Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients With Chronic Lymphocytic Leukemia: Extended Follow-Up From the E1912 Trial
Chemoimmunotherapy consisting of fludarabine, cyclophosphamide, and rituximab (FCR) remains a key first-line treatment for patients with chronic lymphocytic leukemia (CLL). This regimen is particularly effective for patients with mutations in the immunoglobulin heavy chain variable (IGHV) region.1 The phase 3 Eastern Cooperative Oncology Group (ECOG) 1912 trial (E1912) compared ibrutinib plus rituximab vs FCR in patients with treatment-naive CLL.2,3 Eligible patients had an ECOG performance status of 0 to 2, were ages 70 years or younger, and did not have the 17p deletion (del[17p]) according to fluorescence in situ hybridization. After stratification by age, disease stage, performance status, and deletion 11q23 status, patients were randomly assigned 2:1 to receive ibrutinib plus rituximab vs FCR. For the first 28-day cycle, patients in the ibrutinib/rituximab arm received ibrutinib monotherapy (420 mg daily). For cycles 2 to 6, these patients also received rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and 500 mg/m2 on day 1 of cycles 3-7). Patients then received daily ibrutinib monotherapy starting with cycle 8 and continued until disease progression. Patients in the control arm received 6 cycles of FCR therapy, consisting of fludarabine (25 mg/m2, days 1-3) and cyclophosphamide (250 mg/m2, days 1-3), plus rituximab.
After a median follow-up of 34 months, initial results from 529 patients showed a survival benefit with ibrutinib plus rituximab compared with FCR.3 The median progression-free survival (PFS) was 89.4% with ibrutinib plus rituximab vs 72.9% with FCR (hazard ratio [HR], 0.35; 95% CI, 0.22-0.56; P<.001). Three-year median overall survival (OS) was 98.8% with ibrutinib plus rituximab vs 91.5% with FCR (HR, 0.17; 95% CI, 0.05-0.54; P<.001). However, only a small number of deaths had occurred at the time of this report. Subset analysis showed a significant benefit from ibrutinib plus rituximab in patients with unmutated IGHV, but not in those with mutated IGHV.
Dr Tait Shanafelt presented an extended follow-up analysis from the E1912 trial.2 The median duration of follow-up was 48 months. This second analysis focused on ibrutinib tolerability, reasons for discontinuation, impact of TP53 mutations, and efficacy.2 The TP53 mutation was observed in 9% of patients (27/272) in the ibrutinib/rituximab arm and 3% of those in the FCR arm (4/134).
Among 354 patients originally assigned to ibrutinib plus rituximab, 257 (73%) remained on ibrutinib monotherapy, with a median time on treatment of 43 months. Among the 95 patients (27%) who discontinued ibrutinib, the median time on treatment was 20.3 months. The most common reasons for treatment discontinuation were adverse events (AEs; 51%) and disease progression or death (24%). Among the 72 patients who discontinued ibrutinib for reasons other than disease progression or death, the median PFS was 22.5 months. Multivariable analysis identified only a higher Cumulative Illness Rating Scale (CIRS) score as a predictor of discontinuation (HR, 1.13 per CIRS unit increase; 95% CI, 1.03-1.23; P=.009). The HR for PFS continued to favor ibrutinib plus rituximab over FCR (89% vs 71%; HR, 0.39; 95% CI, 0.26-0.57; P<.0001; Figure 1). Among patients with unmutated IGHV, PFS was 89% with ibrutinib plus rituximab vs 65% with FCR (HR, 0.28; 95% CI, 0.17-0.48; P<.0001; Figure 2). In patients with mutated IGHV, PFS was 88% vs 82%, respectively, a difference that was not significant (HR, 0.42; 95% CI, 0.16-1.16; P=.086). For the overall study population, 3-year OS was 99% with ibrutinib plus rituximab vs 93% with FCR (HR, 0.34; 95% CI, 0.15-0.79; P=.009).
The rate of grade 3 or higher treatment-related AEs was 70% with ibrutinib plus rituximab vs 80% with FCR (odds ratio, 0.56; 95% CI, 0.34-0.90; P=.013). The most common grade 3 or higher AEs in the FCR arm included decreased neutrophil count (43% vs 27% with ibrutinib/rituximab), anemia (15.8% vs 4.3%), decreased platelet count (15.8% vs 3.1%), and febrile neutropenia (15.8% vs 2.3%). Patients in the ibrutinib combination arm were more likely to develop hypertension (8.5% vs 1.9% with FCR), cardiac events (5.4% vs 0%), and arthralgia (5.1% vs 0.6%).
The trial investigators concluded that PFS and OS were superior with ibrutinib plus rituximab compared with FCR. At a median follow-up of 48 months, 73% of patients in the ibrutinib/rituximab arm were still receiving treatment. Among the patients who discontinued ibrutinib for reasons other than progressive disease or death, disease did not progress for a median of 23 months after the last dose.
References
1. Jain N. Selecting frontline therapy for CLL in 2018. Hematology Am Soc Hematol Educ Program. 2018;2018(1):242-247.
2. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia: extended follow-up from the E1912 trial [ASH abstract 33]. Blood. 2019;134(suppl 1).
3. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
A Randomized Phase 3 Trial of Blinatumomab Vs Chemotherapy as Post-Reinduction Therapy in High and Intermediate Risk First Relapse of B-Acute Lymphoblastic Leukemia in Children and Adolescents/Young Adults Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report From Children’s Oncology Group Study AALL1331
The phase 3 AALL1331 study (Blinatumomab in Treating Younger Patients With Relapsed B-Cell Acute Lymphoblastic Leukemia) evaluated standard therapy vs blinatumomab in patients ages 1 to 30 years with relapsed disease after first-line treatment for B-cell acute lymphoblastic leukemia.1 All patients received initial treatment with block 1 induction chemotherapy that contained mitoxantrone.2 Patients with less than 25% marrow blasts were stratified by risk factors and then randomly assigned into the 2 arms. Patients in the control arm received block 2 and block 3 induction chemotherapy.2 Patients in the experimental arm received 2 cycles of blinatumomab (15 µg/m2 daily) for 28 days per cycle, followed by 7 days off. During cycle 1, patients also received dexamethasone (5 mg/m2). All patients then underwent hematopoietic stem cell transplant. The primary endpoint was disease-free survival. The study assumed enrollment of 110 patients per arm and an increase in 2-year disease-free survival from 45% to 63%, providing an 85% power to detect an HR of 0.58 with a 1-sided α of 0.025. The monitoring committee stopped enrollment into the control arm after a planned interim analysis showed that blinatumomab improved disease-free survival, OS, and clearance of minimal residual disease (MRD).
