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

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.

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

2020 ◽  
Vol 4 (23) ◽  
pp. 6009-6018
Author(s):  
Meletios Dimopoulos ◽  
Ramon Garcia Sanz ◽  
Hui-Peng Lee ◽  
Marek Trneny ◽  
Marzia Varettoni ◽  
...  
Keyword(s):  
Partial Response ◽  
Progression Free Survival ◽  
Waldenström Macroglobulinemia ◽  
Activating Mutations ◽  
Waldenstrom Macroglobulinemia ◽  
Mutational Status ◽  
Major Response ◽  
Duration Of Response ◽  
Treatment Naïve ◽  
Poor Outcomes

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.

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

2019 ◽  
Vol 3 (19) ◽  
pp. 2800-2803 ◽  
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.

scholarly journals Safety and Efficacy of Purine Analogs for Treatment of Waldenstrom Macroglobulinemia

Blood ◽  
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.

MYD88 Negative Waldenstrom Macroglobulinemia Has Distinct Clinical & Biological Features As Compared To Its MYD88 Mutant Counterpart

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4299-4299
Author(s):  
Nikhil V Patkar ◽  
Prashant Deshpande ◽  
Russel Mascarenhas ◽  
PG Subramanian ◽  
Prashant Tembhare ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Partial Response ◽  
Conflicts Of Interest ◽  
International Prognostic Index ◽  
Post Treatment ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia ◽  
Myd88 L265p Mutation ◽  
Myd88 L265p

Abstract Introduction Waldenstrom Macroglobulinemia (WM) harbors a mutation in MYD88 gene (MYD88L265P) with frequencies varying from 67% to 91%. Although of diagnostic use its clinical significance in terms of prognosis and treatment response is unclear. We retrospectively analyzed WM for MYD88 L265P mutation, immunogenetic profile (presence of somatic hypermutations and biased gene usage) & correlated these with standard clinical variables including prognosis and patient outcome. Patients & Methods 32 cases WM (diagnosed as per WHO 2008/2001 criteria) were retrospectively accrued from 2007-2013. Genomic DNA extracted from bone marrow aspirate smears was subjected to an allele specific oligonucleotide PCR to detect the MYD88L265P mutation using fluorescently labeled primers followed by capillary electrophoresis. Immunogenetics was assessed in 29 patients. Clonal FR1/FR2 regions of the VH gene were amplified & sequenced. Sequence data was compared to the closest germline sequences on NCBI & IMGT databases. Laboratory variables (Hb, WBC, platelet, M Protein concentration, S. IgM, b2M level, S. Globulin, LDH, %of lymphoplasmacytic lymphocytes) were evaluated at baseline along with the International Prognostic Index (ISSWM). Response evaluation was done as per VIth International Consensus guidelines after treatment as well as at last follow up. 2-tailed Student's t-Test & Chi squared test were applied for statistical analysis. Results Median age was 60 years (range: 46-77), male predominant (87.5%).Majority of patients had cytopenia (90.6%) of one or more blood lineages. Median IWSSM was 3 (n=26). The median follow up was 21.5 months (range: 1 week to 82 months). Majority of patients were treated with cyclophosphamide/vincristine/prednisone ± rituximab (55.1%), followed in others by bendamustine/rituximab(13.8%) or fludarabine/cyclophosphamide/rituximab,(13.8%) or cyclophosphamide/thalidomide/dexamethasone (10.3%). MYD88 L265P mutation was found in 84.3% (27/32) of patients. The immunogenetic results here pertain only to samples with productive IGHV gene rearrangement [22/29 (∼76%) cases]. 96% of cases revealed somatic hypermutations. 59% of cases showed a biased use for the VH3 gene followed by VH4 (22.7%) and VH1 (18.18%). The commonest gene used was IGHV3-7 (27.3%) followed by IGHV1-18 (18.2%). Clinical features separating MYD88 negative from MYD88 mutated WM are seen in Table 1. MYD88 negative WM presented with lower number of infiltrating tumor cells in the bone marrow (p=0.05), older age (p=0.02) and had a lower IWSSM score at presentation (p=0.03) as compared to mutated WM. Majority of the MYD88 negative group were in VGPR,(very good partial response) or CR (complete response) (75%:VGPR/CR) post treatment as compared to MYD88 mutated patients [21%: VGPR/CR, 31.6%: PR (partial response): 26.3%, SD (stable disease):15.8%, PD (progressive disease):6.3%]. At the last follow up 44.4% of MYD88 mutated WM had PD where as no patient in MYD88 WT had changed their initial post treatment status. Two patients with MYD88 mutation died due to disease related complications. Conclusion Our data indicates that WM is a biologically heterogeneous subset dichotomized by MYD88 mutations. WM patients with MYD88 mutations present at younger age with high tumor burden in the bone marrow, high risk of progression and poor therapeutic response. Although limited in number, MYD88 negative WM patients were not associated with PD as compared to the mutated group. Overall MYD88mutation may be considered as an adverse prognostic factor in WM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Obinutuzumab and idelalisib in symptomatic patients with relapsed/refractory Waldenström macroglobulinemia

2021 ◽  
Vol 5 (9) ◽  
pp. 2438-2446
Author(s):  
Cécile Tomowiak ◽  
Stéphanie Poulain ◽  
Charles Herbaux ◽  
Aurore Perrot ◽  
Béatrice Mahé ◽  
...  
Keyword(s):  
Partial Response ◽  
Response Rate ◽  
Liver Toxicity ◽  
Univariate Analysis ◽  
Maintenance Phase ◽  
Induction Phase ◽  
Minor Response ◽  
Apparent Lack ◽  
Waldenström Macroglobulinemia ◽  
Waldenstrom Macroglobulinemia

Abstract We present the results of a phase 2 study evaluating the combination of obinutuzumab + idelalisib in relapsed/refractory (R/R) Waldenström macroglobulinemia (WM). The goal was to determine the safety and efficacy of a fixed-duration chemotherapy-free treatment. During the induction phase, patients received idelalisib + obinutuzumab for 6 cycles, followed by a maintenance phase with idelalisib alone for ≤2 years. Forty-eight patients with R/R WM were treated with the induction combination, and 27 patients participated in the maintenance phase. The best responses, reached after a median of 6.5 months (interquartile range, 3.4-7.1; range, 2.6-22.1 months), were very good partial response in 5 patients, partial response in 27 patients, and minor response in 3 patients, leading to overall response rate and major response rate estimates of 71.4% (95% confidence interval [CI], 56.7-83.4) and 65.3% (95% CI, 50.4-78.3), respectively. With a median follow-up of 25.9 months, median progression-free survival was 25.4 months (95% CI, 15.7-29.0). Univariate analysis focusing on molecular screening found no significant impact of CXCR4 genotypes on responses and survivals but a deleterious impact of TP53 mutations on survival. Although there was no grade 5 toxicity, 26 patients were removed from the study because of side effects; the most frequent were neutropenia (9.4%), diarrhea (8.6%), and liver toxicity (9.3%). The combination of idelalisib + obinutuzumab is effective in R/R WM. Nonetheless, the apparent lack of impact of genotype on outcome could give new meaning to targeting of the phosphatidylinositol 3-kinase pathway in WM. This trial was registered at www.clinicaltrials.gov as #NCT02962401.

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

Blood ◽  
2020 ◽  
Vol 136 (18) ◽  
pp. 2038-2050 ◽  
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.

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

2018 ◽  
Vol 36 (27) ◽  
pp. 2755-2761 ◽  
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.

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

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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