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Abstract Background: Advantages of covalent Bruton Tyrosine Kinase inhibitor (cBTKi) treatment (tx), as compared to BCL2 inhibitor (BCL2i) containing regimens, include ease of initial administration without a requirement for frequent laboratory monitoring, even in patients (pts) with bulky disease. However, limitations of cBTKi monotherapy include acquired resistance, cumulative toxicity and the financial burden associated with continuous administration. CLL pts treated on the E1912 study who discontinued (dc) ibrutinib for reasons other than progression of disease (PD) had a median progression free survival (PFS) of ~2.7 years from ibrutinib dc, suggesting that a time-limited cBTKi strategy may be feasible for some pts(Shanafelt et al. Blood Advances 2025). We hypothesized that acalabrutinib (acala) and obinutuzumab (O) could be administered as a time-limited initial tx for CLL with duration guided by minimal residual disease (MRD). Methods: This is an ongoing phase II, multicenter, investigator-initiated study of acala and O for previously untx pts with CLL/small lymphocytic lymphoma (SLL) requiring tx per iwCLL 2018 criteria (NCT04722172). Pts with TP53 aberrancy are excluded. Pts receive acala 100 mg twice daily and O during 28-day cycles (C) 2-7. Undetectable MRD is defined with a 10-4 sensitivity in the peripheral blood (PB) by ClonoSeq next generation sequencing (uMRD4). Pts undergo MRD testing at C13; if uMRD4 at C13 with a complete response (CR) or partial response (PR), pts dc acala and enter tx free observation (TFO). If detectable MRD4 (dMRD4) at C13, pts continue acala until uMRD4, with repeat MRD testing occurring at C16, 19, 22 and 25. All pts dc acala after a maximum of 26C and enter TFO, even if dMRD4. If pts have PD meeting iwCLL criteria for tx during TFO, re-tx consists of acala + 6 cycles of O. Pts are followed for 13C of re-tx. Primary endpoint is 36-month PFS. Results: 55 pts initiated tx. Baseline characteristics include: median age 67, 64% male, 47% LN ≥ 5 cm, 73% IGHV unmutated. Best overall response rate (ORR) was 95% (CR: 4, PR: 48, SD: 0, PD: 1, unknown: 2). Best uMRD4 rate at any time during the study was 49% (n=27 pts, intention-to-treat, IIT). 5 pts dc tx prior to C13 MRD testing (2 pt decision, 2 AE, 1 due to PD after ~4C). At C13, 22 pts (40% of IIT) were uMRD4; 21 entered TFO after 13C and 1 pt had 19C tx prior to TFO. 28 pts had dMRD4 (51% ITT) at C13. Between C13 and 26, 2 pts became uMRD4 and entered TFO, 1 pt died (COVID-19), and 2 pts stopped acala for tx of other cancers. 21 pts completed 26C acala per protocol prior to entering TFO; 2 additional pts had PD at C25 and EOT. Median tx duration was 19C. In univariate analyses, age, del11q, del13q, IGHV mutational status and baseline LN ≥ 5 cm were not predictive of uMRD4 at C13. At a median follow-up of 38 months, the median PFS for the overall cohort is 42 months (95% confidence interval (CI): 37, not reached), with an estimated 36-month PFS of 69% (95% CI: 57%, 84%). At data cutoff, of 46 pts entering TFO, 29 pts remained in TFO without PD, 7 pts had PD during TFO but had not met iwCLL criteria for re-tx, and 10 pts had PD requiring tx (5 pts re-tx pe protocol, 5 came off study for non-protocol tx approach). The overall median TFO period (measured from acala dc to PD) was 25 months (95% CI: 21 – not reached, n=46 pts). 5 pts have initiated re-tx with acala + O (1 pt best response PR and uMRD4; 4 ongoing tx). Median time to re-tx was 18 months (range 6-34, n=5 pts). Conclusions: This study is proof-of-concept that cBTKi may be administered as a time-limited tx without the addition of a BCL2i. While the initial PFS is shorter than historical studies examining continuous cBTKi, of patients entering TFO after 1-2 years of acala, the median duration of TFO until PD is 25 months, and longer follow-up will provide re-tx outcomes. Potential advantages to MRD-guided, time-limited cBTKi tx include time off tx for pts, limiting acquired resistance, the ability to re-challenge with cBTKi at progression, and reserving BCL2i for third-line or later tx.

