Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes

Abeykoon, Jithma P.; Zanwar, Saurabh; Ansell, Stephen M.; Gertz, Morie A.; Kumar, Shaji; Manske, Michelle K.; Novak, Anne J.; King, Rebecca; Greipp, Patricia T.; Go, Ronald S.; Inwards, David J.; Muchtar, Eli; Habermann, Thomas M.; Witzig, Thomas E.; Thompson, Carrie A.; Dingli, David; Lacy, Martha Q.; Leung, Nelson; Dispenzieri, Angela; Gonsalves, Wilson I.; Warsame, Rahma; Kyle, Robert A.; Rajkumar, Vincent; Parikh, Sameer A.; Kapoor, Prashant

doi:10.1111/bjh.16168

Cited by 40 publications

(38 citation statements)

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“…Differences in overall survival or survival after first treatment initiation were not assessed due to a small number of deaths in this cohort (n = 37; 13%) at the time of this report. Calculations were obtained using STATA 15…”

Section: Discussionmentioning

confidence: 99%

Partial response or better at six months is prognostic of superior progression‐free survival in Waldenström macroglobulinaemia patients treated with ibrutinib

et al. 2020

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Summary Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression‐free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three‐year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three‐year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

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Section: Discussionmentioning

confidence: 99%

Partial response or better at six months is prognostic of superior progression‐free survival in Waldenström macroglobulinaemia patients treated with ibrutinib

et al. 2020

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“…Atrial fibrillation was seen in 11%. The IgM rebound was seen in 36% of patients following ibrutinib discontinuation 138,139 …”

Section: Managementmentioning

confidence: 99%

Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management

Gertz

2021

American J Hematol

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Disease Overview: Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with immunoglobulin M (IgM) monoclonal protein. Clinical features include anemia, thrombocytopenia, hepatosplenomegaly, lymphadenopathy, and rarely hyperviscosity. Diagnosis: Presence of IgM monoclonal protein associated with ≥10% clonal lymphoplasmacytic cells in bone marrow confirms the diagnosis. The L265P mutation in MYD88 is detectable in more than 90% of patients and is found in the majority of IgM MGUS patients. Risk Stratification: Age, hemoglobin level, platelet count, β 2 microglobulin, LDH and monoclonal IgM concentrations are characteristics that are predictive of outcomes. Risk-Adapted Therapy: Not all patients who fulfill WM criteria require therapy; these patients can be observed until symptoms develop. Rituximab-monotherapy is inferior to regimens that combine it with bendamustine, an alkylating agent, a proteosome inhibitor, or ibrutinib. Purine nucleoside analogues are active but usage is declining in favor of less toxic alternatives. The preferred Mayo Clinic induction is rituximab and bendamustine. Management of Refractory Disease: Bortezomib, fludarabine, thalidomide, everolimus, Bruton Tyrosine Kinase inhibitors, carfilzomib, lenalidomide, and bendamustine have all been shown to have activity in relapsed WM. Given WM's natural history, reduction of therapy toxicity is an important part of treatment selection. PATIENT A 55-year-old male was found to have an IgM monoclonal gammopathy in January 2001. He was observed until November 2006 when his IgM level climbed to 9135 mg/dL. He was treated with rituximab, bortezomib and dexamethasone for 4 months. Treatment was interrupted due to neuropathy, but the IgM level fell to 1150 mg/dL. He was observed until April 2011. At the time of progression his IgM was 11 500 mg/dL and he was treated with single agent rituximab. At that time he was found to have acquired von Willebrand disease. Rituximab failed to produce a minor response so he was placed on a trial of bendamustine, lenalidomide and rituximab. His response lasted less than 1 year. In 2014 he was placed on an experimental trial of oprozomib. This resulted in a response of 5 years duration. At relapse in August of 2019 he was placed on a trial of ixazomib and ibrutinib. Ixazomib was poorly tolerated due to diarrhea and he continued on ibrutinib alone. He has now been on ibrutinib 15 months and has achieved a very good partial response.

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“…The differential effect of ibrutinib on the molecular subtypes of WM has been striking: 100% of MYD88 L265P, CXCR4 WT patients responded to ibrutinib, compared to 85.7% and 60% of patients in the double mutant and double WT groups respectively [ 110 ]. In a retrospective analysis of WM patients treated with ibrutinib, Abeykoon et al [ 111 ] reported on five MYD88 WT patients, among whom two achieved a partial response, one achieved a minor response, and the other did not respond [ 111 ]. These data indicate the potential for use of MYD88 mutation status as a biomarker for response to BTK inhibition.…”

Section: Future Directionsmentioning

confidence: 99%

Immunoglobulin M Paraproteinaemias

Girard

Soekojo

Ooi

et al. 2020

Cancers

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Monoclonal paraproteinaemia is an increasingly common reason for referral to haematology services. Paraproteinaemias may be associated with life-threatening haematologic malignancies but can also be an incidental finding requiring only observation. Immunoglobulin M (IgM) paraproteinaemias comprise 15–20% of monoclonal proteins but pose unique clinical challenges. IgM paraproteins are more commonly associated with lymphoplasmacytic lymphoma than multiple myeloma and can occur in a variety of other mature B-cell neoplasms. The large molecular weight of the IgM multimer leads to a spectrum of clinical manifestations more commonly seen with IgM paraproteins than others. The differential diagnosis of B-cell and plasma cell dyscrasias associated with IgM gammopathies can be challenging. Although the discovery of MYD88 L265P and other mutations has shed light on the molecular biology of IgM paraproteinaemias, clinical and histopathologic findings still play a vital role in the diagnostic process. IgM secreting clones are also associated with a number of “monoclonal gammopathy of clinical significance” entities. These disorders pose a novel challenge from both a diagnostic and therapeutic perspective. In this review we provide a clinical overview of IgM paraproteinaemias while discussing the key advances which may affect how we manage these patients in the future.

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Ibrutinib monotherapy outside of clinical trial setting in Waldenström macroglobulinaemia: practice patterns, toxicities and outcomes

Cited by 40 publications

References 29 publications

Partial response or better at six months is prognostic of superior progression‐free survival in Waldenström macroglobulinaemia patients treated with ibrutinib

Partial response or better at six months is prognostic of superior progression‐free survival in Waldenström macroglobulinaemia patients treated with ibrutinib

Waldenström macroglobulinemia: 2021 update on diagnosis, risk stratification, and management

Immunoglobulin M Paraproteinaemias

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