scholarly journals Moxetumomab pasudotox for hairy cell leukemia: preclinical development to FDA approval

2019 ◽  
Vol 3 (19) ◽  
pp. 2905-2910 ◽  
Author(s):  
Adam Yuh Lin ◽  
Shira Naomi Dinner
Keyword(s):  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Cell Surface Expression ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Recombinant Immunotoxin ◽  
Fda Approval

Abstract Moxetumomab pasudotox (MP) is an immunotoxin that recently received US Food and Drug Administration (FDA) approval for the treatment of hairy cell leukemia (HCL) that has failed at least 2 prior lines of therapy, including a purine analog. MP is a recombinant immunotoxin that consists of an anti-CD22 immunoglobulin variable domain genetically joined to Pseudomonas exotoxin (PE38). Unlike most antibody-drug conjugates, which use a chemical linker, recombinant DNA techniques are used to produce MP. MP and its predecessor, BL22, were initially developed to treat non-Hodgkin lymphoma, acute lymphoblastic leukemia, and HCL. However, MP was found to be particularly effective in HCL due to the high level of CD22 cell-surface expression. The recent pivotal phase 3 trial of MP in relapsed/refractory HCL demonstrated a durable complete remission rate of 30%, and 85% of complete responders achieved minimal residual disease negativity, which is associated with improved disease-free survival outcomes in HCL. In addition to an exceptional depth of response, MP appears to be less immunosuppressive than purine analogs. MP is generally well tolerated but has unique toxicities, including capillary leak syndrome and hemolytic uremic syndrome, which are poorly understood. This review will encompass the preclinical and clinical development of MP, with particular attention to its current indication in HCL.

scholarly journals Development of Recombinant Immunotoxins for Hairy Cell Leukemia

Biomolecules ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 1140 ◽  
Author(s):  
Robert J. Kreitman ◽  
Ira Pastan
Keyword(s):  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Apoptotic Cell ◽  
Initial Response ◽  
Braf V600e ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Recombinant Immunotoxin ◽  
Fda Approval ◽  
B Cell Malignancy

Hairy cell leukemia (HCL) is an indolent B-cell malignancy with excellent initial response to purine analogs pentostatin or cladribine, but patients are rarely, if ever, cured. Younger patients will usually need repeat chemotherapy which has declining benefits and increasing toxicities with each course. Targeted therapies directed to the BRAF V600E mutation and Bruton’s tyrosine kinase may be helpful, but rarely eradicate the minimal residual disease (MRD) which will eventually lead to relapse. Moxetumomab pasudotox (Moxe) is an anti-CD22 recombinant immunotoxin, which binds to CD22 on HCL cells and leads to apoptotic cell death after internalization and trafficking of the toxin to the cytosol. Phase I testing achieved a complete remission (CR) rate of 57% in relapsed/refractory HCL. Most CRs were without MRD and eradication of MRD correlated with prolonged CR duration. Patients were often MRD-free after five years. Important mild-moderate toxicities included capillary leak and hemolytic uremic syndromes which could be prevented and managed conservatively. A phase 3 trial met its endpoint of durable CR with acceptable toxicity, leading to FDA approval of Moxe for relapsed/refractory HCL, under the name Lumoxiti. Moxe combined with rituximab is currently being evaluated in relapsed/refractory HCL to improve the rate of MRD-free CR.

Responses in Refractory Hairy Cell Leukemia to a Recombinant Immunotoxin

Blood ◽  
1999 ◽  
Vol 94 (10) ◽  
pp. 3340-3348 ◽  
Author(s):  
Robert J. Kreitman ◽  
Wyndham H. Wilson ◽  
David Robbins ◽  
Inger Margulies ◽  
Maryalice Stetler-Stevenson ◽  
...  
Keyword(s):  
Hairy Cell Leukemia ◽  
Bone Marrow Aspirate ◽  
Residual Disease ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Single Cycle ◽  
Pseudomonas Exotoxin ◽  
Pseudomonas Exotoxin A ◽  
Circulating Cells ◽  
Recombinant Immunotoxin

