Ibrutinib Monotherapy Research Articles

P1221: DIFFUSE LARGE B-CELL LYMPHOMA RICHTER SYNDROME IN CHRONIC LYMPHOCYTIC LEUKEMIA – A RETROSPECTIVE ANALYSIS OF TREATMENT OUTCOMES IN POLISH ADULT LEUKEMIA STUDY GROUP

Background: Richter syndrome (RS) is a recognized uncommon manifestation and evolution of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) with a dismal prognosis. It occurs in 2-10% of CLL patients. It is associated with a clonal evolution and progression, generally with a transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL) or, less frequently, to Hodgkin Lymphoma (HL). Despite the advances in understanding pathogenesis of the disease, the DLBCL variant of RS (DLBCL-RS) is associated with a dismal prognosis with a median survival < 1 year. The treatment options and risk factors of worse outcome for RS still need to be further expanded. Aims: To study the characteristic and treatment outcomes of patients with DLBCL-RS. Methods: The retrospective analysis of 99 patients diagnosed with DLBCL-RS treated in hematology centers of the Polish Adult Leukemia Study Group (PALG) between 2011 and 2021. Results: Clinical data of 124 patients with Richter syndrome was collected. Ninety-nine patients were diagnosed with DLBCL-RS (79.8%) and further analyzed. Median time since CLL diagnosis to Richter transformation was 43.0 months (range 0-252.0). At the time of transformation 31.3% patients had CLL Rai stage IV, 74.7% were ECOG< 2, while the median Cumulative Illness Rating Scale (CIRS) was 4 (range 0-16). Thirty-seven patients transformed during CLL treatment, 56.7% of them were receiving novel agents (Brutons tyrosine kinase inhibitor or BCL2 inhibitor). Median time of observation after transformation was 10.7 months (range 0-98.6). Median overall survival (OS) after DLBCL-RS diagnosis was 17.3 months (95% Cl 11.9-46.8) and median progression-free survival (PFS) 13.5 months (95% Cl 9.6-22.7). Seventy-six patients (76.8%) had RS treated with intensive chemotherapy protocols, mainly R-CHOP-like regimens for the first line treatment. Only 42.3% had response to the treatment (25/76 complete responses and 11/76 partial responses). Worth mentioning is that in the group of patients with response two patients had ibrutinib monotherapy and one had rituximab-ibrutinib. In forty patients RS was primarily resistant to administered treatment and 65% of them died due to progression or treatment related complications. In the primary resistant DLBCL-RS p53 pathway aberration was noted in 47.5% of patients (17p deletion in 13 patients or TP53 mutation in 6 patients). Better results were achieved for patients who proceeded to autologous hematopoietic stem cell transplantation (auto-HSCT; n=8) and allogeneic HSCT (allo-HSCT; n=10). The median OS in auto-HSCT recipients was 46.1 months, while in allo-HSCT the median OS reached 18.3 months (3 patients died due to allo-HCST-related complications). Significantly lower OS (3.4 months, 95% Cl 14.13-not reached) was observed for RS in heavily pretreated CLL patients (>3 lines of therapy preceding transformation) compared to those treated with up to 3 lines of therapy (23.7 months) (p=0.0002). Median OS for treatment naïve patients at DLBCL-RS diagnosis was not reached. Other factors identified as predictors of poor OS in univariate analysis were ECOG ≥2 (p=0.0014), hemoglobin level <10 g/dl (p=0.017) and platelet count <100x109/L (p=0.0065). Summary/Conclusion: Our study represents the largest dataset of DLBCL-RS patients in Polish hematology centers and confirms the poor outcomes and prognosis associated with RS. The worst treatment results were observed in RS receiving >3 lines of CLL therapy preceding transformation. Only proceeding to hematopoietic stem cell transplantation may improve the prognosis.

S149: LONG TERM OUTCOMES OF IFCG REGIMEN FOR FIRSTLINE TREATMENT OF PATIENTS WITH CLL WITH MUTATED IGHV AND WITHOUT DEL(17P)/TP53 MUTATION