Abstract Background: Undetectable minimal residual disease (uMRD) at the end of first-line (1L) treatment (tx) with 12-cycles (C) of venetoclax (ven) + obinutuzumab (obin) is associated with prolonged survival for patients (pts) with chronic lymphocytic leukemia (CLL, Al Sawaf et al. Blood 2024). We hypothesized that MRD may be used to guide ven tx duration for CLL pts treated with 1L ven + obin. Methods In this ongoing phase II, multicenter investigator-initiated study, pts receive ven + obin for 1L tx of CLL/small lymphocytic lymphoma (NCT04447768). Eligible pts have a CIRS score of ≤ 6 and require 1L tx per iwCLL 2018 criteria. Pts receive 6 x 28-day C of obin and initiate ven on C1D22. Ven duration is dependent on peripheral blood (PB) MRD status measured by ClonoSeq next generation sequencing. At C7, pts undergo MRD testing. Pts uMRD6 (<10-6 sensitivity) at both C7 and C9 dc ven after 9C and enter treatment free observation (TFO). Pts with detectable MRD6 (dMRD6) at C7 undergo repeat testing at C12; if uMRD5 (<10-5) pts dc ven after 12C. Pts dMRD5 at C12 continue ven for an additional 12C (24C total) prior to TFO. The primary study endpoint is 36-month PFS; the unpromising rate is set at 82% and will be tested by a nonparametric survival estimate (Kaplan-Meier) along with Greenwood's formula. RNA sequencing (RNAseq) was performed pre-tx on patient bone marrow (or PB if inaspirable) samples. Unsupervised clustering using machine learning (ML) based on consensus nonnegative matrix factorization was applied to the most variable genes to identify patient clusters. Clusters were then biologically characterized by gene signature scoring using xCell algorithm and assessed for association with uMRD6 at C7 using a Fisher exact test. Results Baseline characteristics of the 100 pts who initiated tx include: median age 58 (range 34-81); 71% male, 90% White, 3% Black and 2% Asian, 5% unknown; 49% IGHV unmutated, 16% TP53 mutation, 8% del17p (previously reported, Roeker et al. ASH 2024). 3 pts stopped tx prior to C7. 51 pts were uMRD6 at C7 and C9 and completed 9C ven. 46 pts were dMRD6 at C7; 6 pts stopped tx outside of meeting protocol requirements and are included in intention-to-treat (IIT) analyses. 32 pts were uMRD5 at C12 and dc ven after 12C. 8 pts were dMRD5 at C12: 5 continued ven per protocol (3 completed 24C ven, 2 ongoing tx as of 15 May 2025 data cut-off), 2 stopped ven outside of protocol requirements (included in ITT analyses), and 1 pt withdrew consent. At a median follow-up of 35 months, the 36-month PFS rate is 90% (95% CI: 84%, 97%). 36-month OS is 94% (95% CI: 89%, 99%). Landmark PFS analyses from EOT were performed for pts who dc ven after 9C due to uMRD6 (24-month PFS 92%, 95% CI: 85, 100%, n=51) and pts who dc ven after 12C due to uMRD5 (24-month PFS 96%, 95% CI: 89%, 100%, n=32). For pts dc ven after 9C due to uMRD6 (n=51), PB MRD at 12C after EOT was: 59% uMRD6, 12% uMRD5, 4% uMRD4, 8% dMRD4 and 18% unknown. For pts dc ven after 12C due to uMRD5 status (n=32), PB MRD at 12C following EOT was: 9% uMRD6, 31% uMRD5, 9% uMRD4, 25% dMRD4 and 25% unknown. Of the 5 pts with PD, 3 pts have had Richter Transformation to diffuse large B-cell lymphoma (all uMRD6 at C7 / 9). Two pts with PD have not met iwCLL tx criteria and remain in TFO. Five pts have died (suicide, West Nile encephalitis, COVID-19, complications of glioblastoma and RT DLBCL). Five C12 dMRD5 pts who continued ven have reached C18, with only 1 of 5 converting to uMRD5 in PB. However, all 5 maintained uMRD4 (<10-4). Of 3 pts that completed 24C ven (2 ongoing tx), 1 pt had deepening of response to uMRD5 at C24, and 2 pts had rising MRD on ven (dMRD4 at C24). To investigate patient heterogeneity at baseline