Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: a substudy of the phase 3 ASPEN trial

Abstract Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

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A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study

Blood ◽

10.1182/blood.2020006844 ◽

2020 ◽

Vol 136 (18) ◽

pp. 2038-2050 ◽

Cited By ~ 6

Author(s):

Constantine S. Tam ◽

Stephen Opat ◽

Shirley D'Sa ◽

Wojciech Jurczak ◽

Hui-Peng Lee ◽

...

Keyword(s):

Progression Free Survival ◽

Complete Response ◽

Phase 3 ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Major Response ◽

Significant Difference ◽

Duration Of Response ◽

Btk Inhibitor ◽

Grade 3

Abstract Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

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Ixazomib, dexamethasone, and rituximab in treatment-naive patients with Waldenström macroglobulinemia: long-term follow-up

Blood Advances ◽

10.1182/bloodadvances.2020001963 ◽

2020 ◽

Vol 4 (16) ◽

pp. 3952-3959

Author(s):

Jorge J. Castillo ◽

Kirsten Meid ◽

Catherine A. Flynn ◽

Jiaji Chen ◽

Maria G. Demos ◽

...

Keyword(s):

Median Time ◽

Progression Free Survival ◽

Primary Treatment ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Mutational Status ◽

Long Term Follow Up ◽

Treatment Naïve

Abstract Proteasome inhibition is a standard of care for the primary treatment of patients with Waldenström macroglobulinemia (WM). We present the long-term follow-up of a prospective, phase II clinical trial that evaluated the combination of ixazomib, dexamethasone, and rituximab (IDR) in 26 treatment-naive patients with WM. IDR was administered as 6 monthly induction cycles followed by 6 every-2-month maintenance cycles. The MYD88 L265P mutation was detected in all patients, and CXCR4 mutations were detected in 15 patients (58%). The median time to response (TTR) and time to major response (TTMR) were 2 and 6 months, respectively. Patients with and without CXCR4 mutations had median TTR of 3 months and 1 month, respectively (P = .003), and median TTMR of 10 months and 3 months, respectively (P = .31). The overall, major, and very good partial response (VGPR) rates were 96%, 77%, and 19%, respectively. The rate of VGPR in patients with and without CXCR4 mutations were 7% and 36%, respectively (P = .06). The median progression-free survival (PFS) was 40 months, the median duration of response (DOR) was 38 months, and the median time to next treatment (TTNT) was 40 months. PFS, DOR, and TTNT were not affected by CXCR4 mutational status. The safety profile was excellent with no grade 4 adverse events or deaths to date. IDR provides a safe and effective frontline treatment option for symptomatic patients with WM. This study was registered at www.clinicaltrials.gov as #NCT02400437.

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Long-term follow-up of ibrutinib monotherapy in treatment-naive patients with Waldenstrom macroglobulinemia

Leukemia ◽

10.1038/s41375-021-01417-9 ◽

2021 ◽

Author(s):

Jorge J. Castillo ◽

Kirsten Meid ◽

Joshua N. Gustine ◽

Carly Leventoff ◽

Timothy White ◽

...

Keyword(s):

Progression Free Survival ◽

Final Report ◽

Minor Response ◽

Upper Respiratory Infection ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Major Response ◽

Treatment Naïve ◽

A Minor

AbstractHerein, we present the final report of a single-center, prospective phase II study evaluating ibrutinib 420 mg once daily in 30 treatment-naive patients with Waldenstrom macroglobulinemia (WM). The present study is registered with ClinicalTrials.Gov (NCT02604511). With a median follow-up of 50 months, the overall, major, and VGPR response rates were 100%, 87%, and 30%. The VGPR rate was numerically but not significantly lower in patients with than without CXCR4 mutations (14% vs. 44%; p = 0.09). The median time to a minor response was 0.9 months, and to a major response was 1.9 months, though were longer in those with mutated CXCR4 at 1.7 months (p = 0.07) and 7.3 months (p = 0.01). Six patients had disease progression. The median progression-free survival (PFS) was not reached, and the 4-year PFS rate was 76%. There was also a non-significant lower 4-year PFS rate in patients with than without CXCR4 mutations (59% vs. 92%; p = 0.06). The most common treatment-related adverse events were fatigue, upper respiratory infection, and hematoma. Atrial fibrillation occurred in 20% of patients. Ibrutinib monotherapy induced durable responses in treatment-naive patients with WM. CXCR4 mutations impacted VGPR attainment, time to major response, and 4-year PFS rate.

