the pivotal, multicenter, open-label trial (NCT01829711) of moxetumomab pasudotox in patients with relapsed/refractory (R/R) hairy cell leukemia (HCL). Methods Eligible patients had received ≥ 2 prior systemic therapies, including ≥ 2 purine nucleoside analogs (PNAs), or ≥ 1 PNA followed by rituximab or a BRAF inhibitor. Patients received 40 µg/kg moxetumomab pasudotox intravenously on Days 1, 3, and 5 of each 28-day cycle for up to six cycles. Disease response and minimal residual disease (MRD) status were determined by blinded independent central review. The primary endpoint was durable complete response (CR), defined as achieving CR with hematologic remission (HR, blood counts for CR) lasting > 180 days. Results Eighty adult patients were treated with moxetumomab pasudotox and 63% completed six cycles. Patients had received a median of three lines of prior systemic therapy; 49% were PNA-refractory, and 38% were unfit for PNA retreatment. At a median follow-up of 24.6 months, the durable CR rate (CR with HR > 180 days) was 36% (29 patients; 95% confidence interval: 26–48%); CR with HR ≥ 360 days was 33%, and overall CR was 41%. Twenty-seven complete responders (82%) were MRD-negative (34% of all patients). CR lasting ≥ 60 months was 61%, and the median progression-free survival without the loss of HR was 71.7 months. Hemolytic uremic and capillary leak syndromes were each reported in ≤ 10% of patients, and ≤ 5% had grade 3–4 events; these events were generally reversible. No treatment-related deaths were reported. Conclusions Moxetumomab pasudotox resulted in a high rate of durable responses and MRD negativity in heavily pre-treated patients with HCL, with a manageable safety profile. Thus, it represents a new and viable treatment option for patients with R/R HCL, who currently lack adequate therapy. Trial registration ClinicalTrials.gov identifier: NCT01829711; first submitted: April 9, 2013. https://clinicaltrials.gov/ct2/show/NCT01829711

scholarly journals A single cycle of 2-chlorodeoxyadenosine results in complete remission in the majority of patients with hairy cell leukemia

Blood ◽  
1992 ◽  
Vol 80 (9) ◽  
pp. 2203-2209 ◽  
Author(s):  
MS Tallman ◽  
D Hakimian ◽  
D Variakojis ◽  
D Koslow ◽  
GA Sisney ◽  
...  
Keyword(s):  
Complete Remission ◽  
Interferon Alpha ◽  
Hairy Cell Leukemia ◽  
Complete Recovery ◽  
Community Acquired Pneumonia ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Single Cycle ◽  
Severe Pancytopenia

Abstract Twenty-six patients with hairy cell leukemia (HCL) were treated with 2- chlorodeoxyadenosine (2-CdA), a purine analogue resistant to adenosine deaminase, at 0.1 mg/kg/d for 7 days by continuous intravenous infusion. Fifteen patients were previously untreated, while 11 patients had received prior treatment with splenectomy alone (three patients), interferon alpha alone (four), splenectomy, then interferon alpha (two), or splenectomy, interferon alpha, then 2-deoxycoformycin (2-DCF) (two). Sixteen (80%) of 20 patients evaluable at 3 months achieved complete remission (CR), and four (20%) achieved partial remission (PR) following a single cycle of therapy. All four patients in PR had complete recovery of their peripheral blood counts (except one patient whose platelet count remained 84,000/microL), but had residual HCL in the bone marrow (three patients) or residual splenomegaly (one). Patients with bulky adenopathy, massive splenomegaly, and severe pancytopenia responded as well as those with only modest marrow involvement. The three patients with residual marrow disease received a second cycle of 2-CdA, and two have attained CR. Therefore, 18 of 20 (90%) achieved CR with either one or two cycles of therapy. No patient achieving CR has relapsed at a median follow-up of 12 (+/- 2.1) months. Toxicities included myelosuppression and culture-negative fever. A community-acquired pneumonia was the only infectious complication. Since a single cycle of 2-CdA induces sustained CR in the vast majority of patients with minimal toxicity, this agent is emerging as the treatment of choice for all patients with HCL.

