Castillo, Jorge J.

The treatment of Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) has evolved to include several new options. The NCCN Guidelines for WM/LPL provide a framework on which to base decisions regarding diagnosis, treatment, assessment of response to treatment, and follow-up of both newly diagnosed and previously treated WM/LPL.

Background:Ibrutinib is approved in Europe and the US for the treatment of Waldenstrom macroglobulinemia (WM) with a median progression‐free survival (PFS) measured on several years. As PFS is commonly used for drug approval by regulatory entities, there is an unmet need of reliable surrogate markers for PFS that could help accelerating such process. This is of importance with novel BTK inhibitors currently in clinical trials.Aims:We hypothesized that the depth of response at 6 months can be predictive of PFS in patients with WM treated with the BTK inhibitor ibrutinib.Methods:We evaluated our hypothesis in two separate cohorts of WM patients treated with ibrutinib. The learning cohort was composed by participants of two prospective clinical trials at Dana‐Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center and Stanford Cancer Center. The validation cohort was composed by consecutive WM patients treated with ibrutinib off clinical trial at DFCI and Mayo Clinic. Categorical responses at 6 months were assessed based on criteria from the 6thInternational Workshop for WM. PFS6 was defined as the time from the 6‐month response assessment until progression of disease or death from any cause. PFS6 curves were generated using the Kaplan‐Meier method and compared using the log‐rank test. Cox proportional hazard regression models were fitted for PFS6. Pvalues <0.05 were considered statistically significant.Results:The learning and validation cohorts were composed by 92 and 190 WM patients treated with ibrutinib, repsectively. There were no statistical differences between cohorts with regards to age, sex, serum IgM level, hemoglobin level, bone marrow involvement, prior treatment status, and MYD88 and CXCR4 mutational status (p>0.05 for all variables). The rates of partial response (PR) or better at 6 months in the learning and validation cohorts were 63% (54/86) and 72% (114/159), respectively (p = 0.15). The median PFS6 was not reached in the learning cohort and was 53 months (95% CI 44‐not reached) in the validation cohort. In the learning cohort, the median PFS6 for patients who attained a PR or better at 6 months was not reached, while for the patients who did not attained PR at 6 months was 48 months (95% CI 33‐not reached). The 3‐year PFS rate for patients who attained a PR or better at 6 months was 83% (95% CI 68–91%), while for patients who did not attained PR at 6 months was 58% (95% CI 33–76%) (Figure, left, log‐rank p = 0.02). Attaining PR or better at 6 months was associated with a hazard ratio (HR) or progressing or dying of 0.37 (95% CI 0.16–0.87; p = 0.02).In the validation cohort, the median PFS6 for patients who attained a PR or better at 6 months was 53 months (95% CI 44‐not reached), while for the patients who did not attained PR at 6 months was 32 months (95% CI 22‐not reached). The 3‐year PFS rate for patients who attained a PR or better at 6 months was 79% (95% CI 67–87%), while for patients who did not attained PR at 6 months was 50% (95% CI 26–70%) (Figure, right, log‐rank p = 0.04). Attaining PR or better at 6 months was associated with a hazard ratio (HR) or progressing or dying of 0.46 (95% CI 0.22–0.98; p = 0.04). Age, sex, serum IgM level, hemoglobin level, bone marrow involvement and prior treatment status were not prognostic of PFS6 in both cohorts.Summary/Conclusion:Attaining a PR or better at 6 months to ibrutinib is associated with longer median PFS and higher rates of 3‐year PFS in WM patients. Depth of response at 6 months could serve as a surrogate for PFS in clinical trials evaluating BTK inhibitors in WM patients.image

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered. The NCCN Guidelines for MM provide a framework on which to base decisions regarding workup, treatment, and follow-up of newly diagnosed and previously treated MM. This manuscript outlines the recommendations from NCCN Guidelines for MM specific to relapsed/refractory disease.