Background: Chemoimmunotherapy with FCR has been an effective treatment for patients (pts) with CLL. Pts with mutated IGHV (IGHV-M) have favorable long-term outcomes after receiving FCR. We designed an investigator-initiated, phase 2 trial with ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) for previously untreated pts with IGHV-M CLL (NCT02629809). We report here long-term outcomes with a median follow-up of 56.8 months. Aims: Investigate the role of combined chemoimmunotherapy and targeted therapy in CLL. Methods: Eligibility included age ≥18, IGHV-M, no del(17p)/TP53 mutation. Pts received 3 courses of iFCG. Pts achieving CR/CRi with undetectable MRD (U-MRD) in bone marrow (4-color flow-cytometry, sensitivity 10-4) after 3 courses of iFCG received ibrutinib with obinutuzumab (iG) for 3 cycles, followed by ibrutinib monotherapy for 6 months. All other pts received iG for 9 cycles (C4-12). Pts with marrow U-MRD at end of Cycle 12 stop all therapy. Response assessment was per 2008 iwCLL criteria with BM and CT scans every 3 months during the first year. After completion of all therapy, pts were followed by exam, blood counts and peripheral blood MRD every 6 months. NGS MRD (sensitivity 10-6) was performed in bone marrow in pts with available samples. Results: 45 pts initiated treatment. Median age was 60 [range, 25-71]. 69% had del(13q). After three cycles of iFCG, 39/45 (87%) pts achieved marrow U-MRD. Responses improved with continued therapy with 40/45 (89%) and 41/45 (91%) achieving marrow U-MRD after Cycles 6 and 12, respectively. Overall, 44/45 (98%) pts achieved marrow U-MRD as best response at any time during the study. The 5-year PFS and OS are 97.7% (95% CI 94–100%) and 97.8% (95% CI 94–100%), respectively. No pt had CLL progression or Richter transformation. One pt developed therapy-related MDS; this pt is being monitored for 38+ months without any therapy for MDS with normal blood counts. The sole event noted on both the PFS and OS curve is a pt death from heart failure. 41/45 pts completed 12 cycles of treatment (4 pts came off study prior to C12). All 41 pts achieved marrow U-MRD4 by flow-cytometry and per protocol, all 41 pts discontinued ibrutinib. After a median follow-up of 44.2 mos post-discontinuing ibrutinib, 6 pts had an MRD recurrence (defined as 2 consecutive values of ≥0.01% in peripheral blood by flow cytometry) at a median of 27.2 mos (range, 20.7-49.0 mos) after stopping all therapy. All 6 pts are being monitored with no clinical progression or active therapy; notably, all 6 pts were MRD+ at 10-6 by marrow NGS after the completion of 3 cycles of iFCG and 4/5 (1 missed sample) were MRD+ at 10-6 by marrow NGS after the completion of Cycle 12. Of the 16 pts who were marrow NGS MRD+ at 10-6 after 3 cycles of iFCG, 6/16 had an MRD recurrence in blood in follow-up vs. 0/20 who were NGS MRD negative/indeterminate (p = 0.004). Of the 12 pts who were marrow NGS MRD+ at 10-6 after Cycle 12, 4/12 had an MRD recurrence in blood in follow-up vs. 1/26 who were NGS MRD negative/indeterminate (p = 0.02). Image:Summary/Conclusion: The iFCG regimen, using only 3 cycles of chemotherapy (as opposed to 6 cycles of chemoimmunotherapy) achieves a very high rate of U-MRD in previously-untreated pts with CLL with IGHV-M CLL. No pt had disease progression with a median follow-up of close to 5 years. The 5-year PFS is 97.7%; this is favorable compared to 5-year PFS of ≈65% with FCR (CLL10), ≈70% with ibrutinib (A041202 trial), and 81% with ibrutinib (RESONATE-2) for IGHV-M CLL. Not unexpectedly, MRD recurrence during follow-up correlated with MRD positivity by NGS during therapy.

P637: FRONTLINE THERAPY CLL WITHOUT 17P DEL/P53 ABERRATIONS: SYSTEMATIC REVIEW AND BAYESIAN NETWORK META-ANALYSIS

Background: Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia, with a median age at diagnosis of 72 years. IgVh unmutated CLL without 17p del/p53 aberrations (UN-only CLL) still carry a poorer prognosis as compared to IgVh mutated (MU-only) cases. Although many treatment options are currently available for the front-line therapy, the best choice and treatment sequencing stratified on efficacy and tolerability for UN/MU-only CLL remains to be defined. Aims: We performed a systematic review and Bayesian network meta-analysis to define best frontline therapy and treatment sequence for UN/MU-only CLL. Methods: Analysis of the literature was performed through the main databases. Due to different therapeutic approaches to front-line therapy of CLL, we chose to conduct a Bayesian Network Meta-Analysis (NMA), allowing to rank (from best to worst) multiple treatments in a single analysis. We generated a rank for Progression Free Survival (PFS), Overall Response Rate (ORR), Minimal Residual Disease (MRD), assessed by flow cytometry on peripheral blood, and tolerability. PFS was evaluated in unselected population for IgVh, and in UN/MU-only CLL patients. Results: Fifteen clinical trials, with a total of 7958 patients, have been included, while 16 different treatments were considered to build four different network meta-analyses to identify the best treatment in PFS, ORR, MRD, and tolerability: Acalabrutinib (ACA); ACA + Obinutuzumab (ACA-O); Alemtuzumab; Bendamustine + Rituximab; Chlorambucil; Chlorambucil + O; Chlorambucil + Ofatumumab; Chlorambucil + Rituximab; Fludarabine + Cyclophosphamide + Rituximab; Fludarabine + Cyclophosphamide; Ibrutinib (IBR); IBR + O; IBR + Rituximab; Lenalidomide, Venetoclax + IBR (VEN-IBR), Venetoclax + Obinutuzumab + Ibrutinib (VEN-O-IBR), Venetoclax + O (VEN-O). ACA-O scored the best in PFS in an unselected population (SUCRA 100%, probable the best 99.9%), UN- and MU- only CLL patients. Our analysis showed that VEN-O ranked the first for ORR (SUCRA value 100%, probably the best 100%). VEN-O ranked the first also for MRD (SUCRA 90.4%, probably best 36.2%) versus the second VEN-O-IBR (SUCRA 84.0%, probably best 35.9); in the direct comparison, the difference between VEN-O and VEN-O-IBR is not statistically significant (Odds Ratio 1.44, CrI 0.00,563.57). Finally, ACA monotherapy is the most tolerable therapy (SUCRA value 100%, probably the best 100%), whereas IBR-O turned to be the most toxic treatment (SUCRA value 0%, probably the best 1%). Interestingly, IBR monotherapy ranked the 9th in the network, whereas all combination regimens including Obinutuzumab carried a high risk of toxicity. Image:Summary/Conclusion: To our knowledge, this is the first network meta-analysis that compares at the same time PFS, tolerability, ORR, and MRD. Our PFS analysis showed that ACA-O was the best treatment in both MU/UN-only patients. Furthermore, ACA turned out to be the most tolerated regimen, whereas the BTKis-O based regimens significantly carried a high toxicity profile as compared to BTKis alone, counterbalancing the advantage of O-addition in terms of ORRs, where O-based regimens achieved the higher rank, when combined either with VEN or BTKis. ACA-O was the best treatment for PFS, although with a worse toxicity profile as compared to ACA monotherapy. VEN-O scores as the best in ORR and MRD. The combination ACA-O has the highest probability to be the best treatment for prolonging the PFS in untreated, UN/MU-only CLL patients. ACA monotherapy is a valuable alternative considering both the safety and efficacy profile.