The study enrolled 103 patients into the control arm and 105 into the experimental arm. The patients’ median age was 9 years (range, 1-27 years). After stratification, one-third of patients in each arm had intermediate-risk disease, based on late relapse and high MRD. Two-thirds of patients had high-risk disease, as indicated by early relapse. After a median follow-up of 1.4 years, 2-year disease-free survival was 59.3% ± 5.4% in the blinatumomab arm vs 41.0% ± 6.2% in the control arm (P=.05). Two-year OS was 79.4% ± 4.5% with blinatumomab vs 59.2% ± 6.0% with chemotherapy (P=.005; Figure 3). After block 1 chemotherapy, the rate of undetectable MRD—defined as no more than 0.01% malignant cells—was 18% in the blinatumomab arm vs 22% in the control arm (P=.65). After the second cycle, the rate of undetectable MRD was 76% with blinatumomab vs 29% with the control treatment (P<.0001). This trend was also observed after the third treatment cycle, with rates of 66% vs 33%, respectively (P<.0001). A higher proportion of patients in the blinatumomab arm proceeded to transplant (73% vs 45%; P<.0001), which likely contributed to the improved OS in this arm.
After induction therapy, 4 patients died; all were in the control arm and all died from infections. Rates of febrile neutropenia, infection, sepsis, and mucositis were all significantly higher after block 2 induction vs cycle 1 of blinatumomab (P<.001). After block 3 chemotherapy and cycle 2 of blinatumomab, rates of febrile neutropenia, infection, and sepsis were again significantly higher in the control arm (P<.001). Rates of mucositis were similar (P=.16). The most common AE associated with blinatumomab was any-grade cytokine-release syndrome, which occurred in 22% of patients after cycle 1 but dropped to 1% after cycle 2. Neurotoxicity occurred in 18% after cycle 1 and 11% after cycle 2.
References
1. Brown PA, Ji L, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk first relapse of B-acute lymphoblastic leukemia in children and adolescents/young adults demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group study AALL1331 [ASH abstract LBA1]. Blood. 2019;134(suppl 1).
2. Parker C, Waters R, Leighton C, et al. Effect of mitoxantrone on outcome of children with first relapse of acute lymphoblastic leukaemia (ALL R3): an open-label randomised trial. Lancet. 2010;376(9757):2009-2017.
Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: Results
From the MRD Cohort of the Phase 2 CAPTIVATE Study
Ibrutinib and venetoclax have complementary mechanisms of action and have demonstrated synergistic activity in preclinical, ex vivo, and clinical studies.1,2 The multicenter, phase 2 CAPTIVATE study (Ibrutinib Plus Venetoclax in Subjects With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) evaluated ibrutinib plus venetoclax in patients with previously untreated CLL or small lymphocytic lymphoma (SLL).3 Eligible patients had active disease requiring treatment and were younger than 70 years. They had an ECOG performance status of 0 or 1. Patients first received 3 cycles of daily ibrutinib (420 mg/day), followed by 12 cycles of ibrutinib plus venetoclax (escalated to 400 mg/day). Further treatment was based on MRD status. Patients with undetectable MRD (<10-4 by 8-color flow cytometry) were randomly assigned to receive either ibrutinib monotherapy or placebo. Patients with detectable MRD were randomly assigned to receive open-label ibrutinib or ibrutinib plus venetoclax.
The MRD cohort included 164 patients, with a median age of 58 years (range, 28-69 years). Thirty-two percent of patients had Rai stage III/IV disease. Genetic abnormalities included unmutated IGHV in 59%, del(17p)/TP53 mutation in 20%, complex karyotype in 19%, and del(11q) in 17%. Thirty-two percent of patients had a lymph node with a diameter of at least 5 cm, and 3% had a nodal diameter of at least 10 cm. Cytopenias were observed in 36% of patients. At baseline, the risk of tumor lysis syndrome was high in 24% and medium in 63%. After 3 cycles of ibrutinib lead-in, the risk of tumor lysis syndrome was high in 2%, medium in 65%, and low in 30%. In patients with a high risk of tumor lysis syndrome at baseline, 90% shifted to medium or low risk after ibrutinib lead-in therapy, and 74% were not hospitalized after initiation of venetoclax.
Ninety percent of patients completed all 12 cycles of ibrutinib plus venetoclax. The median duration of treatment was 14.7 months for ibrutinib (range, 0.5-19.9 months) and 12 months for venetoclax (range, 0.8-12.7 months). Among patients who initiated ibrutinib lead-in therapy, 4 discontinued owing to AEs and 1 discontinued after Richter transformation. Among patients who completed lead-in therapy and initiated the combination treatment, 4 discontinued owing to AEs, 1 discontinued owing to disease progression, 1 discontinued based on the investigator’s decision, and 1 withdrew. No deaths occurred. The lead-in and combination treatment cycles were completed by 152 patients (93%).