Background: A pivotal clinical trial comparing the efficacy and safety of ibrutinib with zanubrutinib in patients with Waldenström macroglobulinemia (WM) did not achieve its primary endpoint of complete response or very good partial response. In addition, median progression-free survival was not reached in either treatment arm. In the absence of treatment effectiveness differentiation based on clinical trial evidence, we conducted a real-world study to assess patient characteristics, treatment patterns, and all-cause healthcare resource utilization (HRU) in patients with WM who received ibrutinib or zanubrutinib as first-line (1L) therapy. Methods: In this retrospective cohort study, we used the ConcertAI Database to collect claims data of patients with WM aged ≥18 years who initiated single-agent ibrutinib (420 mg/day) or zanubrutinib (320 mg/day) as 1L therapy on or after 9/1/2021 (index date). A 6-month washout period of guideline-recommended WM antineoplastic agents was required to confirm 1L status. Patients were excluded if they were receiving ibrutinib and zanubrutinib concurrently, died within 30 days of the index date, had a record of hematopoietic stem cell transplant, had a record of other ibrutinib indications in the 6 months before index, or were participating in a clinical trial. Baseline demographics and clinical characteristics, therapy duration (number of days between the first and last day of the medication supply), and HRU (all-cause and WM-specific) per-patient-per-month (PPPM) were assessed. Results: The study included 51 patients (ibrutinib, n=30; zanubrutinib, n=21). In both cohorts, most participants were male (ibrutinib, n=20 [67%]; zanubrutinib, n=16 [76%]), and the mean age at baseline was 73 years and 75 years, respectively. At baseline, the median Charlson Comorbidity Index was 0, and the WM-related and ibrutinib/zanubrutinib-related clinical events were similar between the two cohorts. While the zanubrutinib cohort had a higher prevalence of infections (33% vs 3%) and musculoskeletal pain (24% vs 7%) at baseline, the ibrutinib cohort had a higher prevalence of hypertension (20% vs 14%). The baseline prevalence of anemia was similar in both cohorts (ibrutinib, 27%; zanubrutinib, 29%). Mean follow-up was 6.9 months (ibrutinib) and 6.3 months (zanubrutinib). The mean ± SD duration of therapy was 152 ± 112 days (ibrutinib) and 113 ± 99 days (zanubrutinib; p=0.195). The ibrutinib cohort had a significantly lower all-cause HRU PPPM (4.53 ± 3.96 vs 8.53 ± 6.66, p=0.020) and lower WM-specific HRU PPPM (0.11 ± 0.26 vs 0.54 ± 1.14, p=0.104). Conclusions: In this real-world analysis, patients with WM treated with 1L ibrutinib had a numerically longer duration of therapy and lower all-cause and WM-specific HRU PPPM, compared to those treated with 1L zanubrutinib. Due to a small sample size and short follow-up, these findings should be interpreted cautiously.

Background: Waldenström Macroglobulinemia (WM) is an indolent lymphoma with heterogeneous outcomes. The recently developed, Revised International Prognostic Scoring System for WM (rIPSS-WM) did not examine the prognostic impact of MYD88L265P, a somatic alteration present in most patients with WM. Moreover, rIPSS-WM could only be partially validated in an external cohort. Here, we report the performance of rIPSS-WM and propose a refined prognostic model with external validation. Methods: We reviewed medical records of treatment-naïve patients with active WM consecutively seen at Mayo Clinic, Rochester (MCR) between 01/01/1996 and 12/31/2017. We applied the rIPSS-WM model in patients with data available for all required parameters, including age, serum beta-2 microglobulin (β2M), serum lactate