Characteristics and clinical outcomes among patients receiving either ibrutinib or anti-CD20 monotherapy as first-line (1L) treatment for chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): A retrospective analysis in community oncology practice.

e19056 Background: Ibrutinib is an oral, once daily Bruton’s tyrosine kinase inhibitor and is a targeted treatment that has demonstrated progression-free survival and overall survival benefits in multiple phase 3 trials across age, fitness, and high-risk markers for CLL/SLL. Despite ibrutinib established as a preferred first-line (1L) treatment option, anti-CD20 monotherapy (rituximab or obinutuzumab) has been prescribed as symptomatic or palliative therapy. This retrospective study compared outcomes between ibrutinib and anti-CD20 monotherapy for CLL/SLL patients who initiated a 1L of therapy in community oncology practice. Methods: The nationwide Flatiron Health Electronic Health Record-derived de-identified database (03/04/2016-08/31/2021) was used to select patients with CLL/SLL who had ≥2 clinic visits and started 1L therapy with ibrutinib or anti-CD20 monotherapy. Patient baseline characteristics prior to 1L initiation were compared between the two treatment groups. Propensity score-based inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences between treatment groups. Kaplan-Meier (KM) analysis was used to evaluate time to next treatment (TTNT) from 1L initiation. Two subgroup analyses were performed among patients with high-risk cytogenetic markers (deletion 17p or 11q, or unmutated IGHV) and those without IGHV testing. Results: Overall, 3,226 patients were included in the analysis, of whom 2,188 (67.8%) received ibrutinib and 1,038 (32.2%) received an anti-CD20 antibody. The average age was 71.4 years for ibrutinib patients and 72.9 years among anti-CD20 users. Patients treated with ibrutinib were more likely to have high-risk cytogenetic markers (42.6% vs 27.9%). Ibrutinib-treated patients overall had a significant 70% risk reduction of initiating a subsequent treatment compared with anti-CD20 group (Table). Similar results were also found in subgroups of patients with high-risk and those without IGHV testing. Conclusions: IPTW-adjusted analysis showed that in the real-world community practice setting, treatment with ibrutinib resulted in a statistically significantly lower risk of initiating subsequent treatment than the anti-CD20 group including patients with high cytogenetic risk features and without IGHV testing.[Table: see text]

Real-world clinical outcomes in patients receiving either ibrutinib or chemo-immunotherapy (CIT) as first-line (1L) treatment for chronic lymphocytic leukemia (CLL) / small lymphocytic lymphoma (SLL): A retrospective analysis.

e19057 Background: Ibrutinib is an oral, once daily Bruton’s tyrosine kinase inhibitor and is the only targeted treatment that has demonstrated progression-free survival and overall survival in multiple phase 3 trials across age, fitness, and high-risk markers for CLL/SLL. This study examined the trends in genomic testing and compared outcomes of first line (1L) CLL patients treated with ibrutinib or CIT in clinical practice. Methods: The nationwide Flatiron Electronic Health Record-derived de-identified database (03/04/2016-08/31/2021) was used to select patients with CLL/SLL who had ≥2 clinic visits and started 1L therapy with ibrutinib or CIT. Patient baseline characteristics prior to 1L initiation were compared between the two treatment groups. Propensity score-based inverse probability of treatment weighting (IPTW) was used to adjust for baseline differences between treatment groups. Kaplan-Meier (KM) analysis was used to evaluate time to next treatment (TTNT) from 1L initiation. Two subgroup analyses were performed among patients with high-risk cytogenetic markers (deletion 17p, 11q or unmutated IGHV) and those without IGHV testing. Results: Overall, the rate of testing for high-risk markers remain suboptimal, while cytogenetic testing for del17p or del11q improved from 52.3% to 74.3%, coinciding with approval of ibrutinib for del17p in 2014, IGHV testing remains infrequent and low at 37.7%. 1882 patients (61.4%) received 1L ibrutinib monotherapy (mean age 71, median follow-up 26 months), and 1182 (38.6%) received a CIT regimen (mean age 68, median follow-up 33 months). More patients treated with ibrutinib had a known high-risk cytogenetic marker (44% vs. 34%), especially in those with deletion 17p (15% vs. 4%), than those treated with CIT. Ibrutinib-treated patients significantly decreased risk of initiating a subsequent treatment by 51% (Table), the high-risk group by 60%, and those with unknown IGHV status by 49%. Conclusions: Consistent with clinical trial evidence, treatment with ibrutinib among 1L CLL patients resulted in a statistically significantly lower risk of initiating subsequent treatment than those treated with CIT, both overall and in the subgroups of patients with high-risk cytogenetic markers and patients without IGHV testing. Assessment of cytogenetic/molecular risk status for appropriate treatment is vital to optimize clinical outcomes, especially in the novel agent era. Recent IGHV testing in community practice to assess genetic risk in CLL remains suboptimal.[Table: see text]