Among patients treated with up to 12 cycles of ibrutinib plus venetoclax, the rate of undetectable MRD was 75% (95% CI, 67%-81%) in the peripheral blood and 72% (95% CI, 64%-79%) in the bone marrow. Among patients who achieved undetectable MRD in the peripheral blood at cycle 16 and who had matched bone marrow samples, 93% also had undetectable MRD in the bone marrow. In the intention-to-treat population of 164 patients, rates of undetectable MRD were 74% in the peripheral blood and 68% in the bone marrow. The proportion of patients with undetectable MRD (<10-4) in the peripheral blood increased throughout the 12 cycles of 2-drug therapy, from 57% after 6 cycles to 73% after 12 cycles (Figure 4). Undetectable MRD was observed across all subgroups, including those based on age, Rai disease stage, bulky disease, cytogenetics, del(17p) or TP53 mutation, IGHV status, and complex karyotype.
The most common AE arising during the single-agent ibrutinib lead-in period was grade 1 diarrhea. The combination of ibrutinib plus venetoclax was generally well tolerated. The most common grade 3/4 AEs overall were neutropenia (35%), hypertension (7%), thrombocytopenia (5%), and diarrhea (5%). There were no cases of clinical tumor lysis syndrome. Laboratory tumor lysis syndrome was reported as an AE in 3 patients (with 1 case meeting the Howard criteria). Grade 3/4 AEs were most common during the first 3 cycles of combination treatment (39%) and decreased during subsequent cycles (15% during the final 3-4 treatment cycles). AEs that required discontinuation of treatment (ibrutinib during the lead-in period or both ibrutinib and venetoclax during combination treatment) were reported in 5% of patients.
References
1. Cervantes-Gomez F, Lamothe B, Woyach JA, et al. Pharmacological and protein profiling suggests venetoclax (ABT-199) as optimal partner with ibrutinib in chronic lymphocytic leukemia. Clin Cancer Res. 2015;21(16):3705-3715.
2. Deng J, Isik E, Fernandes SM, Brown JR, Letai A, Davids MS. Bruton’s tyrosine kinase inhibition increases BCL-2 dependence and enhances sensitivity to venetoclax in chronic lymphocytic leukemia. Leukemia. 2017;31(10):2075-2084.
3. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the MRD cohort of the phase 2 CAPTIVATE study [ASH abstract 35]. Blood. 2019;134(suppl 1).
Combined Ibrutinib and Venetoclax for Patients With Chronic Lymphocytic Leukemia
The combination of ibrutinib plus venetoclax for the treatment of patients with CLL or SLL was evaluated in 2 investigator-initiated phase 2 studies, one in treatment-naive patients and the other in patients with relapsed/refractory disease.1,2 The study in the treatment-naive setting required patients to have at least 1 risk factor: del(17p) or mutated TP53, del(11q), unmutated IGHV, or older age (≥65 years).1 Patients first received 3 cycles of ibrutinib (420 mg daily) as lead-in therapy, in cycles of 28 days. Starting with the fourth treatment cycle, venetoclax was included at a starting dose of 20 mg daily, with escalation to 400 mg daily. Patients received 24 cycles of combination therapy. Patients with detectable MRD after completing combination therapy continued to receive ibrutinib monotherapy until disease progression. Response was evaluated based on 2008 International Workshop CLL criteria.3 Bone marrow MRD was assessed by flow cytometry with a sensitivity of 10-4.
Among 80 enrolled patients, 75 (94%) initiated combination therapy with ibrutinib plus venetoclax. The median age of enrolled patients was 65 years (range, 26-83 years), and 71% were male. Eighty-three percent of patients had unmutated IGHV. Fluorescence in situ hybridization identified del(11q) in 25%, del(13q) in 24%, trisomy 12 in 21%, and del(17p) in 18%. Among the 49 patients who completed study therapy, the rate of undetectable MRD in the bone marrow was 75% (Figure 5). The rate of undetectable MRD at 12 months was similar across all subgroups. Among the patients with detectable MRD at 12 months, improvement continued through month 24.
Grade 3/4 neutropenia occurred in 51% of patients. Ten percent of patients developed atrial fibrillation of grade 3 or higher. Infections of grade 3 or higher were reported in 19%. The dose of ibrutinib was reduced in 52%, and the dose of venetoclax was reduced in 29%.
A related investigator-initiated, phase 2 study evaluated patients with relapsed or refractory CLL/SLL requiring treatment.2,3 Patients in this study received 3 cycles of ibrutinib monotherapy, followed by 24 cycles of ibrutinib plus venetoclax. MRD-positive patients received subsequent therapy with daily ibrutinib monotherapy. Bone marrow MRD was assessed by flow cytometry with a sensitivity of 10-4. Among 79 enrolled CLL patients, 74 initiated combination treatment. Among the enrolled patients, the median age was 61 years (range, 32-79 years), and 72% were male. The median number of prior therapies was 1 (range, 1-4). Eighty-five percent of patients had unmutated IGHV. Fluorescence in situ hybridization identified del(11q) in 32%, del(17p) in 25%, del(13q) in 24%, and trisomy 12 in 13%. The median follow-up was 27 months.
In the intention-to-treat population, the rate of undetectable MRD in the bone marrow was 40% after 12 months of treatment (ibrutinib monotherapy followed by the combination). The response rates improved with ongoing treatment (Figure 6).
Among the 16 patients (20%) who left the study, 5 did so during ibrutinib monotherapy, 7 during combination therapy, and 4 during or after combination therapy. AEs of interest included grade 3/4 neutropenia (43%), atrial fibrillation (8%), and grade 3/4 thrombocytopenia (1%). The dose of ibrutinib was reduced in 57%, and the dose of venetoclax was reduced in 35%.
References
1. Jain N, Keating M, Thompson P, et al. Combined ibrutinib and venetoclax for first-line treatment for patients with chronic lymphocytic leukemia [ASH abstract 34]. Blood. 2019;134(suppl 1).
2. Jain N, Keating M, Thompson P, et al. Combined ibrutinib and venetoclax in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASH abstract 359]. Blood. 2019;134(suppl 1).
3. Hallek M, Cheson BD, Catovsky D, et al; International Workshop on Chronic Lymphocytic Leukemia. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood. 2008;111(12):5446-5456.