dehydrogenase (LDH) and serum albumin at diagnosis to assess the prognostic utility of this model. We then identified the dichotomized clinical and laboratory parameters prognostic for overall survival (OS) by univariate analyses (UVA) in our cohort. The significant parameters were analyzed to independently predict OS in a multivariable analysis (MVA) and to create a prognostic model, which was subsequently validated in an independent multi-institutional cohort. Results: We identified 889 patients with active WM at MCR, with a median follow-up of 8.2 [95% confidence interval (CI): 7.5-9] years. The estimated median OS for this cohort was 10.6 (95%CI: 9.7-11.4) years. Patients with available data in this cohort for the validation of rIPSS-WM (n=241) were risk stratified into very low (n=46), low (n=64), intermediate (n=58), high (n=46) and very-high risk groups (n=27) per rIPSS-WM, with the respective 5-year OS rates of 96%, 76%, 72%, 77% and 32%, demonstrating overlapping survival curves for the low, intermediate and the high-risk groups. Because rIPSS-WM could not be validated, we used the data from the MCR cohort and identified age at diagnosis of active WM, LDH &gt;upper limit of normal (ULN), β2M &gt;3µg/mL and albumin &lt;3.5g/dL as statistically significant prognostic markers for OS on UVA. Notably, the presence of MYD88 L265P did not impact OS [median 11.4 years (95%CI: 10.1-not reached (NR) for MYD88 L265P genotype (n=231) versus 10 years (95% CI: 8.1-NR) for MYD88 WT genotype (n=65); p=0.33]. On MVA, LDH &gt;ULN (HR 2.34), serum albumin &lt;3.5 g/dL (HR 1.5) and age groups 65-75 years (HR 1.4) and &gt;75 years (HR 2.6) were independently prognostic. Based on comparable HRs, we assigned a score of 1 point each to serum albumin &lt;3.5 g/dL and age group 66-75 years and similarly, 2 points each for age &gt;75 years and serum LDH &gt;ULN per their impact on OS. Patients with the composite scores of 0, 1 and 2 were categorized as low risk, low- intermediate risk and intermediate risk, respectively. Due to similar OS for the scores of 3 to 5, these were combined to form the high-risk group of our proposed model: Modified Staging System for WM (MSS-WM). The median OS was 14.6 years [95%CI: 9.1 years-NR] for low-risk (score 0, n=71, 21%), 11.2 years (95% CI: 9.1-15.2 years) for low-intermediate risk (score 1, n=110, 32%), 8.1 years (95% CI: 6.4-12.2) for intermediate risk (score 2, n=81, 24%) and 5.5 years (95 % CI: 3.9-11 years) for the high-risk group (score ≥3, n=79, 23%); p&lt;0.0001. In this derivation cohort, the 5-year OS rate was 93%, 82%, 69% and 55% and 10-year OS rate was 60%, 53%, 45% and 30% for the low, low-intermediate, intermediate, and high-risk cohort, respectively ( Figure 1A). We also validated MSS-WM using competing risk analysis (p=0.001) and in the cohort of rituximab treated patients (p&lt;0.0001). We then used data from an independent series of 335 treatment-naïve symptomatic patients from academic institutions (n=5) across the US and Europe for external validation of the MSS-WM model. The median follow-up for the validation cohort was 6.3 years (95% CI: 5.5-7.2 years). The 5-year OS was 93%, 90%, 75% and 57% and the estimated 10-year OS was 91%, 80%, 64% and 35% for the low risk (n= 86, 26%), low-intermediate (n=107, 32%), intermediate (n=86, 26%) and high-risk (n=59, 18%) cohorts, respectively (p&lt;0.0001, Figure 1B). Conclusions: Our proposed model, MSS-WM, is a simple, clinically useful, externally validated model that reliably risk stratifies previously untreated patients with active WM into four groups that have distinct outcomes based on the composite scores derived from the patients' age, serum albumin and serum LDH at diagnosis.