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CXCR4 S338X clonality is an important determinant of ibrutinib outcomes in patients with Waldenström macroglobulinemia

Blood Advances ◽

10.1182/bloodadvances.2019000635 ◽

2019 ◽

Vol 3 (19) ◽

pp. 2800-2803 ◽

Cited By ~ 7

Author(s):

Joshua N. Gustine ◽

Lian Xu ◽

Nicholas Tsakmaklis ◽

Maria G. Demos ◽

Amanda Kofides ◽

...

Keyword(s):

Partial Response ◽

Important Determinant ◽

Progression Free Survival ◽

Free Survival ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Key Points ◽

Clonality Assessment ◽

Good Partial Response

Key Points CXCR4 S338X clonality ≥25% is associated with lower very good partial response and shorter progression-free survival to ibrutinib. CXCR4 S338X clonality assessment represents a novel biomarker to predict outcomes to ibrutinib in Waldenström macroglobulinemia patients.

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Predictors of response and survival in a large cohort of 319 Waldenström macroglobulinemia patients treated with ibrutinib monotherapy

Blood Advances ◽

10.1182/bloodadvances.2021006106 ◽

2021 ◽

Author(s):

Jorge J. Castillo ◽

Shayna Sarosiek ◽

Joshua N Gustine ◽

Catherine Flynn ◽

Carly Leventoff ◽

...

Keyword(s):

Risk Factors ◽

Partial Response ◽

Multiple Imputation ◽

Progression Free Survival ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Predictors Of Response ◽

Two Factors ◽

Cox Proportional Hazard Regression ◽

Btk Inhibitors

Bruton tyrosine kinase (BTK) inhibitors are the only FDA-approved treatments for Waldenström macroglobulinemia (WM). Factors prognostic of survival and predictive of response to BTK inhibitors remained to be clarified. We evaluated 319 patients with WM to identify predictive and prognostic factors on ibrutinib monotherapy. Logistic and Cox proportional-hazard regression models were fitted for response and survival. Multiple imputation analyses were used to address bias associated with missing data. Major (partial response or better) and deep responses (very good partial response or better) were attained in 78% and 28% of patients. CXCR4 mutations were associated with lower odds of major (OR 0.2, 95% CI 0.1-0.5; p<0.001) and deep response (OR 0.3, 95% CI 0.2-0.6; p=0.001). CXCR4 mutations (HR 2.0, 95% CI 1.2-3.4; p=0.01) and platelet count 100 K/uL or less (HR 2.5, 95% CI 1.3-4.9; p=0.007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these two factors. The median PFS for patients with zero, one and two risk factors were not reached, 5 years and 3 years (p<0.001). Patients with two risk factors had HR 2.2 (95% CI 1.3-3.8; p=0.004) compared with one factor, and patients with one factor had HR 2.3 (95% CI 1.1-5.1; p=0.03) compared with zero factors. Age 65 years or older was the only factor associated with overall survival (HR 3.2, 95% CI 1.4-7.0; p=0.005). Multiple imputation analyses did not alter our results. Our study confirms the predictive and prognostic value of CXCR4 mutations in patients with WM treated with ibrutinib monotherapy.

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Ibrutinib Monotherapy in Symptomatic, Treatment-Naïve Patients With Waldenström Macroglobulinemia

Journal of Clinical Oncology ◽

10.1200/jco.2018.78.6426 ◽

2018 ◽

Vol 36 (27) ◽

pp. 2755-2761 ◽

Cited By ~ 49

Author(s):

Steven P. Treon ◽

Joshua Gustine ◽

Kirsten Meid ◽

Guang Yang ◽

Lian Xu ◽

...