ELEVATE TN: Phase 3 Study of Acalabrutinib Combined With Obinutuzumab (O) or Alone vs O Plus Chlorambucil (Clb) in Patients With Treatment-Naive Chronic Lymphocytic Leukemia
The phase 3 ELEVATE TN study (Study of Obinutuzumab + Chlorambucil, Acalabrutinib [ACP-196] + Obinutuzumab, and Acalabrutinib in Subjects With Previously Untreated CLL) evaluated acalabrutinib plus obinutuzumab, chlorambucil plus obinutuzumab, and acalabrutinib monotherapy in patients with previously untreated CLL.1 The study enrolled patients ages 65 years or older, as well as younger patients with a CIRS score higher than 6 or creatinine clearance below 70 mL/min. The patients were randomly assigned into the 3 treatment arms. Acalabrutinib (100 mg, twice daily) was administered every day. Obinutuzumab (1000 mg) was given on days 1 and 2 of cycle 1, on days 8 and 15 of cycle 2, and subsequently on day 1 of each 28-day cycle for a total of 6 cycles. Chlorambucil (0.5 mg/kg) was administered on days 1 and 15 of each cycle for 6 cycles. Crossover from the chlorambucil/obinutuzumab arm was allowed after disease progression. Patients were stratified according to presence of the del(17p) mutation, ECOG performance status, and geographic location. The primary endpoint was PFS, as assessed by independent review. An interim analysis was planned after approximately 111 PFS events had occurred in the combination treatment arms or after 24 months.
The trial enrolled 535 patients into the 3 treatment arms. Baseline characteristics were generally well balanced across the 3 arms. The proportion of patients who discontinued treatment was 20.7% in the acalabrutinib/obinutuzumab arm, 20.1% in the acalabrutinib monotherapy arm, and 18.1% in the obinutuzumab/chlorambucil arm. After a median follow-up of 28.3 months, the median PFS was 93% with acalabrutinib plus obinutuzumab vs 47% with chlorambucil plus obinutuzumab (HR, 0.10; 95% CI, 0.06-0.17; P<.0001; Figure 7). Acalabrutinib monotherapy also yielded a superior median PFS compared with the chlorambucil combination (HR, 0.20; 95% CI, 0.13-0.30; P<.0001). A consistent PFS benefit was seen with acalabrutinib, both alone or combined with obinutuzumab, compared with chlorambucil plus obinutuzumab in subgroups based on age, sex, disease stage, and ECOG performance status. Treatment with acalabrutinib plus obinutuzumab led to an overall response rate (ORR) of 93.9% (95% CI, 89.3%-96.5%), including a complete response (CR) rate of 13%, and a CR with incomplete bone marrow recovery rate of 1% (P=.0001 vs chlorambucil plus obinutuzumab). With acalabrutinib monotherapy, the ORR was 85.5% (95% CI, 79.6%-89.9%; P<.0763 vs chlorambucil plus obinutuzumab). One patient (1%) had a CR after acalabrutinib monotherapy. The ORR with the chlorambucil combination was 78.5% (95% CI, 71.6%-89.9%) and included a CR rate of 5%. The median OS was not significantly different for acalabrutinib plus obinutuzumab (P=.0577) or for acalabrutinib monotherapy (P=.1556) vs chlorambucil plus obinutuzumab.
Serious AEs were reported in 38.8% of the acalabrutinib combination arm, 31.8% of the acalabrutinib monotherapy arm, and 21.9% of the chlorambucil/obinutuzumab arm. AEs of grade 3 or higher were observed in 70.2%, 49.7%, and 69.8% of patients, respectively. Deaths occurred in 2.8%, 3.9%, and 7.1%.
Reference
1. Sharman JP. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients with treatment-naive chronic lymphocytic leukemia [ASH abstract 31]. Blood. 2019;134(suppl 1).
A Phase 1/2 Study of Umbralisib, Ublituximab, and Venetoclax in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
A phase 1/2 trial evaluated the safety and efficacy of umbra-lisib, ublituximab, and venetoclax in patients with relapsed or refractory CLL.1 The treatment consisted of three 28-day cycles of daily umbralisib along with ublituximab administered weekly during cycle 1, then once during cycles 2 and 3, followed by umbralisib and venetoclax for 9 additional cycles. The phase 1 portion tested escalating doses of umbralisib at 600 mg and 800 mg and a fixed dose of ublituximab at 900 mg. Venetoclax was increased in standard fashion to 400 mg during cycle 4. The primary endpoints were safety for phase 1 and CR rate for phase 2. MRD negativity (<10-4 by 8-color flow cytometry) was a key secondary endpoint. Patients who were MRD negative after 12 cycles of treatment stopped therapy. Other patients continued treatment with single-agent umbralisib.
At the time of the report, the trial had enrolled 27 patients: 9 in phase 1 and 18 in phase 2. The patients’ median age was 63 years, and 67% were male. The median number of prior therapies was 1 (range, 1-5). Among the 21 patients tested, 13 were IGHV unmutated. Other high-risk genetic features were the 11q deletion (23%) and the del(17p)/TP53 mutation (19%).
During the dose-escalation phase, there was 1 dose-limiting toxicity (a lower gastrointestinal bleed), which occurred at the 800-mg dose. The maximum tolerated dose was not reached. The phase 2 doses were 900 mg for ublituximab and 800 mg for umbralisib.
The trial provided efficacy results after cycles 3, 7, and 12. For cycles 3 and 7, the CR rate was not available because CT was used without bone marrow testing. Among the 23 patients who completed the 3-cycle induction phase, the ORR was 87%. All responses were partial. Stable disease was reported in 13%. Among the 13 patients who completed cycle 7, the ORR was 100%, consisting entirely of partial responses. At cycle 12, the ORR was 100% for the 9 patients who completed therapy. Responses were complete in 44% and partial in 56%. Lymph node reduction from baseline reached 87% at cycle 12 (Figure 8).
The study investigators analyzed response according to the method of MRD assessment. At cycle 12, the ORR was 100% in patients who were MRD-negative according to peripheral blood testing and 78% among those tested using bone marrow.