Монотерапия ибрутинибом при В-клеточной лимфоме экстранодальной маргинальной зоны

The article presents a clinical case of treatment of orbital B-cell lymphoma of the extranodal marginal zone. This case report demonstrates the safety and efficacy of ibrutinib monotherapy in patients with relapsed/refractory LMZ previously reported in the PCYC-1121 study. Research and clinical evidence support the use of ibrutinib monotherapy as an alternative to chemotherapy in this patient population with a favorable benefit-risk profile and a convenient once-daily regimen.

A clinical practice comparison of patients with chronic lymphocytic leukemia with and without deletion 17p receiving first-line treatment with ibrutinib.

Among patients with chronic lymphocytic leukemia (CLL) with deletion 17p (del[17p]), evidence from clinical trials for the effectiveness of single-agent ibrutinib as first-line therapy is limited. This retrospective analysis compared real-world clinical outcomes among patients with CLL, with and without del(17p), treated with first-line ibrutinib monotherapy. Overall survival, time to next treatment, time to treatment discontinuation, and reasons for ibrutinib discontinuation were evaluated. Using data from a real-world database, patients included were aged ≥18 years, had been diagnosed with CLL between January 1, 2011 and December 31, 2019, had undergone cytogenetic testing, and had received first-line ibrutinib monotherapy. A total of 1,069 patients were included in the analysis (62.7% male; median age 69 years); 23.8% (n=254) had del(17p). The median overall survival was significantly shorter in patients with del(17p) than in patients without (57.7 months vs. not reached; P=0.0006). Similar results were observed for median time to next treatment (49.4 months vs. not reached, P=0.0330). The median time to treatment discontinuation was non-significantly shorter in the group of patients with del(17p) (32.5 months vs. 42.9 months, P=0.3370). Results of an adjusted Cox proportional hazards model showed that the group with del(17p) was at significantly higher risk of death than was the group without del(17p) (hazard ratio=1.70, P=0.0031). Event rates for switching to new treatment and discontinuation were higher but not statistically significantly so. The most common reason for discontinuing ibrutinib treatment in both groups was toxicity, but discontinuation due to progression was significantly more frequent among patients with del(17p) (20% vs. 6%; P<0.0001). This study identifies an unmet need for more effective first-line therapeutic options in patients with CLL/small lymphocytic lymphoma and del(17p), despite the advent of ibrutinib.

Guideline for the treatment of chronic lymphocytic leukaemia

Guideline for the treatment of chronic lymphocytic leukaemia

Targeting Mcl-1 by AMG-176 During Ibrutinib and Venetoclax Therapy in Chronic Lymphocytic Leukemia.

B-cell receptor (BCR) signaling pathway and Bcl-2 family prosurvival proteins, specifically Bcl-2 and Mcl-1, are functional in the pathobiology of chronic lymphocytic leukemia (CLL). A pivotal and apical molecule in the BCR pathway is Bruton’s tyrosine kinase (BTK). Together, BTK, Bcl-2, and Mcl-1 participate in the maintenance, migration, proliferation, and survival of CLL cells. Several ongoing and published clinical trials in CLL reported high rates of remission, namely, undetectable measurable residual disease (u-MRD) status with combined BTK inhibitor ibrutinib and Bcl-2 antagonist, venetoclax. While the majority of patients achieve complete remission with undetectable-measurable residual disease, at least one third of patients do not achieve this milestone. We hypothesized that cells persistent during ibrutinib and venetoclax therapy may be sensitive to combined venetoclax and Mcl-1 inhibitor, AMG-176. To test this hypothesis, we took peripheral blood samples at baseline, after Cycle 1 and Cycle 3 of ibrutinib monotherapy, after one week and 1 cycle of ibrutinib plus venetoclax therapy. These serial samples were tested for pharmacodynamic changes and treated in vitro with AMG-176 or in combination with venetoclax. Compared to C1D1 cells, residual cells during ibrutinib and venetoclax treatment were inherently resistant to endogenous cell death. Single agent exposure induced some apoptosis but combination of 100 nM venetoclax and 100 or 300 nM of AMG-176 resulted in 40–100% cell death in baseline samples. Cells obtained after four cycles of ibrutinib and one cycle of venetoclax, when treated with such concentration of venetoclax and AMG-176, showed 10–80% cell death. BCR signaling pathway, measured as autophosphorylation of BTK was inhibited throughout therapy in all post-therapy samples. Among four anti-apoptotic proteins, Mcl-1 and Bfl-1 decreased during therapy in most samples. Proapoptotic proteins decreased during therapy. Collectively, these data provide a rationale to test Mcl-1 antagonists alone or in combination in CLL during treatment with ibrutinib and venetoclax.