We report major responses in 4 of 4 patients with hairy cell leukemia (HCL) who have recently been treated on a phase I trial with the recombinant immunotoxin LMB-2. The immunotoxin, designed to target CD25+ malignancies, is composed of the Fv portion of the anti-Tac (anti-CD25) antibody, fused to a 38-kD truncated form of Pseudomonas exotoxin A, and has previously been called anti-Tac(Fv)-PE38. All 4 HCL patients were resistant to standard and salvage therapies for HCL, including 2-chlorodeoxyadenosine (CdA) and interferon , and all patients responded to LMB-2 after a single cycle. One patient treated with 2 cycles had a complete remission (CR), with regression of HCL cells from the blood and marrow and resolution of splenomegaly and pancytopenia. As is typical for patients in CR after treatment with CdA, minimal residual disease was detectable by flow cytometry of the bone marrow aspirate. This patient has not relapsed after 11 months. Three other patients had 98% to 99.8% reductions in malignant circulating cells. These results represent a proof of principal that targeted therapy with recombinant Fv-containing proteins can be clinically useful. LMB-2 may be an effective new therapy for patients with chemotherapy-resistant CD25+HCL.

Modern Strategies for Hairy Cell Leukemia

2011 ◽  
Vol 29 (5) ◽  
pp. 583-590 ◽  
Author(s):  
Michael R. Grever ◽  
Gerard Lozanski
Keyword(s):  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Nucleoside Analogs ◽  
High Rate ◽  
Leukemic Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Minimal Residual

Enormous progress in the treatment of hairy cell leukemia over the last five decades has emerged as a result of organized clinical investigations. Although interferon represented one of the initial major therapeutic advances in the management of this disease in 1984, the subsequent introduction of purine nucleoside analogs (pentostatin and cladribine) changed the natural history of this rare disease by achieving a high rate of complete and durable remissions. The disease-free survival after effective therapy has not reached a plateau, suggesting control but not cure of the disease. Identification of minimal residual disease in patients achieving a complete hematologic remission provides insight into the potential source for predicting eventual relapse. Modern strategies of targeted therapies directed against immunophenotypic markers on the leukemic cells provide hope that improved long-term control of the disease is possible. Combined chemoimmunotherapy may hold the highest promise for disease eradication, but the optimal strategy for using this approach is under active investigation. Despite the perception by hematologists that this disease has already been conquered, there are critically important unanswered questions that remain. Investigation of the bone marrow microenvironment and its impact on minimal residual disease may ultimately prevent relapse. Consideration of the median age of patients at diagnosis combined with a substantial relapse rate mandates continued pursuit of improved therapy. The ultimate goal will be to achieve cure rather than simple control of the disease.

Eradication of minimal residual disease in hairy cell leukemia

Blood ◽  
2006 ◽  
Vol 107 (12) ◽  
pp. 4658-4662 ◽  
Author(s):  
Farhad Ravandi ◽  
Jeffrey L. Jorgensen ◽  
Susan M. O'Brien ◽  
Srdan Verstovsek ◽  
Charles A. Koller ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Nucleoside Analogs ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Consensus Primer ◽  
Number Of Patients ◽  
Minimal Residual

AbstractAlthough the nucleoside analogs cladribine and pentostatin produce high response rates in patients with hairy cell leukemia (HCL), a significant number of patients eventually relapse. Several studies have demonstrated that patients with complete remission (CR) have a longer disease-free survival. Therefore, strategies to improve on the initial response to nucleoside analog therapy are likely to be beneficial, at least for a proportion of patients. We have treated 13 patients with newly diagnosed HCL (n = 11) or after failure of one prior chemotherapy (n = 2) with cladribine (5.6 mg/m2 given intravenously over 2 hours daily for 5 days) followed by 8 weekly doses of rituximab (375 mg/m2). All patients achieved a CR and minimal residual disease (MRD) assessed by consensus primer polymerase chain reaction (PCR) or flow cytometry was eradicated in 11 (92%) of 12 and in 12 (92%) of 13 of patients, respectively. There was no decline in the absolute CD4 and CD8 lymphocyte number after rituximab. We conclude that eradication of MRD in HCL is possible. Whether this leads to a reduced risk of relapse would need to be evaluated in a larger number of patients and with longer follow-up. Disease characteristics may potentially be used to identify patients that are more likely to benefit from such additional therapy.

scholarly journals How I treat hairy cell leukemia

Blood ◽  
2010 ◽  
Vol 115 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Michael R. Grever
Keyword(s):  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Nucleoside Analogs ◽  
Leukemic Cells ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Patient Responses ◽  
Classic Form