Three cycles of debulking with ublituximab and umbralisib reduced the risk of tumor lysis syndrome associated with venetoclax. No patients remained at high risk, and no patients developed clinical or laboratory tumor lysis syndrome during the venetoclax ramp-up period.
The treatment was well tolerated at the phase 2 doses. The most common all-cause AE was infusion reaction, which occurred in 67% of patients. Grade 3/4 infusion reactions were reported in 7%. Other all-cause, all-grade AEs included neutropenia (56%), leukopenia (48%), creatinine increase (48%), thrombocytopenia (48%), and anemia (44%). The most common grade 3/4 AEs were neutropenia (19%) and leukopenia (15%).
Reference
1. Barr PM, Hill BT, Ma S, et al. A phase 1/2 study of umbralisib, ublituximab, and venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia [ASH abstract 360]. Blood. 2019;134(suppl 1).
KTE-X19, an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, in Patients With Relapsed/Refractory Mantle Cell Lymphoma:
Results of the Phase 2 ZUMA-2 Study
KTE-X19 is a chimeric antigen receptor (CAR) T-cell therapy directed at CD19.1 In addition to a single-chain Fv fragment that binds to CD19, the KTE-19 construct has a CD28 signaling domain and a CD3ζ T-cell activation domain.
The phase 2 ZUMA-2 trial (A Phase 2 Multicenter Study Evaluating Subjects With Relapsed/Refractory Mantle Cell Lymphoma) evaluated KTE-X19 in patients with relapsed or refractory mantle cell lymphoma.2 Eligible patients had developed disease progression after their most recent treatment or had not achieved a CR or a partial response. The trial enrolled patients who had received up to 5 prior treatments. These prior treatments included chemotherapy with an anthracycline or bendamustine, an anti-CD20 monoclonal antibody, and ibrutinib or acalabrutinib. Patients had at least 1 measurable lesion and an ECOG performance status of 0 or 1. Bridging therapy after leukapheresis was allowed. Conditioning chemotherapy consisted of fludarabine plus cyclophosphamide. The treatment was administered at 2 × 106 KTE-X19 cells/kg, by means of a single infusion. The primary endpoint was independently assessed ORR.
The trial enrolled 74 patients, all of whom underwent leukapheresis. Two patients died from disease progression, and 3 patients were not treated because the manufacture of CAR T cells failed. Sixty-nine patients received conditioning chemotherapy, and 68 patients (92%) received the CAR T-cell infusion. The median time from leukapheresis to delivery of the KTE-X19 CAR T-cell product to the study site was 16 days.
Among the 68 patients who received the CAR T-cell infusion, the median age was 65 years (range, 38-79 years). Eighty-five percent had stage IV mantle cell lymphoma, and 56% had intermediate- or high-risk disease. Bone marrow involvement was observed in 54% of patients, and 69% had a Ki-67 proliferation index of 50% or higher. Patients had received a median of 3 prior therapies (range, 1-5), and 43% had relapsed after autologous stem cell transplant.
After a median follow-up of 12.3 months (range, 7.0-32.3 months), the independently assessed ORR among 60 evaluable patients was 93% (95% CI, 84%-98%). The CR rate was 67% (95% CI, 53%-78%). The ORR was consistent across most subgroups. The median duration of response was not reached (95% CI, 8.6 months to not estimable; Figure 9). Of the initial 28 patients treated, 43% remained in remission after more than 2 years of follow-up.
Most AEs occurred early, and most cases were reversible. The most common grade 3/4 AEs were hematologic in nature, and included thrombocytopenia (16% grade 3; 69% grade 4), thrombocytopenia (16% grade 3; 35% grade 4), and anemia (50% grade 3; 0% grade 4). Cytokine-release syndrome of grade 3 or 4 occurred in 15% of patients. All cases of cytokine-release syndrome resolved. There were no deaths from cytokine-release syndrome or neurologic events. Neurologic AEs of grade 3 or higher were reported in 31% of patients. Neurologic toxicity resolved in 86% of patients.
References
1. Sabatino M, Choi KS, Chiruvolu V, Better M. Production of anti-CD19 CAR T cells for ZUMA-3 and -4: phase 1/2 multicenter studies evaluating KTE-C19 in patients with relapsed/refractory B-precursor acute lymphoblastic leukemia (R/R ALL) [ASH abstract 1227]. Blood. 2016;128(suppl 22).
2. Wang M, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor T-cell therapy, in patients with relapsed/refractory mantle cell lymphoma: results of the phase 2 ZUMA-2 study [ASH abstract 754]. Blood. 2019;134(suppl 1).
Efficacy and Safety of Ibrutinib in Combination With Rituximab as Frontline Treatment for Indolent Clinical Forms of Mantle Cell Lymphoma: Preliminary Results of the Geltamo IMCL-2015 Phase II Trial
The phase 2 IMCL-2015 study evaluated tailored treatment with ibrutinib plus rituximab in treatment-naive patients with indolent forms of mantle cell lymphoma.1 The study was conducted at 14 treatment sites in Spain. Patients had indolent mantle cell lymphoma, as defined by the absence of symptoms related to the disease, an ECOG performance status of 0 or 1, stable disease without the need for therapy for at least 3 months, and nonblastoid histology. Patients with blastic or pleomorphic mantle cell lymphoma variants were excluded, as were patients with lymph nodes larger than 3 cm and/or a Ki-67 proliferation index higher than 30%. Patients received ibrutinib (560 mg daily) until disease progression, unacceptable toxicity, or MRD negativity (<10-5) lasting at least 6 months after 2 years of therapy. Patients also received rituximab (375 mg/m2) on days 1, 8, 15, and 22 of cycle 1, and then on day 1 of cycles 3, 5, 7, and 9. The primary endpoint was the CR rate at 12 months by central review.