COVID-19 in patients with chronic lymphocytic leukemia: a Moscow observational study

We describe a retrospective cohort, 156 patients with chronic lymphocytic leukemia (CLL) diagnosed with COVID-19, analyze factors associated with a severe disease course and the effects of various treatment regimens. Anti-SARS-CoV-2 IgG and IgM levels are significantly lower. Patients with CLL are more likely to have a severe course of COVID-19, with IL-6 levels acting as a consistent biomarker of disease severity. Ten patients had recurrent episodes, fatality rate of 20%. Overall survival did not differ between patients receiving ibrutinib monotherapy and anti-CD20 antibodies ± chemotherapy. It seems that the immunodeficiency inherent to CLL influences outcomes to a larger degree than does the treatment. Glucocorticoids are not associated with significant OS improvement whereas anti-cytokine compounds usage seemed to be beneficial in patients with mild pulmonary involvement. Our data attest to the necessity of reorganizing health care for patients with CLL. Early administration of effective antiviral compounds and tailored vaccination protocols are warranted.

New Treatment Approaches in Relapsing/Refractory Primary Central Nervous System Lymphomas

Background: Primary central nervous system lymphoma (PCNSL) is a rare disease that affects the brain, leptomeninges, spinal cord, cerebrospinal fluid, or vitreoretinal compartment without evidence of systemic disease. Although some treatment success is achieved with high dose methotrexate-based regimens, the prognosis is still poor. In this respect, new therapeutic approaches are needed. Methods: The clinical data of 6 patients diagnosed with primary central nervous system lymphoma in a hematology center of a university hospital were analyzed for 3 years. Ibrutinib monotherapy was applied to these 6 refractory patients as the last-stage treatment. The results were analyzed. Results: 6 patients (5 women, 1 man) with relapsed and refractory PCNSL received ibrutinib as monotherapy. As initial treatment, 3 patients received high-dose methotrexate + rituximab, 1 patient received MATRix (Rituximab, Methotrexate, Cytarabine, Thiotepa), 1 patient received high-dose methotrexate, and then only one patient received radiotherapy (RT). Two patients were consolidated with autologous transplantation and one patient with RT. All patients received treatment at a dose of 560 mg. No serious side effects have been detected. 5 patients who received ibrutinib monotherapy for the shortest 1 month and the longest 24 months died. The patient, who has been on ibrutinib monotherapy for 11 months, is being followed up stably. Conclusions: We have seen the therapeutic benefit of ibrutinib as monotherapy in our refractory patients. However, we believe that using ibrutinib as part of combination therapy at the initial stage of the disease will yield better results.

Response and survival predictors in a cohort of 319 patients with Waldenström macroglobulinemia treated with ibrutinib monotherapy

AbstractBruton 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 (odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; P < .001) and deep response (OR, 0.3; 95% CI, 0.2-0.6; P = .001). CXCR4 mutations (hazard ratio [HR], 2.0; 95% CI, 1.2-3.4; P = .01) and platelet count 100 K/uL or less (HR, 2.5; 95% CI, 1.3-4.9; P = .007) were associated with worse progression-free survival (PFS). We proposed a scoring system using these 2 factors. The median PFS for patients with 0, 1, and 2 risk factors were not reached, 5 years and 3 years (P < .001). Patients with 2 risk factors had HR 2.2 (95% CI, 1.3-3.8; P = .004) compared with 1 factor, and patients with 1 factor had HR 2.3 (95% CI, 1.1-5.1; P = .03) compared with 0 factors. Age ≥65 years was the only factor associated with overall survival (HR, 3.2; 95% CI, 1.4-7.0; P = .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.

Obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) frontline treatment for high-risk chronic lymphocytic leukemia

AbstractDespite considerable treatment advances with targeted therapies for patients with chronic lymphocytic leukemia (CLL) deemed high-risk [del(17p) and/or TP53 mutation], the outcome is still inferior compared with other CLL patients. Combining multiple agents with distinct mechanisms of action may further improve outcomes. CLL2-GIVe is an open-label, multicenter trial which enrolled patients with previously untreated CLL with del(17p) and/or TP53 mutation. Patients received induction therapy with obinutuzumab (GA-101), ibrutinib, and venetoclax (GIVe) for cycles 1 through 6 and consolidation therapy with venetoclax and ibrutinib for cycles 7 through 12. Ibrutinib monotherapy was continued for cycles 13 through 36 in patients not reaching a complete response (CR) with serial undetectable minimal residual disease (uMRD) after consolidation. The primary endpoint was CR rate at cycle 15 (final restaging). Secondary endpoints included MRD, survival, and safety. All 41 patients enrolled between September 2016 and August 2018 received study treatment and were included in efficacy and safety populations. With a CR rate of 58.5% at cycle 15, the primary endpoint was met (95% CI: 42.1-73.7; P < .001). At final restaging, 78.0% of patients had uMRD in peripheral blood (PB); 65.9% of patients had uMRD in bone marrow (BM). Estimated progression-free survival (PFS) and overall survival (OS) rates at 24 months were both 95.1%. Adverse events were reported in all patients; most were low grade (grade ≥3: 23.9%). Two deaths were reported (cardiac failure and ovarian carcinoma), neither related to study treatment. The CLL2-GIVe treatment regimen has a manageable safety profile and is a first-line treatment of good efficacy for patients with high-risk CLL.