Background: Data on the clinical activity of venetoclax (ven) in lymphoplasmacytic lymphoma (LPL) are primarily limited to a phase 2 trial of ven monotherapy for a 2-year duration in 32 patients (pts) with relapsed/refractory IgM LPL who received a median of 2 prior treatments (tx), including 16 pts with prior BTK inhibitors (BTKi) (Castillo et al, JCO 2021). Overall response rate (ORR) was 84% and median progression-free survival (PFS) was 30 months (mos). We report the clinical activity of ven and prognostic factors associated with outcomes in a larger cohort. Methods: We included pts with LPL treated with ven alone at 9 US centers. The primary outcome was ORR, which included minor response (MR), partial response (PR), very good PR (VGPR), and complete response (CR) per IWWM-7. Secondary outcomes included PFS, overall survival (OS), safety of ven, and predictors of ORR, PFS, and OS. Results: Sixty-two pts were included. Twenty pts (32%) received ven on a clinical trial. At ven initiation, median age was 65 years (range 38 - 87) , 61% were male, serum monoclonal (M) protein was IgM in 50 pts (91%) (IgG/IgA in 3 (5%), absent in 2 (4%), missing n=7), median hemoglobin (Hb) was 10.4 g/dL (range 5.7-16.4), and median serum IgM was 2580 mg/dL (range 5-9300). Mutations of MYD88 and CXCR4 were present in 52 (95%; missing n = 7) and 19 (38%; missing n = 12) pts, respectively. Median lines of tx (LOT) before ven was 3 (range 1-11, 58% ≥3) including antiCD20 monoclonal antibody n=54 (87%), BTKi n=48 (77%), proteasome inhibitor n=40 (65%), and bendamustine n=31 (50%). Pts who received ven on a clinical trial were less heavily pretreated (median prior LOT = 1.5, 20% ≥3) compared with pts treated off trial (median prior LOT = 4, 76% ≥3). ORR to prior BTKi was 71% (CR 4%, VGPR 10%, PR 35%, MR 21%) (missing n=5), with a median duration of tx of 14 mos (range 0.5-119). BTKi was stopped due to progressive disease (PD) in 60% and toxicity in 40%. ORR to most recent tx before ven was 58% (CR 3%, VGPR 8%, PR 32%, MR 15%); 21% SD, 7% PD, and 15% missing. BTKi was the most frequently used tx immediately before ven (48%). Six pts (10%) required plasmapheresis up to 30 days before starting ven. Median time from diagnosis to ven initiation was 5.9 years (range 0.3-23). Ven starting dose was 200 mg in 33 pts (55%), 20 mg in 11 (18%), and 100 mg in 10 (17%) (other n=6, missing n=2). Ten pts (17%) were admitted for ven tx initiation. Maximum ven dose was 400 mg in 16 (27%) and 800 mg in 38 pts (63%) (other n=6, missing n=2). ORR to ven (missing n=3) was 73% (95% confidence interval [CI] 63-86%) (CR 2%, VGPR 21%, PR 44%, MR 7%); 23% were refractory (SD 13%, PD 10%). Median time to best response was 4 mos (range 0.5-30). Median time to peak Hb was 5 mos (range 0.1-24) and to nadir serum M protein level was 8 mos (range 0.5-34). With a median follow-up of 21.9 mos (range 2.3-70.4), the median and 3-year PFS were 30.4 mos (95% CI 11.0-38.6) and 40% (95% CI 25-54%), respectively (Figure). Median and 3-year OS were not reached (NR) (95% CI NR-NR) and 83% (95% CI 70-91%), respectively. Lymphoma was the most common cause of death (n=8/11, 73%). In univariable analyses (UVA), tx with ven on a clinical trial was associated with higher ORR (90% vs 64%; odds ratio = 8.67, 95% CI 1.04-72.16, p=.046) and superior PFS (median 39 mos (95% CI, 28.4-NR) vs 11 mos (95% CI 6.4-NR), p=.028) without a significant difference in OS. Other factors evaluated in UVA to assess association with ORR, PFS and OS were age at ven start, response to last prior tx, prior tx with BTKi, and CXCR4 mutation status. Of these, receipt of prior tx with BTKi was associated with inferior PFS (HR=2.7, 95% CI 1.1-6.5, p=.024), whereas age &gt;65 years at ven start (HR=8.6, 95% 1.1-67.8, p=0.042) and receipt of ≥3 prior tx (HR=12.0, 95% 1.5-95.9, p=.019) were associated with inferior OS. Four pts (7%) developed laboratory tumor lysis syndrome (TLS) including 2 (3%) with clinical TLS. TLS occurred at the 400 or 800 mg dose in 3 pts (missing n=1). Ven dose interruptions and/or reductions occurred in 39%. Three pts (5%) had febrile neutropenia. Ven was stopped due to PD in 21 pts (34%), planned tx completion in 15 (24%) (median tx duration = 25 mos, range 24-28), toxicity 6 (10%), and other 4 (6%); 16 pts (26%) remain on ven. Median duration of tx for those who stopped ven was 12 mos (range 1-33). Conclusion: Ven is an effective tx option for pts with relapsed or refractory LPL. Compared with the phase 2 study, ORR and PFS were lower in this cohort of more heavily pretreated pts.