Keyword(s):

Tract Infection ◽

Bone Marrow Involvement ◽

Progression Free Survival ◽

Symptomatic Treatment ◽

Primary Therapy ◽

Upper Respiratory Tract ◽

Waldenström Macroglobulinemia ◽

Highly Active ◽

Waldenstrom Macroglobulinemia ◽

Treatment Naïve

Purpose Ibrutinib is active in previously treated Waldenström macroglobulinemia (WM). MYD88 mutations ( MYD88MUT) and CXCR4 mutations ( CXCR4MUT) affect ibrutinib response. We report on a prospective study of ibrutinib monotherapy in symptomatic, untreated patients with WM, and the effect of CXCR4MUT status on outcome. Patients and Methods Symptomatic, treatment-naïve patients with WM were eligible. Ibrutinib (420 mg) was administered daily until progression or unacceptable toxicity. All tumors were genotyped for MYD88MUT and CXCR4MUT. Results A total of 30 patients with WM received ibrutinib. All carried MYD88MUT, and 14 (47%) carried a CXCR4MUT. After ibrutinib treatment, median serum IgM levels declined from 4,370 to 1,513 mg/dL, bone marrow involvement declined from 65% to 20%, and hemoglobin level rose from 10.3 to 13.9 g/dL ( P < .001 for all comparisons). Overall (minor or more than minor) and major (partial or greater than partial) responses for all patients were 100% and 83%, respectively. Rates of major (94% v 71%) and very good partial (31 v 7%) responses were higher and time to major responses more rapid (1.8 v 7.3 months; P = 0.01) in patients with wild-type CXCR4 versus those with CXCR4MUT, respectively. With a median follow-up of 14.6 months, disease in two patients (both with CXCR4MUT) progressed. The 18-month, estimated progression-free survival is 92% (95% CI, 73% to 98%). All patients are alive. Grade 2/3 treatment-related toxicities in > 5% of patients included arthralgia (7%), bruising (7%), neutropenia (7%), upper respiratory tract infection (7%), urinary tract infection (7%), atrial fibrillation (10%), and hypertension (13%). There were no grade 4 or unexpected toxicities. Conclusion Ibrutinib is highly active, produces durable responses, and is safe as primary therapy in patients with symptomatic WM. CXCR4MUT status affects responses to ibrutinib.

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Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia

Journal of Clinical Oncology ◽

10.1200/jco.20.00555 ◽

2020 ◽

pp. JCO.20.00555

Author(s):

Steven P. Treon ◽

Kirsten Meid ◽

Joshua Gustine ◽

Guang Yang ◽

Lian Xu ◽

...

Keyword(s):

Progression Free Survival ◽

Response Rates ◽

Immunoglobulin M ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Major Response ◽

Previously Treated Patients ◽

Previously Treated

PURPOSE We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM). PATIENTS AND METHODS Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity. RESULTS The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL ( P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88Mut CXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88Mut CXCR4WT and MYD88Mut CXCR4Mut WM, respectively ( P = .02). In patients with MYD88WT, the median PFS was 0.4 years ( P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management. CONCLUSION Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.

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Safety and Efficacy of Purine Analogs for Treatment of Waldenstrom Macroglobulinemia

Blood ◽

10.1182/blood-2020-138750 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Abdul Jabbar Dar ◽

Qasim Khurshid ◽

Muhaddis Ejaz Ahmad ◽

Muhammad Ali Mirza ◽

Farhan Khalid ◽

...

Keyword(s):