Longer Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia

Longer Term Follow-up of a Multicenter, Phase 2 Study of Ibrutinib Plus Fludarabine, Cyclophosphamide, Rituximab (iFCR) As Initial Therapy for Younger Patients with Chronic Lymphocytic Leukemia

A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

A Phase 2 Study Evaluating the Addition of Ublituximab and Umbralisib (U2) to Ibrutinib in Patients with Chronic Lymphocytic Leukemia (CLL): A Minimal Residual Disease (MRD)-Driven, Time-Limited Approach

Factors Associated with Treatment Among Older Adults Diagnosed with Chronic Lymphocytic Leukemia: An Analysis Using Medicare Claims Data

INTRODUCTION: Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults in the US. Sixty-seven percent of patients diagnosed with CLL are age 65 years or older. While new agents and treatment combinations have been approved for CLL and treatment guidelines take into consideration age, frailty, and comorbidity status, limited information exists on current prescribing patterns or the demographic and clinical characteristics of individuals receiving them. The objectives of this study were to: 1) characterize CLL treatment patterns and timing of treatment; 2) identify factors associated with the receipt of CLL treatment in the US Medicare population.METHODS: The study sample included Medicare beneficiaries diagnosed with CLL from 2017 to 2019 using the Chronic Conditions Data Warehouse. Medicare beneficiaries were identified using billing diagnosis codes. Patients who were not treated for CLL during a continuous 6-month period (i.e., baseline period), continuously enrolled in Medicare Parts A, B, and D at baseline with no evidence of enrollment in Medicare Advantage, and age 65 or older at the index date were included. The index date was defined as the date of the first claim with a CLL diagnosis code during the cohort identification period (7/1/2017-6/30/2019). Individuals were followed from the index date until loss of eligibility, death, or end of the study period on 12/31/2019, whichever occurred first. We characterized CLL treatments using National Comprehensive Cancer Network guidelines and grouped individuals based on the first treatment received. The CLL treatments included: rituximab monotherapy, ibrutinib monotherapy, bendamustine/rituximab (BR), obinutuzumab, and other treatments. We reported the proportion of individuals who received the first course of treatment (COT), the top-ranked regimens within the first COT, and the median time to starting the first COT. Time-to-initiation was calculated as the time (in days) from the index date until the first evidence of treatment receipt. We utilized EventFlow visual analytics software to characterize longitudinal patterns of CLL treatments received from the index date (Day 0) until the end of follow-up. EventFlow facilitates exploratory, visual analyses of temporal event sequences using patient-level information about single events (e.g., infusion date), interval events (prescription start and end date), and the end-of-study indicator. We characterized the sample using the following baseline measures: age, race/ethnicity, gender, Charlson Comorbidity Index score, and use of preventive health services, among other measures. We identified factors associated with receipt of CLL treatment using a logistic regression model and reported the covariate-adjusted odds ratio (AOR). An AOR<1 indicates the comparison was negatively associated with receipt of CLL treatment.RESULTS: After applying the inclusion/exclusion criteria, 3,440 CLL patients were identified. Sixteen percent (n=556) of individuals received CLL treatment and the median follow up time was 540 days. Overall, the mean (standard error) age was 77 (8); 49% male. Among the 556 treated patients, the distribution of first COT was 35% ibrutinib, 34% rituximab, 12% BR, 4% obinutuzumab, and 14% other treatment. The median (interquartile range, mean) time to receipt of CLL treatment was 61 (224, 166) days. The median time to receipt of ibrutinib, rituximab, BR, or obinutuzumab was 109, 49, 53, and 140 days, respectively. The EventFlow graphic (Figure 1) illustrates treatments received (prescriptions or chemotherapy administrations) post-index date and through the end of the study period. Less than half of the patients in the BR group completed six doses of BR. Compared to patients in the rituximab group, a larger proportion of patients in the ibrutinib and BR groups remained on the first COT over time. In the logistic regression model age (≥85 vs 65-74; AOR=0.69; 95% CI:0.53-0.91) and gender (male vs female; AOR=1.28; 95% CI: 1.06 - 1.54) were statically significant; no other statistically significant differences based on baseline measures were observed.CONCLUSIONS: Among Medicare beneficiaries diagnosed with CLL, less than 2 out of 10 patients received CLL treatment. The most common treatments administered during this time period were ibrutinib or rituximab. Younger age and male gender were factors associated with increased receipt of treatment. [Display omitted] DisclosuresOnukwugha: BeiGene, Ltd.: Research Funding; Sanofi Aventis: Other: Faculty mentor on a pre-doctoral fellowship. Cooke: BeiGene, Ltd.: Research Funding. Yang: BeiGene, Ltd.: Current Employment. Liu: BeiGene, Ltd.: Current Employment. Tang: BeiGene, Ltd.: Current Employment.