Abstract The description of hairy cell leukemia as a specific clinical entity was published 50 years ago. The clinical outcome for patients was hampered by ineffective chemotherapy, and splenectomy was the major therapeutic approach to improve peripheral blood counts. The median survival after diagnosis was 4 years. With the introduction of α-interferon in 1984, marked improvements in patient responses were observed. Shortly thereafter, the introduction of the purine nucleoside analogs transformed this disease into a highly treatable form of leukemia, and patients with the classic form of this rare leukemia now have a near-normal life expectancy. However, other clinical entities mimicking this disease do not respond; thus, accurate diagnosis is important. Immunophenotypic features in classic hairy cell leukemia show that the leukemic cells express CD11c, CD25, CD103, and CD123 and display bright CD20. Despite the high percentage of durable complete remissions with modern therapy, the long-term disease-free survival curves have not reached a plateau. Many patients who achieve a complete remission by morphologic criteria have minimal residual disease demonstrable by either flow cytometry or immunohistochemical staining, and this population may be at higher risk for earlier relapse. Continued clinical research is essential to optimize therapy for this disease.

Long Term Results of BL22 (CAT-3888) in Multiply Relapsed Hairy Cell Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3442-3442 ◽  
Author(s):  
Robert J Kreitman ◽  
Wyndham H Wilson ◽  
Maryalice Stetler-Stevenson ◽  
Pierre Noel ◽  
David J. FitzGerald ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Hairy Cell Leukemia ◽  
Disease Free Survival ◽  
Long Term Results ◽  
Average Dose ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Recombinant Immunotoxin ◽  
Phase I And Ii

Abstract Abstract 3442 Poster Board III-330 BL22 is a 63 kDa anti-CD22 recombinant immunotoxin containing truncated Pseudomonas exotoxin and variable domains from an anti-CD22 antibody. Patients with multiply relapsed/refractory hairy cell leukemia received BL22 and achieved 19 (61%) complete remissions (CRs) and 6 (19%) partial responses (PRs) in phase I testing, and 17 (47%) CRs plus 9 (25%) PRs in phase II testing (n=36), for overall response rates (ORR) of 72-81%. The average dose/cycle was the same for phase I and II (29 vs 33 ug/Kg x3). The dose for phase II was 40 ug/Kg x3 initially and 30 ug/Kg x3 for retreatment, but retreatment was held if patients had hematologic remission (HR, neutrophils ≥ 1500/mm3, Hgb ≥ 11 g/dL, and platelets ≥ 100,000/mm3) after cycle 1. Disease-free survival (DFS, CR duration) for phase II has not yet been reached at a median of 32 (range 4-62) months, with 12 (71%) of 17 CRs still ongoing. Considering all 36 CRs from phase I and II testing, median DFS was 33 (3-112) months with 15 (42%) of 36 CRs ongoing. Patients in CR usually underwent bone marrow biopsy every 6 months for 2 years and yearly thereafter, and after relapsing usually remained in HR. In fact, the median HR duration of these patients has not yet been reached at 42 (range 4-112) months, with 24 (67%) of the 36 patients remaining in HR or CR. Outcomes were better for those with pre-BL22 spleens measuring ≤ 200 mm in height than those with either prior splenectomy or spleens > 200 mm, in terms of CR (68% vs 34%, p=0.007), ORR 95% vs 48%, p=0.000003), and DFS (median 69+ vs 27 mo, p=0.002). In contrast, CR rates or DFS was not related to whether patients had <1 (n=28) or >1 (n=8) years of response to their last course of purine analog (p=0.5-0.75). Of 69 patients who received BL22, 8 (12%) had a completely reversible hemolytic uremic syndrome (HUS) and all maintained normal renal function after a median 80 (9-112) months of follow-up. We conclude that BL22 is highly active producing durable remissions in chemoresistant HCL, particularly in patients with limited disease burden. Testing is underway with a high-affinity version of BL22, called HA22 (CAT-8015). Disclosures Kreitman: NIH: Patents & Royalties. Off Label Use: BL22 is a recombinant immunotoxin which targets CD22+ cells. FitzGerald:NIH: Patents & Royalties. Pastan:NIH: Patents & Royalties.

scholarly journals Phase I Trial of Anti-CD22 Recombinant Immunotoxin Moxetumomab Pasudotox (CAT-8015 or HA22) in Patients With Hairy Cell Leukemia