The 48 enrolled patients had a median age of 65.7 years (range, 41-84 years), and 69% were male. The disease was stage III/IV in 96% of patients, and 77% had intermediate- or high-risk disease. The median follow-up was 23 months (range, 2-41 months).
Among the 35 evaluable patients, the ORR after treatment cycle 12 was 83%, with a CR rate of 77%. Undetectable MRD was reported in both the peripheral blood and bone marrow in 74% of patients overall and in 84% of patients with a CR (Figure 10). Among 22 patients who had completed 24 cycles of treatment, no clinical progression was observed. Thirteen patients with undetectable MRD stopped ibrutinib. One of these patients converted to positive MRD after 30 months, and 6 patients continued to have undetectable MRD after 12 months. Three-year OS was 85% (95% CI, 67%-100%), 3-year PFS was 92% (95% CI, 80%-100%), and 3-year event-free survival was 78% (95% CI, 63%-96%).
The most common AEs consisted of diarrhea (38%), neutropenia (31%), fatigue (31%), upper respiratory infections (25%), and nausea (21%). Grade 3/4 hematologic AEs included neutropenia (16%) and thrombocytopenia (2%).
Reference
1. Giné E, de la Cruz F, Grande C, et al. Efficacy and safety of ibrutinib in combination with rituximab as frontline treatment for indolent clinical forms of mantle cell lymphoma (MCL): preliminary results of Geltamo IMCL-2015 phase II trial [ASH abstract 752]. Blood. 2019;134(suppl 1).
Highlights in B-Cell Malignancies From the 61st American Society of Hematology Annual Meeting: Commentary
Richard R. Furman, MD
Director, CLL Research Center
Morton Coleman, MD Distinguished Professor of Medicine
Weill Cornell Medical College
NewYork-Presbyterian Hospital
New York, New York
Many abstracts presented at the 61st American Society of Hematology (ASH) annual meeting focused on chronic lymphocytic leukemia (CLL), mantle cell lymphoma, diffuse large B-cell lymphoma (DLBCL), and Waldenström macroglobulinemia. Studies provided updated data for treatments such as ibrutinib, venetoclax, acalabrutinib, and chimeric antigen receptor (CAR) T-cell therapy, as well as novel agents in early development.
Chronic Lymphocytic Leukemia
One of the most important questions for a physician caring for patients with CLL is whether to recommend chemoimmunotherapy or novel agents as frontline therapy. There is a great deal of long-term phase 2 data for fludarabine, cyclophosphamide, and rituximab (FCR) and for ibrutinib.1-3 Two cooperative group trials were designed to address this question in different populations. A study from the Alliance group evaluated bendamustine plus rituximab, ibrutinib alone, or ibrutinib plus rituximab in patients with previously untreated CLL who were older than 65 years.4 The Eastern Cooperative Oncology Group (ECOG) 1912 trial compared FCR vs ibrutinib and rituximab in patients younger than 70 years.5 The initial results of both studies were presented at the 60th ASH meeting and demonstrated the superiority of ibrutinib-based therapy over chemoimmunotherapy.6,7 One aspect of these data was how early the curves on Kaplan–Meier plots separated and demonstrated a difference. (The median follow-up was 38 months for the Alliance trial and 33 months for the ECOG study.)
Dr Tait Shanafelt and colleagues presented updated results from the ECOG 1912 study.8 With a median follow-up of 48 months, Dr Shanafelt confirmed the benefits previously seen with ibrutinib plus rituximab compared with FCR in patients with CLL who are younger than 70 years.8 The 3-year rate of progression-free survival (PFS) was 89% with ibrutinib plus rituximab vs 71% with FCR (95% CI, 0.26-0.57; P<.0001). The PFS benefit was seen primarily in patients without the immunoglobulin heavy chain variable (IGHV) mutation, likely because patients with the mutation did well with both treatments. These data also confirmed the previously seen benefit in overall survival for ibrutinib plus rituximab compared with FCR. Only 7% of patients treated with ibrutinib progressed during therapy. These data further support the superiority of ibrutinib-based therapy over chemoimmunotherapy in patients younger than 70 years.
The next logical progression in the treatment paradigm for patients with CLL is the use of combinations of novel agents. It is hoped that utilization of agents with non-overlapping toxicities and synergistic efficacy will achieve deeper and more prolonged responses. Two phase 2 trials investigating the combination of ibrutinib plus venetoclax have been undertaken.9,10 The first trial, conducted at MD Anderson Cancer Center, investigated ibrutinib plus venetoclax for 24 cycles in treatment-naive and previously treated patients with CLL.9 With a median follow-up of 27 months for 80 patients in the treatment-naive cohort, 14 patients discontinued therapy for various reasons. Only 2 patients progressed while receiving therapy, both with Richter’s transformations. In 75% of patients, minimal residual disease (MRD) was undetectable in the bone marrow after 24 months of combined therapy. Dr Nitin Jain and colleagues presented the results from the relapsed/refractory cohort of the trial.9 With a median follow-up of 27 months, MRD was undetectable in 56% of patients. Of note, all patients who remained MRD-detectable were allowed to continue single-agent ibrutinib.
The second study is the international CAPTIVATE trial, which investigated 12 cycles of ibrutinib plus venetoclax combination therapy in patients with treatment-naive CLL.10 The study divided patients into 2 cohorts. The first cohort (known as the MRD cohort) randomly assigned MRD-negative patients to either placebo or ibrutinib and MRD-positive patients to ibrutinib or ibrutinib plus venetoclax. The second cohort (known as the fixed-duration cohort) treated all patients with 12 cycles of combination therapy and then discontinued therapy. At the ASH meeting, Dr Constantine S. Tam reported on the results of the 12 cycles of combination therapy from the MRD cohort of the CAPTIVATE trial.10 Among 164 patients, including 20% with either deletion 17p or the TP53 mutation, MRD negativity was achieved in the peripheral blood in 75% and in the bone marrow in 72%.