Reduced-Dose Ibrutinib Is Well Tolerated and Cost Effective for the Treatment of Chronic Lymphocytic Leukemia in Frail Older Adults

Ibrutinib is an inhibitor of Bruton's tyrosine kinase (BTK) that is used for the treatment of multiple hematologic malignancies including chronic lymphocytic leukemia (CLL) with promising outcomes. Its use has been associated with significant side effects including diarrhea, fatigue, infections, arthralgias, hemorrhage, and atrial fibrillation among others. Ibrutinib-associated adverse events have led to its discontinuation in more than one-fifth of CLL patients treated. Specifically, in the real-world setting, 21% to 30% of patients have needed an Ibrutinib dose interruption or reduction. Moreover, the associated toxicity seems to be more prominent in the geriatric population given the poor functional reserve, impaired mobility, and preexisting comorbidities. In the elderly, moderate to severe treatment-related toxicity often times leads to a higher number of hospitalizations, which ultimately increases the risk of complications and health care costs. Some studies have reported that Ibrutinib dose reductions have not had a significant impact on the progression-free-survival or overall survival in the general population. Nevertheless, there is not sufficient data or consent about the use of a reduced dose of Ibrutinib for treatment of CLL in frail older adults. In addition, annual costs of treatment with complete-dose Ibrutinib for veterans exceed $100,000. As it is common to reach complete remission with Ibrutinib monotherapy, patients will remain on therapy long-term, compounding financial impact over their treatment lifetime. Reduced dose Ibrutinib can lower total cost by 50% or more and thereby increase patient adherence due to decreased economic burden. Therefore, we present a retrospective review of a series of 7 cases involving frail older adults with CLL treated with Ibrutinib at the Washington DC Veterans Affairs Medical Center. Six out of seven patients received a reduced Ibrutinib dose and had a complete response whereas one patient received the dose recommended by the manufacturer leading to a prolonged hospital stay due to the adverse effects. We report the disease control evidenced by a decrease in white blood cell count, alleviation of “B symptoms”, and resolution of lymphadenopathy along with side effects with an Ibrutinib dose ranging from 140 to 280 mg per day. We also report the cost benefits obtained with the use of a reduced Ibrutinib dose. We hope that sharing our experience encourages clinical trials aiming to determine the minimal dose needed to effectively treat CLL while limiting toxicity, decreasing health care costs, and preserving quality of life in frail older adults. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): Focus on Long-Term MRD Results

Real World Experience on the Use of Ibrutinib Monotherapy in Waldenström Macroglobulinemia

BACKGROUNDIbrutinib is approved as a second line treatment option for Waldenström Macroglobulinemia (WM) patients in the United Kingdom and for patients unsuitable for chemo-immunotherapy. In a clinical trial setting, Ibrutinib monotherapy produced a major response rate (MRR) of 79.4% and a predicted five-year overall survival (OS) rate of 87%1. Valuable insights can be gained on the response and tolerability outcomes of Ibrutinib monotherapy in WM outside of the clinical trial setting. This study aimed to evaluate these outcomes in a large specialist centre which receives referrals from across the UK.METHODSA retrospective analysis was performed on consecutive patients with WM who commenced Ibrutinib between December 2014 and February 2021; all included patients were treated for at least 3 months. Data were collated from the WMUK Rory Morrison Registry. The primary outcomes were depth of response, event free survival (EFS, defined as time from commencement to permanent ibrutinib discontinuation due to toxicity, disease progression or death), duration of response (time from best response to progressive disease, PD), progression free survival (PFS) and overall survival (OS). Response was determined in accordance with the Sixth International Workshop on WM (IWWM) response criteria 2. Baseline characteristics and toxicity data were also collated.RESULTSOf the 84 patients who had commenced ibrutinib, sufficient data was available for 62 patients; median age was 69 years (range 44 - 85) and 40 (64.5%) were male. Among the 50 patients for whom International Prognostic Scoring System for WM (IPSSWM) data were available, the IPSSWM risk score at the time of ibrutinib initiation was low (n=8, 16%), intermediate (n=25, 50%) and high (n=17, 34%). The median number of prior therapy lines was 2 (range 1 - 7). The median time from diagnosis to commencement of ibrutinib was 70 months (Range 2 - 243).The median follow-up was 29 months (Range 3 - 71). Objective response rate (≥MR) was 79% (n=49) and MRR was 62.9% (n=39). Best response achieved was CR in 12.9%, VGPR in 24.2%, PR in 25.8%, MR in 16.1% and SD in 11.2%; 9.7% of patients experienced PD. The median time to best response was 5 months (Figure 1A) and the median EFS was 37 months (Range 3 - 71). Of the 49 patients who achieved an objective response, the median PFS was not reached and the two-year predicted PFS rate was 73.5%. At the time of analysis, 15 patients (24.2%) had discontinued ibrutinib due to disease progression, 5 (8.1%) due to adverse effects and 4 (6.5%) due to death. The median OS was not reached, and the predicted two-year OS rate was 87.8% (Figure 1B).The most common adverse effects were diarrhoea (14.5%), atrial fibrillation (AF, 9.7%) and rash (9.7%). Six of the seven patients who developed treatment-emergent AF continued ibrutinib with concurrent anticoagulants and either rate or rhythm control. Ibrutinib was permanently discontinued due to heart failure/AF (n=1), intracranial haemorrhage whilst taking ibrutinib and warfarin concurrently for brittle antiphospholipid syndrome and WM (n=1), significant liver function derangement (n=2) and intractable diarrhoea (n=1). Ibrutinib dose was reduced to 280 mg daily (n=13) and 140 mg daily (n=4) due to adverse reactions.CONCLUSIONIn a real-world setting, ibrutinib produces clinically meaningful objective responses in patients with relapsed WM; these response rates are comparable to those achieved in a clinical trial setting. Ibrutinib can produce durable disease control with long remission intervals. The toxicity profile is acceptable.REFERENCES1. Treon, S., Meid, K., Gustine, J., Yang, G., Xu, L., & Liu, X. et al. (2021). Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia. Journal Of Clinical Oncology, 39(6), 565-575. doi: 10.1200/jco.20.005552. Owen, S., Kyle, R., Stone, M., Rawstron, A., Leblond, V., Merlini, G. et al. (2013). Response assessment in Waldenström Macroglobulinemia: updated from the VIth International Workshop. British Journal of Haematology, 60, 171-176. doi: 10.1111/bjh.12102 [Display omitted] DisclosuresD'Sa: Sanofi: Honoraria; BeiGene: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding.