2012 ◽  
Vol 30 (15) ◽  
pp. 1822-1828 ◽  
Author(s):  
Robert J. Kreitman ◽  
Martin S. Tallman ◽  
Tadeusz Robak ◽  
Steven Coutre ◽  
Wyndham H. Wilson ◽  
...  
Keyword(s):  
Phase I ◽  
Hairy Cell Leukemia ◽  
Neutralizing Antibodies ◽  
Disease Free Survival ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Free Survival ◽  
Recombinant Immunotoxin ◽  
Uremic Syndrome ◽  
Dose Levels

Purpose To conduct a phase I dose-escalation trial assessing safety and response of recombinant immunotoxin moxetumomab pasudotox (CAT-8015, HA22) in chemotherapy-resistant hairy cell leukemia (HCL). Patients and Methods Eligible patients had relapsed/refractory HCL after ≥ two prior therapies and required treatment because of abnormal blood counts. Patients received moxetumomab pasudotox 5 to 50 μg/kg every other day for three doses (QOD ×3), with up to 16 cycles repeating at ≥ 4-week intervals if patients did not experience disease progression or develop neutralizing antibodies. Results Twenty-eight patients were enrolled, including three patients each at 5, 10, 20, and 30 μg/kg, four patients at 40 μg/kg, and 12 patients at 50 μg/kg QOD ×3 for one to 16 cycles each (median, four cycles). Dose-limiting toxicity was not observed. Two patients had transient laboratory abnormalities consistent with grade 2 hemolytic uremic syndrome with peak creatinine of 1.53 to 1.66 mg/dL and platelet nadir of 106,000 to 120,000/μL. Drug-related toxicities in 25% to 64% of the 28 patients included (in decreasing frequency) grade 1 to 2 hypoalbuminemia, aminotransferase elevations, edema, headache, hypotension, nausea, and fatigue. Of 26 patients evaluable for immunogenicity, 10 patients (38%) made antibodies neutralizing more than 75% of the cytotoxicity of 1,000 ng/mL of immunotoxin, but this immunogenicity was rare (5%) after cycle 1. The overall response rate was 86%, with responses observed at all dose levels, and 13 patients (46%) achieved complete remission (CR). Only 1 CR lasted less than 1 year, with the median disease-free survival time not yet reached at 26 months. Conclusion Moxetumomab pasudotox at doses up to 50 μg/kg QOD ×3 has activity in relapsed/refractory HCL and has a safety profile that supports further clinical development for treatment of this disease.

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 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.

scholarly journals Detection of minimal residual disease by immunostaining of bone marrow biopsies after 2-chlorodeoxyadenosine for hairy cell leukemia

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1798-1802 ◽  
Author(s):  
D Hakimian ◽  
MS Tallman ◽  
C Kiley ◽  
L Peterson
Keyword(s):  
Minimal Residual Disease ◽  
Hairy Cell Leukemia ◽  
Residual Disease ◽  
Additional Patient ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Bone Marrow Biopsies ◽  
Hairy Cells ◽  
B Lineage ◽  
Minimal Residual

Abstract 2-Chlorodeoxyadenosine (2-CdA) yields high complete remission (CR) rates in patients with hairy cell leukemia (HCL). In an effort to detect minimal residual disease, we studied two B-lineage antibodies, L26 and MB2, and a T-lineage antibody, UCHL-1, in fixed marrow core biopsies from 34 patients with HCL before and after 2-CdA. Before therapy, hairy cells exhibited intense cytoplasmic membrane reactivity with L26 and strong intracytoplasmic reactivity with MB2. UCHL-1 did not react with hairy cells. Thirty-one patients were assessable 3 months after therapy. Five of 24 (21%) patients in CR by routine evaluation had residual HCL detected by immunostaining. Four of these 5 patients have been reevaluated at 1 year. One patient relapsed by routine evaluation, 2 remained positive by immunostaining alone, and 1 patient became negative by immunostaining. A total of 19 patients have been evaluated at 1 year. Only 1 additional patient has become positive by immunostaining alone. Immunostaining using the B-lineage antibodies highlighted the presence of hairy cells with preservation of morphology. This assisted in quantifying the extent of disease, particularly when hairy cells were interstitial and blended with surrounding hematopoietic tissue, when hairy cells were present in hypocellular marrows, when hairy cells were spindle-shaped, and when marrows were markedly fibrotic. Because immunostaining can be easily performed on routinely processed marrows, it is an attractive method to detect minimal residual disease. Our data suggest that some patients in apparent CR after 2-CdA may have minimal residual disease. Patients will need to be observed prospectively to determine if residual disease will be predictive of relapse.

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