Both studies utilized a strategy of administering 3 months of treatment with ibrutinib alone to debulk patients prior to initiation of venetoclax, in order to reduce the risk for tumor lysis syndrome.9,10 In the CAPTIVATE study, the risk of tumor lysis syndrome at enrollment was high, at 24%. This rate was reduced to 2% after 3 cycles of ibrutinib.10
The data from these studies are striking for the similar rates of MRD negativity in the bone marrow (75% and 72%), even with different durations of combination therapy. In Dr Jain’s data, the MRD negativity rate in the bone marrow after 12 months of combination therapy was 65%.9 It will be important to determine the best duration of treatment to ensure we are not denying patients therapeutic benefit. The CAPTIVATE study will provide important insight into this issue when the data mature.10 Regardless, this combination is highly effective, and patients will continue to derive benefit from single-agent ibrutinib.
The ELEVATE TN trial investigated obinutuzumab plus chlorambucil vs obinutuzumab plus acalabrutinib vs acalabrutinib alone. This trial led to the US Food and Drug Administration approval of acalabrutinib for the treatment of patients with CLL.11 The ELEVATE TN trial randomly assigned 535 patients with treatment-naive CLL to one of the above treatment arms. Patients could be older than 65 years or younger than 65 years with a Cumulative Illness Rating Scale (CIRS) score higher than 6 or a creatinine clearance less than 70 mL/min. After a median follow-up of 28.3 months, the overall response rates (ORRs) were 78.5% with obinutuzumab plus chlorambucil, 93.9% with obinutuzumab plus acalabrutinib, and 85.5% with acalabrutinib. The 2-year PFS was 93% with acalabrutinib plus obinutuzumab (P<.0001 vs obinutuzumab plus chlorambucil), 87% with acalabrutinib monotherapy (P<.0001 vs obinutuzumab plus chlorambucil), and 47% with chlorambucil plus obinutuzumab. A post-hoc exploratory analysis favored the addition of obinutuzumab to acalabrutinib over acalabrutinib alone, with a hazard ratio of 0.49. No differences in overall survival were seen among the 3 treatment arms.
Several investigators have demonstrated the synergistic efficacy of combining B-cell receptor antagonists, most notably ibrutinib, with venetoclax. Although the preliminary data for this combination are excellent, 20% of patients required dose reductions and 7% discontinued the treatment owing to adverse events.10 In order to take advantage of the synergy of these agents and improve tolerability, Dr Paul M. Barr and colleagues undertook a phase 1/2 trial of the combination of ublituximab, umbralisib, and venetoclax in relapsed and refractory CLL.12 It is hoped that umbralisib, a phosphoinositide 3 (PI3) kinase delta inhibitor, will avoid many of the adverse events associated with ibrutinib. Treatment with umbralisib in combination with ublituximab and venetoclax was well tolerated, with only 2 of 27 patients discontinuing therapy. Using umbralisib plus ublituximab (known as U2) as a lead-in therapy, the number of patients at high or medium risk for tumor lysis syndrome was reduced from 65% to 13%. The regimen proved to be highly efficacious, with an ORR of 100% and a bone marrow MRD-negativity rate of 78% after 12 cycles of treatment. This novel regimen affords an opportunity to replicate the excellent efficacy data reported with ibrutinib plus venetoclax,9,10 but with a different toxicity profile that might enable the treatment of additional patients.
Mantle Cell Lymphoma
Mantle cell lymphoma is currently incurable, and more treatment options are needed. CAR T cells have shown efficacy among patients with relapsed/refractory DLBCL.13 The phase 2 ZUMA-2 trial investigated KTE-X19 CAR T-cell therapy in patients with relapsed and refractory mantle cell lymphoma.14 KTE-X19 differs from axicabtagene ciloleucel (KTE-C19) in its manufacturing process that depletes circulating tumor cells. In 68 patients who received KTE-X19, the ORR was 93%, with a complete response rate of 67% and a partial response rate of 27%. After a median follow-up of 12.3 months, 57% of patients continued to respond, including 78% of those who achieved a complete response. Among the first 28 patients treated, 43% remained in remission at a median follow-up of 27 months. These data suggest that KTE-X19 is able to achieve responses in almost all relapsed/refractory mantle cell patients and may provide sustainable responses for some patients.
Diffuse Large B-Cell
Lymphoma
Limiting exposure to unnecessary treatment is an important goal in B-cell malignancies. Dr Laurie H. Sehn presented data from a long-term follow-up analysis of a positron emission tomography (PET)-guided approach to the treatment of limited-stage DLBCL.15 In the study, 319 patients underwent a PET/computed tomography scan after 3 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); 80% were PET-negative and 18% were PET-positive. Of the 254 PET-negative patients, 92% received 1 additional cycle of R-CHOP, 5% received radiotherapy, and 3% stopped treatment. Of the 59 PET-positive patients, 55 received radiotherapy, 2 received 3 additional cycles of R-CHOP, and 2 patients received 1 additional cycle of R-CHOP. After a median follow-up of 6.25 years, 21 of 254 PET-negative patients (8%) relapsed, compared with 13 of 59 PET-positive patients (22%). These data demonstrate that with a PET-guided approach to treatment, almost 80% of patients will achieve a negative PET scan, and these patients can have excellent outcomes with only 1 more cycle of R-CHOP, thereby safely avoiding radiotherapy and its long-term toxicities.