and its relationship to uMRD, we clustered patient RNAseq samples into two clusters using artificial intelligence/ML based unsupervised clustering. The clusters associated with uMRD6 at C7 (Fisher exact test p=0.038), and patients in the cluster with significantly higher immunosuppressive cells such as T-regulatory cells and M2 macrophages were less likely to be uMRD6 at C7. Conclusions At a median follow-up of 35 months, the estimated 36-month PFS rate is 90%. RNAseq transcriptomic analyses identified that patients with enriched immunosuppressive cells were less likely to be uMRD6 at C7. Additional follow-up is required to confirm the durability of this MRD-guided ven + obin tx strategy.

Abstract The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post–CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.

Background: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment with high efficacy in treating relapsed or refractory (R/R) mantle cell lymphoma (MCL). However, with CAR-T therapy, refractory disease occurs and a continuous pattern of relapse over time has been observed. Limited data exist about post-CAR-T progression of disease (POD) management and outcomes in MCL. Such data would meaningfully inform practice and set a critical benchmark for future studies in the post-CAR-T setting. We characterized treatment patterns and outcomes for pts with POD after CD19 CAR-T therapy for R/R MCL. Methods: We queried institutional databases to identify pts with R/R MCL who received CD19-directed CAR-T therapy. Treatment may have occurred as standard-of-care or in a clinical trial. We performed chart review to extract variables and categorized therapies by mechanism(s) of action. We used descriptive statistics to characterize patient/disease characteristics and treatment patterns, the reverse Kaplan-Meier method to calculate follow-up, the Kaplan-Meier method to calculate survival, and Cox proportional hazards to associate clinical and disease features with survival outcomes. Results: Across 9 sites, we identified 306 pts who received CD19 CAR-T for R/R MCL, of which 104 (34%) experienced POD and were investigated in detail: pts with POD were mostly men (73%), had a median age of 67 yrs (range 36-86) at infusion, and had received a median of 3 lines of therapy pre-leukapheresis, including a BTK inhibitor (BTKi) in 97% of patients; 36% of BTKi-exposed patients had BTKi-unresponsive disease. High-risk tumor features were common pre-CAR-T: 47/68 (69%) with a TP53 mutation, 66/93 (71%) with Ki67 ≥50%, and 47/102 (46%) with blastoid/pleomorphic MCL. Most pts (75%) received bridging therapy. Pts received brexucabtagene autoleucel (88%) or lisocabtagene maraleucel (12%). Regarding best CAR-T response for pts with POD, 71% had a complete response (CR), 13% partial response (PR), and 15% had no response. The median time from CAR-T infusion to POD was 6 months (IQR 3-12). At time of POD, high-risk MCL features were again common: 55% blastoid/pleomorphic, 42/56 (75%) Ki67 ≥50%, 51/83 (61%) MIPIb high-risk, and 21/35 (60%) TP53-mutated MCL. Among 69 pts with CD19 assessed on a post-POD biopsy, 8 (12%) had CD19-negative disease. 30% of pts had an ECOG performance status of ≥2 at time of POD. After POD occurred, 15 pts received no anti-lymphoma therapy (Tx), 11 pts underwent excision or radiation, and 78 pts received systemic therapy. The most commonly used first-line systemic Tx post-CAR-T progression included: pirtobrutinib in 13 pts [overall response rate (ORR) 31%], chemoimmunotherapy in 12 pts (ORR 25%), venetoclax in 10 patients (ORR 20%), bispecific antibodies (BsAb) in 10 pts (ORR 60%), and small molecule combinations (at least 2 of BTK inhibitor, BCL2 inhibitor, and lenalidomide) in 