The Braf Inhibitor Vemurafenib Plus Rituximab Produces a High Rate of Deep and Durable Responses in Relapsed/Refractory Hairy Cell Leukemia: Updated Results of a Phase‐2 Trial

Tiacci, Enrico; Carolis, Luca De; Simonetti, Edoardo; Zaja, Francesco; Capponi, Monia; Ambrosetti, Achille; Lucia, Eugenio; Antolino, Agostino; Pulsoni, Alessandro; Ferrari, Samantha; Zinzani, P. L.; Rigacci, Luigi; Gaïdano, Gianluca; Seta, Roberta Della; Frattarelli, Natalia; Falcucci, Paolo; Visani, Giuseppe; Foà, Robin; Falini, Brunangelo

doi:10.1002/hon.72_2629

Cited by 17 publications

(13 citation statements)

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“…In HCL, the implications of MRD remain unclear; some studies report that MRD positivity after PNA therapy is predictive for disease relapse, suggesting that MRD eradication may improve clinical outcomes [ 26 , 27 ]. Current treatments, including targeted therapies, are unable to completely eradicate MRD in all patients with R/R HCL [ 8 – 19 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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

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Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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“…In comparing Moxe-rituximab to cladribine-rituximab (CDAR), albeit across trials, it is notable that Moxe as a single-agent has a higher MRD-free CR rate than cladribine [ 64 ]. Vemurafenib, which did not eradicate MRD by immunohistochemistry as a single-agent [ 68 ], achieved an MRD-free CR rate of 65% in relapsed HCL when combined with rituximab [ 132 ], and the vemurafenib-obinutuzumab combination is currently being tested in first-line. We believe the Moxe-rituximab regimen, or possibly Moxe-obinutuzumab, may have potential in the future as a chemotherapy-free first-line treatment of HCL.…”

Section: Further Development Of Moxe For Hclmentioning

confidence: 99%

Development of Recombinant Immunotoxins for Hairy Cell Leukemia

Kreitman

Pastan

2020

Biomolecules

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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.

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“…No relapses were seen in the two-thirds of cases negative for MRD by BRAF V600E allelespecific polymerase chain reaction (PCR). 65 Moxetumomab pasudotox (MP) is an anti-CD22 antibody, genetically linked to a pseudomonas exotoxin, and the first FDA-approved treatment for relapsed/refractory HCL. The high expression of CD22 in HCL is in keeping with the high levels of activity with MP seen in this disease.…”

Section: Current Statusmentioning

confidence: 99%

“…Complete responses were seen in 26/27 evaluable patients and at a median of 29·5 months, and PFS in 29 evaluable cases was 83%. No relapses were seen in the two‐thirds of cases negative for MRD by BRAF V600E allele‐specific polymerase chain reaction (PCR) 65 …”

Section: Current Statusmentioning

confidence: 99%

Hairy Cell Leukaemia: From Hairy Beginnings to a BRAF New World

Dearden

Iyengar

2020

Br J Haematol

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SummaryFor a disease initially described in 1958 as a leukaemic reticulo‐endotheliosis associated with poor outcomes, we have come a long way in our understanding of Hairy cell leukaemia. The vast majority of patients diagnosed with this rare, often diagnostically challenging, leukaemia can now expect a lifespan that is similar to the general population. This article covers some of the highlights from the last 6 decades that have led to our current understanding of this fascinating leukaemia ‐ from elucidation of its B‐cell origin to discovery of the almost universal occurrence of the BRAF V600E mutation; from the initial successes reported with splenectomy to the more recent development of targeted therapies such as Vemurafenib and Moxetumomab Pasudotox. It also pays tribute to some of the outstanding research in this field focusing particularly on the significant contributions made by the clinical and scientific community in the UK.

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The Braf Inhibitor Vemurafenib Plus Rituximab Produces a High Rate of Deep and Durable Responses in Relapsed/Refractory Hairy Cell Leukemia: Updated Results of a Phase‐2 Trial

Cited by 17 publications

References 0 publications

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

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

Development of Recombinant Immunotoxins for Hairy Cell Leukemia

Hairy Cell Leukaemia: From Hairy Beginnings to a BRAF New World

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