Clinical Advances in Hematology & Oncology

January 2021 - Volume 19, Issue 1, Supplement 4

Highlights in Chronic Lymphocytic Leukemia From the 62nd American Society of Hematology Annual Meeting and Exposition

With Expert Commentary by:
Matthew S. Davids, MD, MMSc
Associate Professor of Medicine
Harvard Medical School
Director of Clinical Research
Division of Lymphoma
Dana-Farber Cancer Institute
Boston, Massachusetts

A Review of Selected Presentations From the All-Virtual 62nd ASH
Meeting and Exposition • December 5-8, 2020

 

Updated Safety and Efficacy Results From a Phase 2 Study of Acalabrutinib, Venetoclax, and Obinutuzumab for Frontline Treatment of Chronic Lymphocytic Leukemia

Acalabrutinib is a second-generation inhibitor of Bruton tyrosine kinase (BTK) that binds covalently to its target.1 The drug has yielded promising response rates with a manageable safety profile in phase 1/2 trials of patients with chronic lymphocytic leukemia (CLL). Acalabrutinib was evaluated in combination with venetoclax and obinutuzumab in an investigator-initiated phase 2 study of treatment-naive patients with CLL/small lymphocytic lymphoma (SLL).2,3 The trial initially enrolled patients with mutated or wild-type TP53. The protocol was later amended to restrict enrollment to patients with CLL who had the TP53 mutation; these patients were enrolled in a new cohort. All patients required treatment, based on criteria from the International Workshop on CLL (iwCLL) 2018 guidelines.4 The patients had adequate levels of absolute neutrophil and platelet counts, plus adequate hepatic and renal function. To make the 3-drug combination more tolerable, treatment with acalabrutinib, obinutuzumab, and venetoclax was started sequentially. Cycle 1 consisted of acalabrutinib monotherapy at 100 mg, twice daily. Obinutuzumab was added at the standard dose for 2 cycles. Venetoclax was then added over the course of 4 weeks, with a starting dose of 20 mg on day 1 of cycle 4, then 50 mg on day 2 of cycle 4, followed by weekly ramp-up to a dose of 400 mg daily. After a total of 4 cycles of the 3-drug regimen, patients received acalabrutinib plus obinutuzumab for cycles 8 to 15. The patients were assessed for response after 15 cycles. Patients with a complete response (CR) and undetectable minimal residual disease (MRD) in the bone marrow after cycle 15 could discontinue therapy. Patients who had a partial response (PR) or a CR with detectable MRD continued with acalabrutinib plus venetoclax through cycle 24, at which point the responses were assessed again. Patients with undetectable bone marrow MRD discontinued treatment, while the other patients continued to receive acalabrutinib and venetoclax. Responses were assessed based on iwCLL 2018 guidelines, with central testing of MRD by 8-color flow cytometry. The primary endpoint was the rate of CR with undetectable bone marrow MRD by day 1 of cycle 16.

The trial enrolled 44 patients. Their median age was 63 years (range, 41-78 years), and their Eastern Cooperative Oncology Group (ECOG) performance status was 0 or 1. More than half of the patients (54.5%) had Rai stage III/IV disease. The most common genetic abnormalities included TP53 aberrancy in 38.6%, 13q deletion in 45.5%, and 11q deletion (del[11q]) in 27.3%.

The objective response rate (ORR) at the end of 15 treatment cycles was 100% (with a CR rate of 56%; Figure 1). Among the 10 patients with a TP53 abnormality, 4 had a CR. The rate of undetectable bone marrow MRD was 76.5% (26/34; Figure 2) among all patients and 70% (7/10) among patients with TP53 aberrancy.

Serious adverse events (AEs) included grade 4 neutropenia in 4 patients and grade 4 hyperkalemia in 1 patient, as well as 1 case each of grade 3 elevated cardiac troponin 1 and grade 3 lung infection. Infusion-related reactions occurred in 11 patients (25%), including 1 grade 3 event. Grade 1/2 hypertension was observed in 5 patients (11%). One patient developed grade 3 atrial fibrillation during cycle 9, and 2 patients developed grade 3 laboratory tumor lysis syndrome after initiation of obinutuzumab therapy and prior to the addition of venetoclax. The risk of tumor lysis syndrome was reduced by administering 3 cycles of acalabrutinib and obinutuzumab prior to the addition of venetoclax.

References

1. Khan Y, O’Brien S. Acalabrutinib and its use in treatment of chronic lymphocytic leukemia. Future Oncol. 2019;15(6):579-589.

2. Davids MS, Lampson BL, Tyekucheva S, et al. Updated safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab (AVO) for frontline treatment of chronic lymphocytic leukemia (CLL) [ASH abstract 2219]. Blood. 2020;136(suppl 1).

3. Lampson BL, Tyekucheva S, Crombie JL, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia (CLL) [ASH abstract 32]. Blood. 2020;134(suppl 1).

4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.