Background: In patients with Waldenström macroglobulinemia (WM), continuous once-daily ibrutinib-based therapy has been associated with long-term progression-free survival. In addition, patients who continued ibrutinib-based treatment had better survival outcomes than those who discontinued treatment within the first few years. Evidence based on a single-center retrospective study suggests that dose reduction (DR) can be used to effectively manage ibrutinib-related adverse events (AEs) and avoid early treatment discontinuation. However, real-world data on outcomes in patients with WM after ibrutinib DR are limited. In this real-world study, we analyzed short-term (1-year follow-up) dosing patterns and time to treatment discontinuation (TTD) in patients with WM, with and without DR, who were receiving first-line (1L) ibrutinib. Methods: Medicare Fee-for-Service closed-claim medical or pharmacy records were used to identify patients diagnosed with WM who initiated 1L single-agent ibrutinib (420 mg/day) from January 2014 to December 2020. Observed patients were enrolled in Medicare ≥12 months before and after ibrutinib initiation and had post-initiation AEs (both prevalent and incident AEs with DR recommendation from the US Prescribing Information), as identified via ICD-9 or ICD-10 codes. Ibrutinib DR was defined as a reduction of the starting dose following the first AE within the 1-year follow-up period. Patients without a DR were defined as those who had received ibrutinib 420 mg per day during the 1-year follow-up period. Patients with a DR in the absence of AEs and patients with a DR prior to any AE were excluded from the analysis. Demographics, clinical characteristics, time to first AE, and TTD were analyzed among cohorts with and without DR. TTD was defined and evaluated as the time from first observed AE after ibrutinib initiation to the earliest occurrence of (1) a gap of &gt;120 days between the end of 1L therapy and the follow-up period, (2) initiation of a next line of therapy, or (3) death. TTD was analyzed using Kaplan-Meier methodology, log rank test, and a Cox proportional hazards model adjusted for baseline and time-varying covariates. Results: We identified 404 patients (DR, n = 58 [14%]; no DR, 346 [86%]). Overall, 249 patients (62%) were men, 267 patients (66%) had hypertension, 55 patients (14%) had atrial fibrillation, and 114 patients (28%) had other cardiovascular conditions at baseline. The mean ± SD age at baseline was 77 ± 8 years. In both cohorts, the median Charlson Comorbidity Index was 4.0. Among the 404 patients, mean ± SD time from ibrutinib initiation to first AE was 28 ± 44 days. Mean ± SD time between first AE and DR was 137 ± 102 days. Mean TTD was 8.3 months (DR) and 6.2 (no DR) ( P = 0.018; Figure). At 6 and 12 months of follow-up, fewer patients with DR discontinued treatment compared with patients without DR (6 months: 24% vs 46%, P = 0.002; 12 months: 36% vs 50%, P = 0.064). After controlling for baseline and time-varying demographic and clinical characteristics, patients with DR were not significantly more likely to discontinue treatment compared with patients without DR (hazard ratio [95% CI], DR vs no DR: 1.24 [0.86-1.78]). Conclusion: These short-term (1-year follow-up) findings suggest TTD was not impacted by DR of ibrutinib following AEs. Thus, ibrutinib DR can be an effective strategy to manage AEs while maintaining clinical efficacy. Of note, causal association between AE and subsequent DR cannot be inferred from the claims database due to the cross-sectional nature of this study.

AbstractIbrutinib is a first-generation inhibitor of Bruton tyrosine kinase (BTK) that is currently approved to treat patients with B-cell malignancies, including Waldenström macroglobulinemia (WM), relapsed/refractory (R/R) mantle cell lymphoma (MCL), R/R marginal zone lymphoma (MZL), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Off-target adverse effects, such as atrial fibrillation, hypertension, and bleeding, have been observed and may limit a patient’s tolerance for treatment. Currently, there is no well-established treatment regimen for patients who cannot tolerate ibrutinib. Approaches to address such patients include managing ibrutinib side effects with supportive care or dose reductions, switching to an alternative covalent BTK inhibitor, or abandoning covalent BTK inhibitors for alternative forms of treatment. Here we review the literature and provide guidance on treating ibrutinib-intolerant patients with B-cell malignancies.