Rituximab Plus Bendamustine and Cytarabine (R-BAC) in Elderly Patients with Newly Diagnosed Mantle Cell Lymphoma: Long Term Follow-up and Mrd Results of a Phase 2 Study from the Fondazione Italiana Linfomi

The activity of the combination of rituximab, bendamustine, and low dose cytarabine (R-BAC) was evaluated in a phase 2 multicentre trial from the Fondazione Italiana Linfomi (FIL RBAC500) in previously untreated patients with mantle cell lymphoma (MCL) who were not eligible to stem cell transplant. Maintenance treatment was not planned after induction therapy, and no patient in the study received rituximab maintenance. Fifty-seven patients (median age 71 years, range 61-79) were recruited and treated with 4 to 6 cycles between 2012 and 2014. Despite some concern in terms of hematological toxicity, the R-BAC regimen was associated with high complete remission (CR) rate (91%), 2-years overall survival (OS) of 86% (74-93), and 2-years progression free survival (PFS) of 81% (68-89). Here, we present long-term survival outcomes.After 7 years of median follow-up (86 months, range 57-107), the median OS and PFS for all patients were not reached (Figure 1A and 1B). The 7-years PFS and OS rates were 56% (95%CI 41-67) and 63% (95%CI 46-72), respectively. Patients who achieved CR (n=53) had a 7 years PFS of 59% (95% CI 44-71), with the curve that appears to plateau after 6 years. Adverse predictive factors affecting PFS were blastoid morphology (p<0.05), elevated Ki67 > 30% (p<0.05), and failure to achieve CR after 2 cycles (p=0.03). Early-progression of disease (<24 months from start of R-BAC) was associated with impaired overall survival (p<0.05).Eight patients (14%) developed a secondary neoplasia: 1 parotid heteroplasia, 1 parotid nodular hyperplasia, 1 prostate cancer, 1 bladder cancer, 1 larynx, 1 thyroid cancer, 1 lung cancer and 1 secondary acute myeloid leukemia.Among the 25 relapsed patients, 8 did not receive any other treatment. Six had Ibrutinib monotherapy as second line, of whom 4 responded (3 are still in CR), 4 had CHOP or CHOP-like regimens with only partial responses.As per protocol, 31 patients with molecular marker at diagnosis and available samples were followed-up for minimal residual disease (MRD) with ASO-droplet digital polymerase chain reaction (D-PCR). Patients with MRD persistence at the end of induction, either in peripheral blood or bone marrow, had significantly worse 7 years-PFS (p<0.05 for them both).In conclusion, in elderly patients with newly diagnosed MCL, R-BAC showed sustained efficacy over time, which compared favorably with any other reported immuno-chemotherapy regimen (with or without maintenance) in similar populations. With a median OS exceeding 60% after 7-years this regimen has significantly impacted on the life-expectancy of elderly patients with MCL. [Display omitted] DisclosuresTisi: Incyte: Membership on an entity's Board of Directors or advisory committees; BWS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nassi: Takeda: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Roche: Consultancy. Ferrero: Gilead: Research Funding, Speakers Bureau; Morphosys: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Speakers Bureau; EUSA Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Clinigen: Membership on an entity's Board of Directors or advisory committees. Zilioli: Takeda: Other: travel expenses, accommodation; MSD, Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations; Roche, Italfarmaco: Consultancy, Honoraria; Gentili, Takeda, Gilead, Servier: Consultancy, Speakers Bureau. Merli: Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Gilead Science: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; MSD: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accomodations, Expenses; EUSA Pharma: Other: Travel, Accomodations, Expenses; Celgene: Other: Travel, Accomodations, Expenses.