8 patients with ORR 50%. The ORR to all first systemic Tx post-POD was 42%. The median follow-up from POD is 15.2 months among survivors. The median progression-free and overall survival (OS) from time of POD were 2.3 (95% CI 1.9-3.4) and 5.4 months (95% CI 4.5-9.4), respectively, and 1-year OS rate was 33%. TP53 mutations predicted inferior OS (HR 2.83, 95% CI 1.08-7.43, P = 0.026) as did age ≥65 years at time of POD (HR 1.83, 95% CI 1.07-3.15, P = 0.023), MIPIb high-risk (HR 3.56, 95% CI 1.08-11.7, P = 0.042), and non-response to CAR-T (HR 3.55, 95% CI 1.93-6.53, P < 0.001). Discussion: Our data, the largest reported cohort of pts with POD post-CAR-T with R/R MCL, confirm the poor prognosis in this patient population, with a median OS of 5.4 months. BsAbs showed promise with an overall response rate of 60%. The presence of a TP53 mutation significantly predicted inferior OS, corroborating the prognostic importance of this finding in the post-CAR-T context. Data from pts treated at additional sites and updated analyses will be presented at the meeting.

Background: Disseminated marginal zone lymphoma (MZL) is an indolent disease often observable at diagnosis with treatment indications similar to other indolent lymphomas. First-line therapy is typically rituximab alone or in combination with chemotherapy (e.g. bendamustine). Due to the long-life expectancy, avoiding alkylating agents to reduce bone marrow damage could be beneficial. In addition, a “chemotherapy free” option could have fewer and less severe complications. Bruton tyrosine kinase inhibitors (BTKi) are active and approved or NCCN-recommended beyond first line therapy in MZL. Moreover, BTKi are approved for first line therapy in Waldenstrom's Macroglobulinemia, a disease with both diagnostic and pathophysiologic overlap with MZL. We conducted a multicenter randomized trial of rituximab induction plus ibrutinib/placebo (RI vs RP) for patients with MZL in need of first line systemic therapy. Complete response (CR) rate at 30 months was the primary endpoint and progression free survival (PFS) was secondary. The target sample size was 63 in each arm. The study was closed after 22 eligible patients enrolled due to low accrual. Methods: Patients (pts) with either nodal, splenic or extranodal MZL were eligible. Prior surgery, radiation, antibiotic or antiviral therapy for MZL were allowed if followed by disease progression requiring treatment. Documented evidence of need for treatment included, but was not limited to, threatened end-organ function, bulky disease (>5 cm), symptoms, requirement for transfusion or growth factor support, or significant need for intervention. Transformation to DLBCL was excluded prior to entry including bone marrow assessment. Randomization occurred prior to rituximab weekly x 4 to either daily placebo (RP) or ibrutinib (RI) 560 mg starting on day 1 and continued until disease progression (PD), intolerance or CR at 30 months. Those with partial response (PR) or stable disease (SD) at 30 months could continue placebo or ibrutinib. CR assessment required both a negative FDG-PET and bone marrow biopsy. RESULTS: 22 pts enrolled (Feb 2020-March 2023) with baseline characteristics including: median age 67 years (35-78) and White race 17. Stage II (3), III/IV (17). Subtype: splenic 16, nodal 4, extranodal 2. Prior therapy: splenectomy 1, radiation 0, other surgery 0, antiviral/antibiotic 0. Median maximal tumor dimension was 3.7 cm (range 1.6-23.6); with >5 cm in 9 pts. Median time from diagnosis to treatment was 32 days (5-4712 with only 3 > 1 year). 