Waldenström Macroglobulinemia
Dr Marie José Kersten presented results from a HOVON/ECWM phase 1/2 trial investigating the safety and efficacy of ixazomib plus rituximab and dexamethasone in the treatment of patients with Waldenström macroglobulinemia.16 The trial demonstrated the safety of ixazomib at 4 mg orally given on days 1, 8, and 15, and moved this regimen forward as the phase 2 dose. With 45 of 59 patients completing 8 cycles, a 71% ORR was achieved, with 51% of patients achieving a partial response or better. Progression-free survival at 24 months was 56%. Treatment was well tolerated, particularly in comparison with the toxicities seen with proteasome inhibitors in this setting. These data confirm the efficacy previously seen with this regimen in Waldenström macroglobulinemia.17
A Proof-of-Concept Trial
Although ibrutinib demonstrates excellent response rates in patient with CLL, Waldenström macroglobulinemia, mantle cell lymphoma, and marginal zone lymphoma, a significant number of patients will demonstrate progressive disease.18 One mechanism of resistance is the development of a single base pair mutation in the Bruton tyrosine kinase (BTK) gene leading to a replacement of the cysteine at position 481 with a serine. The loss of the sulfhydryl group on the cysteine removes the site where ibrutinib covalently binds to BTK and irreversibly blocks the ATP pocket.19,20 Reversible inhibitors of BTK, such as vecabrutinib, ARQ-531, and LOXO-305, have the potential to overcome this resistance mutation because they do not need to covalently bind the sulfhydryl group to block the ATP pocket.21 Dr Anthony R. Mato presented results of the first in-human, proof-of-concept phase 1 trial of LOXO-305.22 The study examined LOXO-305 in a traditional phase 1 design, testing dose levels from 25 mg/day to 200 mg/day in patients with CLL and B-cell non-Hodgkin lymphoma who progressed during or were intolerant to BTK inhibitor therapy. Treatment was well tolerated, with no dose-limiting toxicities observed. The most common AEs were fatigue in 25% and diarrhea in 18%. Doses of 100 mg/day and higher achieved greater than 90% BTK inhibition over 24 hours. Responses were seen at all dose levels. The ORR was 77% in CLL and 50% in mantle cell lymphoma.
Disclosure
Dr Furman has received research funding from AstraZeneca and Janssen. He is a consultant for AbbVie, AstraZeneca, BeiGene, Genentech, Janssen, Loxo Oncology, OncoTracker, Pharmacyclics, TG Therapeutics, and Verastem Oncology. He has received speaker fees from AbbVie and Janssen, and is a member of the Data and Safety Monitoring Board for Incyte. He has provided expert testimony for AbbVie.
References
1. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016;127(3):303-309.
2. Byrd JC, Furman RR, Coutre S, et al. Up to 7 years of follow-up of single-agent ibrutinib in the phase 1b/2 PCYC-1102 trial of first line and relapsed/refractory patients with chronic lymphocytic leukemia/small lymphocytic lymphoma [ASH abstract 3133]. Blood. 2018;132(suppl 1).
3. Byrd JC, Furman RR, Coutre SE, et al. Ibrutinib treatment for first-line and relapsed/refractory chronic lymphocytic leukemia: final analysis of the pivotal phase 1b/2 PCYC-1102 study. Clin Cancer Res. In press.
4. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL. N Engl J Med. 2018;379(26):2517-2528.
5. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia. N Engl J Med. 2019;381(5):432-443.
6. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib alone or in combination with rituximab produces superior progression free survival (PFS) compared with bendamustine plus rituximab in untreated older patients with chronic lymphocytic leukemia (CLL): results of Alliance North American Intergroup Study A041202 [ASH abstract 6]. Blood. 2018;132(suppl 1).
7. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN Cancer Research Group (E1912) [ASH abstract LBA-4]. Blood. 2018;132(suppl 1).
8. Shanafelt TD, Wang XV, Kay NE, et al. Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia: extended follow-up from the E1912 trial [ASH abstract 33]. Blood. 2019;134(suppl 1).
9. Jain N, Keating M, Thompson P, et al. Combined ibrutinib and venetoclax in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) [ASH abstract 359]. Blood. 2019;134(suppl 1).
10. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the MRD cohort of the phase 2 CAPTIVATE study [ASH abstract 35]. Blood. 2019;134(suppl 1).
11. Sharman JP. ELEVATE TN: phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients with treatment-naive chronic lymphocytic leukemia [ASH abstract 31]. Blood. 2019;134(suppl 1).
12. Barr PM, Hill BT, Ma S, et al. Phase I/II study of umbralisib in combination with ublituximab and venetoclax (U2-Ven) in patients with relapsed/refractory CLL [ASH abstract 360]. Blood. 2019;134(suppl 1).
13. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377(26):2531-2544.
14. Wang M, Munoz J, Goy A, et al. KTE-X19, an anti-CD19 chimeric antigen receptor T-cell therapy, in patients with relapsed/refractory mantle cell lymphoma: results of the phase 2 ZUMA-2 study [ASH abstract 754]. Blood. 2019;134(suppl 1).
15. Sehn LH, Scott DW, Villa D, et al. Long-term follow-up of a PET-guided approach to treatment of limited-stage diffuse large B-cell lymphoma (DLBCL) in British Columbia (BC) [ASH abstract 401]. Blood. 2019;134(suppl 1).
16. Kersten MJ, Minnema MC, Vos JV, et al. Ixazomib, rituximab and dexamethasone (IRD) in patients with relapsed or progressive Waldenstrom’s macroglobulinemia: results of the prospective phase I/II HOVON 124/Ecwm-R2 trial [ASH abstract 344]. Blood. 2019;134(suppl 1).
17. Castillo JJ, Meid K, Gustine JN, et al. Prospective clinical trial of ixazomib, dexamethasone, and rituximab as primary therapy in Waldenström macroglobulinemia. Clin Cancer Res. 2018;24(14):3247-3252.
18. Woyach JA, Ruppert AS, Guinn D, et al. BTKC481S-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443.
19. Woyach JA, Furman RR, Liu TM, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370(24):2286-2294.
20. Furman RR, Cheng S, Lu P, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370(24):2352-2354.
21. Bond DA, Woyach JA. Targeting BTK in CLL: beyond ibrutinib. Curr Hematol Malig Rep. 2019;14(3):197-205.
22. Mato AR, Flinn IW, Pagel JM, et al. Results from a first-in-human, proof-of-concept phase 1 trial in pretreated B-cell malignancies for Loxo-305, a next-generation, highly selective, non-covalent BTK inhibitor [ASH abstract 501]. Blood. 2019;134(suppl 1).