Partial Response ◽

Progression Free Survival ◽

Complete Response ◽

The United States ◽

Cochrane Library ◽

Waldenström Macroglobulinemia ◽

Overall Response ◽

Waldenstrom Macroglobulinemia ◽

Purine Analogs ◽

Number Of Patients

Introduction: There are about 1500 cases every year in the United States of America and while the disease is incurable but it is treatable. Purine analogs are anti-metabolites that mimic the structure of metabolic purines and are used for the treatment of Waldenstrom macroglobulinemia (WM). Methods: We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after 1995, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 580 articles were identified initially and after detailed screening, we finalized 16 studies involving patients with Waldenstrom macroglobulinemia. Results: The total number of patients in the studies involving regimens based on purine analogs were 1211. The doses of Fludarabine ranged from 25-30 mg/m2 and that of Cladribine ranged from 0.1-0.5 mg/kg. The complete response (CR) observed ranged from 2-15% and the partial response (PR) ranged from 11-67%. The overall response rate (ORR) ranged from 38-95%. Fludarabine: In the study Dhodapkar et al., N=231, the highest CR and ORR was observed, 4% and 66% respectively. In the study Zinzani et al., the PR was 41%. Fludarabine and Cyclophasphamide: In the study Dimopoulos et al., the PR was 55% and the progression free survival (PFS) was 24 months. Fludarabine, Cyclophosphamide and ofatumumab: In the study Gavriatopoulou et al., the PR was 67% and very good partial response (VGPR) was 17% and the PFS was 23 months. Fludarabine, rituximab and cyclophosphamide: In the study Tedeschi et al., the CR was 11.60%, ORR was 79% and the PR was 41.8%. Fludarabine and Rituximab: In the study Treon et al., the CR was 4.6%, VGPR was 32.5%, PR was 48%, and ORR was 95.3% with PFS of 51.2 months. Cladribine: In the study Liu et al., the CR was 5% and PR was 50%. In the studies Dimopoulos et al., 1994 the highest CR was observed, 11.5% with an ORR of 85%. The PR was also the highest, 73%. Conclusion: There is limited literature on regimens containing both Fludarabine and Cladribine, which are used for the treatment of WM. Despite heterogenicity in WM patients and various regimens used in literature. Purine analogs containing regimens are a remarkably effective treatment with overall response rates reaching up to 79%. Neutropenia and thrombocytopenia were the main side effects. There is a paucity of phase 3 randomized trials demonstrating a clinical benefit of anyone regimen over another. We recommend future randomized prospective trials better to understand the efficacy and safety profile of regimens containing purine analogs. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

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Results of a Randomized Trial of Chlorambucil Versus Fludarabine for Patients With Untreated Waldenström Macroglobulinemia, Marginal Zone Lymphoma, or Lymphoplasmacytic Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2012.44.7920 ◽

2013 ◽

Vol 31 (3) ◽

pp. 301-307 ◽

Cited By ~ 91

Author(s):

Véronique Leblond ◽

Steve Johnson ◽

Sylvie Chevret ◽

Adrian Copplestone ◽

Simon Rule ◽

...

Keyword(s):

Marginal Zone ◽

Alkylating Agents ◽

Treatment Options ◽

Progression Free Survival ◽

Marginal Zone Lymphoma ◽

Lymphoplasmacytic Lymphoma ◽

Waldenström Macroglobulinemia ◽

Waldenstrom Macroglobulinemia ◽

Duration Of Response ◽

Intent To Treat

Purpose Treatment options for patients with Waldenström macroglobulinemia (WM) and closely related disorders include alkylating agents, purine analogs, and monoclonal antibodies. No large randomized studies have yet been reported comparing any of these approaches. Patients and Methods The randomized WM1 study (Trial Comparing Chlorambucil to Fludarabine in Patients With Advanced Waldenström Macroglobulinemia) was undertaken in 101 centers in five countries enrolling 414 eligible patients (339 with WM, 37 with non–mucosa-associated lymphoid tissue marginal zone lymphoma, and 38 with lymphoplasmacytic lymphoma) who were randomly assigned to receive chlorambucil or fludarabine. The primary end point was the overall response rate (ORR). Results On the basis of intent-to-treat analysis, the ORR was 47.8% (95% CI, 40.9% to 54.8%) in the fludarabine arm versus 38.6% (95% CI, 32.0% to 45.7%) in the chlorambucil arm (P = .07). With a median follow-up of 36 months (interquartile range, 18 to 58 months), median progression-free survival (PFS), and duration of response (DR) were significantly improved in the fludarabine arm compared with the chlorambucil arm: PFS, 36.3 versus 27.1 months (P = .012) and DR, 38.3 versus 19.9 months (P < .001). In patients with WM, median overall survival (OS) was not reached in the fludarabine arm versus 69.8 months in the chlorambucil arm (95% CI, 61.6 to 79.8 months; P = .014). Grade 3 to 4 neutropenia was significantly higher among patients treated with fludarabine (36%) compared with patients treated with chlorambucil (17.8%; P < .001). Second malignancies were significantly more frequent in the chlorambucil arm with 6-year cumulative incidence rate of 20.6% versus 3.7% in the fludarabine arm (P = .001). Conclusion In the complete intent-to-treat study population, fludarabine significantly improved PFS compared with chlorambucil, and in patients with WM, it improved OS.

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