11 pts were randomized to each arm. Responses: RP: 3 CR, 4 PR, 3 SD, 1 inevaluable; RI: 7 CR, 4 PR. No patient achieved CR30, but 3 had CR at 29 months: 2 RP, 1 RI. With a median follow up of 35 months (13-50), the median PFS by Log Rank was 14 mo (RP) vs 29 (RI), though this difference was not statistically significant in the setting of small numbers. Treatment was well tolerated. Only 1 pt experienced grade 3 events at least possibly related: hypoxia and dyspnea. This was attributed to COVID-19 and occurred on the RP arm. 1 CR patient with baseline clonal hematopoiesis developed myelodysplasia. Treatment improved baseline activities in 4/5 pts (1 RP, 3 RI). Baseline pain improved in 8 pt: 4 RP, 4 RI. All pts were alive at the data cuff off. Conclusions: This study is a chemotherapy free frontline trial in MZL and the first to utilize ibrutinib in frontline MZL. All pts received rituximab induction and were randomized at entry to RP vs RI. The COVID-19 pandemic affected site activation and accrual, ultimately contributing to low accrual and early study termination. Nonetheless, the results suggest a marked difference in median PFS favoring the RI arm, although small numbers preclude a statistically significant result. Notably, our results are qualitatively similar to those of Dimopoulos (NEJM, 2018) in Waldenstrom's Macroglobulinemia, a disease with similar characteristics to MZL. In that study, the median PFS by Log Rank was 20 months (RP) vs not reached (RI); and 30-month PFS 28% (RP) vs 82% (RI). (Hazard ratio for progression or death, 0.20; P<0.001). Further, our trial supports pursing a chemotherapy free first line approach in MZL.

Abstract Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is considered the standard-of-care for patients with advanced-stage diffuse large B-cell lymphoma (DLBCL), despite findings that patients with nongerminal center B-cell like (non-GCB) have significantly worse outcome with this regimen. We evaluated the prognostic significance of baseline risk factors, including cell of origin (COO) classified by the Hans algorithm, within an alternative chemoimmunotherapy program. At Memorial Sloan Kettering Cancer Center (MSK), 151 patients with DLBCL received sequential R-CHOP induction and (R)-ICE (rituximab, ifosfamide, carboplatin, and etoposide) consolidation. Outcome analysis based on COO was validated with a propensity score–matched cohort treated with R-CHOP from the Mayo Clinic component of the Molecular Epidemiology Resource (MER). Among the patients with GCB (n = 69) and non-GCB (n = 69) at MSK, event-free survival (EFS) of non-GCB was superior to that of GCB (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.29-0.98). Overall survival (OS) demonstrated an association in the same direction but was not statistically significant (HR, 0.68; 95% CI, 0.33-1.42). Propensity score–matched patients from MSK (n = 108) demonstrated a small attenuation in the HRs for EFS (HR, 0.57; 95% CI, 0.27-1.18) and OS (HR, 0.76; 95% CI, 0.33-1.79) and were no longer statistically significant. In contrast, the matched MER cohort (n = 108) demonstrated an EFS association (HR, 1.17; 95% CI, 0.70-1.95) and OS association (HR, 1.13; 95% CI, 0.64-2.00) in the opposite direction, but were also not statistically significant. R-CHOP induction and (R)-ICE consolidation may overcome the negative prognostic impact of the non-GCB phenotype, per the Hans algorithm, and can be preferentially selected for this population. This trial was registered at www.ClinicalTrials.gov as #NCT00039195 and #NCT00712582.

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

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.

SummaryIbrutinib 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 monthsversusnot 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 monthsversusnot 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.