Randomized comparison of pentostatin versus interferon alfa-2a in previously untreated patients with hairy cell leukemia: an intergroup study.

1995 ◽  
Vol 13 (4) ◽  
pp. 974-982 ◽  
Author(s):  
M Grever ◽  
K Kopecky ◽  
M K Foucar ◽  
D Head ◽  
J M Bennett ◽  
...  
Keyword(s):  
Complete Remission ◽  
Hairy Cell Leukemia ◽  
Partial Remission ◽  
Clinical Status ◽  
Multivariate Logistic Regression Analysis ◽  
Response Rates ◽  
Interferon Alfa ◽  
Hairy Cell ◽  
Cell Leukemia

PURPOSE Therapy of hairy cell leukemia has markedly improved. Interferon alfa-2a and pentostatin are active agents. The National Cancer Institute organized an intergroup trial to compare these agents prospectively in untreated patients. METHODS Patients were randomized to receive either interferon alfa-2a (3 x 10(6) U subcutaneously three times per week) or pentostatin (4 mg/m2 intravenously every 2 weeks). Patients who did not respond to initial treatment were crossed over. RESULTS Of 356 patients on study, 313 were eligible. Among interferon patients, 17 of 159 (11%) achieved a confirmed complete remission and 60 of 159 (38%) had a confirmed complete or partial remission. Among pentostatin patients, 117 of 154 (76%) achieved a confirmed complete remission and 121 of 154 (79%) had a confirmed complete or partial remission. Additional patients achieved criteria for complete remission, but lacked confirmatory follow-up evaluation. Response rates were significantly higher (P < .0001) and relapse-free survival was significantly longer with pentostatin than interferon (P < .0001). The median follow-up duration is 57 months (range, 19 to 82). Myelosuppression was more frequent with pentostatin (P = .013). A multivariate logistic regression analysis of the confirmed complete remissions on pentostatin showed the following factors to be important for achieving a complete remission: high hemoglobin level (two-tailed P = .024), young age (P = .0085), and no or little splenomegaly (P = .0029). CONCLUSION Both agents were well tolerated. Pentostatin produced higher response rates, and the responses were durable. Patient age and clinical status had an impact on outcome with pentostatin. Pentostatin is effective therapy for hairy cell leukemia.

scholarly journals Incidence of response and long-term follow-up in patients with hairy cell leukemia treated with recombinant interferon alfa-2a [see comments]

Blood ◽  
1990 ◽  
Vol 75 (4) ◽  
pp. 839-845 ◽  
Author(s):  
E Berman ◽  
G Heller ◽  
S Kempin ◽  
T Gee ◽  
LL Tran ◽  
...  
Keyword(s):  
Disease Progression ◽  
Hairy Cell Leukemia ◽  
Interferon Alfa ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Minor Response ◽  
Recombinant Interferon ◽  
Long Term Follow Up

Abstract Thirty-five evaluable patients with hairy cell leukemia (HCL) were treated with recombinant interferon alfa-2a (rIFN-alpha 2a), given at a dose of 3 X 10(6) units (U) intramuscularly (IM) daily for 6 months followed by 3 X 10(6) U IM three times a week for an additional 18 months in a single institution study. All treatment was stopped after 24 months. Sixty-nine percent of patients achieved a partial response, 11% a minor response, and 3% (one patient) had stable disease. Six patients (17%) did not respond to rIFN-alpha 2a. Two patients (6%) achieved a response but later progressed on treatment. A total of 23 patients completed 2 years of treatment and are evaluable for long-term follow-up at a median of 20 months postcompletion of therapy (range 9 to 32 months). Eleven patients (48%) have had progression of their disease at a median of 10 months (range .5 to 25 months) after treatment was discontinued. Statistical analysis of pretreatment patient characteristics did not reveal any factor(s) associated with a high probability of responding to rIFN-alpha 2a; however, analysis of post-treatment variables measured after 2 years of treatment suggested that a low platelet count was associated with a high rate of disease progression. These findings are compared with other published trials using rIFN-alpha 2b, a similar but not identical rIFN preparation. We conclude that while rIFN-alpha 2a has a high overall response incidence, the rate of disease progression after therapy is discontinued approaches 50%, and that a subset of patients can be identified who are at high risk for recurrence after completing 2 years of treatment.

Treatment of hairy cell leukemia with alternating cycles of pentostatin and recombinant leukocyte A interferon: results of a phase II study.

1990 ◽  
Vol 8 (4) ◽  
pp. 721-730 ◽  
Author(s):  
A Martin ◽  
S Nerenstone ◽  
W J Urba ◽  
D L Longo ◽  
J B Lawrence ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Hairy Cell Leukemia ◽  
Pathologic Complete Response ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Cell Infiltrate ◽  
Recombinant Interferon ◽  
Bone Marrow Biopsies ◽  
Hairy Cells

Fifteen patients with hairy cell leukemia (HCL) were treated with deoxycoformycin (pentostatin; dCF) (4 mg/m2 intravenous [IV] every week x 3) and recombinant interferon-alpha 2a (rIFN-alpha 2a) (3 x 10(6) units subcutaneously [SC] daily x 4 weeks) in alternating months for a total of 14 months. Eleven patients had undergone splenectomy; four had received prior systemic therapy with chlorambucil and/or steroids. All 15 are evaluable for toxicity and peripheral blood response, while 14 are assessable for bone marrow response. Toxicity was tolerable with grade 3 or 4 nausea and vomiting in three patients, neutropenic fevers in five, transient but significant depression in eight, and localized cutaneous herpes zoster in four. Circulating hairy cells were undetectable by the end of the first month in 10 of 13 patients, and by the end of the second month in the other three. Fourteen patients had bilateral bone marrow biopsies performed at baseline after 6 months of treatment, at the end of treatment (14 months), and at 6-month intervals during follow-up. Before treatment, all patients had hypercellular marrows with hairy cels replacing normal marrow elements; all showed at least a 95% clearing of their hairy cell infiltrate by 6 months of therapy. However, small collections of residual hairy cells could be detected intermittently on at least one side of bilateral samples in all patients. All patients have completed treatment with a median duration of follow-up off therapy of 27 months (range, 15 to 31 months). To date, all peripheral counts and serum soluble interleukin-2 receptor (sIL2R) levels remain stable, and no patient has had progression of the hairy cell infiltrate in the bone marrow. Although no patient achieved a pathologic complete response, alternating monthly cycles of dCF and rIFN-alpha 2a produced durable partial remissions (PRs) in all patients. Continued follow-up is required to determine the length of such remissions.

scholarly journals Minimal residual disease may predict bone marrow relapse in patients with hairy cell leukemia treated with 2-chlorodeoxyadenosine

Blood ◽  
1996 ◽  
Vol 87 (4) ◽  
pp. 1556-1560 ◽  
Author(s):  
S Wheaton ◽  
MS Tallman ◽  
D Hakimian ◽  
L Peterson
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Hematoxylin And Eosin ◽  
Anti Cd20 ◽  
Minimal Residual

Minimal residual disease (MRD) can be detected in bone marrow core biopsies of patients with hairy cell leukemia (HCL) after treatment with 2-chlorodeoxyadenosine (2-CdA) using immunohistochemical (IHC) techniques. The purpose of this study was to determine whether the presence of MRD predicts bone marrow relapse. We studied paraffin- embedded bone marrow core biopsies from 39 patients with HCL in complete remission (CR) 3 months after a single cycle of 2-CdA. Biopsies performed 3 months posttherapy and annually thereafter were examined by routine hematoxylin and eosin (H&E) staining and IHC using the monoclonal antibodies (MoAbs) anti-CD45RO, anti-CD20, and DBA.44. At 3 months after therapy, 5 of 39 (13%) patients had MRD detectable by IHC that was not evident by routine H&E staining. Two of the five patients (40%) with MRD at 3 months have relapsed, whereas only 2 of 27 (7%) patients with no MRD and at least 1 year of follow up relapsed (P = .11). Over the 3-year follow-up period, two additional patients developed MRD. Overall, three of six (50%) patients with MRD detected at any time after therapy have relapsed, whereas only 1 of 25 (4%) patients without MRD has relapsed (P = .016). These data suggest that the presence of MRD after treatment with 2-CdA may predict relapse.

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