 

Clonal Dynamics After Venetoclax-Obinutuzumab Therapy: Novel Insights From the Randomized Phase 3 CLL14 Trial

Achievement of undetectable MRD correlates with time to   relapse and is an important goal during treatment with CLL regimens of fixed duration.1 Evaluation of MRD was a key secondary endpoint of the open-label phase 3 CLL14 trial.2,3 The trial enrolled 445 patients with treatment-naive CLL and coexisting medical conditions, as indicated by a cumulative illness rating scale score higher than 6 and/or a creatinine clearance rate of less than 70 mL/min. The intention-to-treat population included 432 patients. These patients were randomly assigned to treatment with 6 cycles of venetoclax plus obinutuzumab, followed by 6 cycles of venetoclax, or 6 cycles of chlorambucil plus obinutuzumab, followed by 6 cycles of chlorambucil. The primary endpoint was progression-free survival (PFS). After a median follow-up of 28.1 months, the estimated 24-month PFS was 88.2% with venetoclax plus obinutuzumab vs 64.1% with chlorambucil plus obinutuzumab (hazard ratio [HR], 0.35; 95% CI, 0.23-0.53; P<.001). At the end of treatment, the rate of undetectable MRD was 74% vs 32%, respectively. The median PFS continued to improve in the venetoclax arm with longer follow-up.4

In order to calculate a patient-specific clonal growth rate, MRD was evaluated in peripheral blood samples taken at the end of treatment and at subsequent time points. An exponential regression model was used to estimate each patient,s clonal doubling time. The analysis included patients who did not experience disease progression prior to the end of treatment and who had at least 2 available MRD measurements taken after the end of treatment. MRD was analyzed by next-generation sequencing with a limit of quantification of less than 10-6. At the end of treatment, the proportion of patients with undetectable MRD was 40% in the venetoclax arm vs 6% in the control arm. Approximately one-third of patients in the venetoclax combination arm experienced a deepening of MRD response during the 6 cycles of venetoclax monotherapy. At the end of 6 cycles of combination treatment, 20 patients in the venetoclax arm were MRD-positive. Between the initiation of treatment cycle 7 and 3-month follow-up, approximately half of these patients experienced positive growth of their residual CLL cells. The remaining patients experienced a reduction in MRD, and thus could potentially achieve undetectable MRD with extended venetoclax monotherapy. The clonal growth rate was 0.0037 with venetoclax plus obinutuzumab vs 0.0043 with chlorambucil plus obinutuzumab (P=.042; Figure 3). A higher growth rate was observed in patients with high-risk disease features, such as older age (65 years), a high score on the CLL International Prognostic Index, unmutated immunoglobulin heavy chain variable (IGHV) region, and other genetic variants. In approximately 20% of patients in the venetoclax arm, MRD results were below the limit of quantification, indicating very deep remission

With a median observation of 52.4 months, the median PFS was not reached with venetoclax/obinutuzumab vs 36.4 months with chlorambucil/obinutuzumab (HR, 0.33; 95% CI, 0.25-0.45; P<.0001). The 4-year rate of PFS was 74.0% with venetoclax plus obinutuzumab vs 35.4% with chlorambucil plus obinutuzumab (HR, 0.33; 95% CI, 0.25-0.45; P<.0001. The 4-year time-to-next-treatment was 81.08% vs 9.9%, respectively (HR, 0.46; 95% CI, 0.32-0.65; P<.0001). Four-year overall survival was similar for both arms (85.3% with venetoclax vs 83.1% with chlorambucil; HR, 0.85; 95% CI, 0.54-1.35; P=.4929).

The study investigators concluded that individual clonal growth rates can be used to estimate growth dynamics after fixed-duration treatment with venetoclax plus obinutuzumab. The lower rate of clonal growth reported after treatment with venetoclax plus obinutuzumab vs chlorambucil plus obinutuzumab suggests that the former treatment was associated with more effective eradication of MRD and modulation of clonal growth. In approximately 20% of patients treated with venetoclax plus obinutuzumab, no clonal growth was measurable, indicating deep remissions. These remissions led to a sustained benefit in PFS lasting several years after completion of treatment.

References

1. Schiattone L, Ghia P, Scarfò L. The evolving treatment landscape of chronic lymphocytic leukemia. Curr Opin Oncol. 2019;31(6):568-573.

2. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236.

3. Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial [ASH abstract 127]. Blood. 2020;136(suppl 1).

4. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200.

 

Acalabrutinib in Combination With Venetoclax and Obinutuzumab or Rituximab in Patients With Treatment-Naive or Relapsed/Refractory Chronic Lymphocytic Leukemia

The phase 1b ACE-CL-003 trial evaluated acalabrutinib and venetoclax plus either obinutuzumab or rituximab in patients with CLL.1,2 Cohort analyses were performed to assess the efficacy and safety of acalabrutinib, venetoclax, and rituximab (AVR) in patients with relapsed or refractory CLL and of acalabrutinib, venetoclax, and obinutuzumab (AVO) in patients with treatment-naive CLL. All patients had intermediate-risk or high-risk CLL and an ECOG performance status of 0 to 2. Twelve patients who had received at least 1 prior systemic therapy were enrolled into the AVR cohort and 12 treatment-naive patients were enrolled into the AVO cohort. Both cohorts received acalabrutinib (100 mg, twice daily) for up to 24 cycles plus venetoclax (ramped up to 400 mg on day 1 of cycle 4) until the end of cycle 15. According to their cohort, patients received 9 infusions of rituximab (375 mg/m2) or standard dosing of obinutuzumab during cycles 2 to 7. The primary endpoint was safety. The median age was 66.5 years in the AVR cohort vs 60.5 years in the AVO cohort. Patients in the AVR cohort had received a median of 1 prior therapy (range, 1-3). Bulky disease was present in 25% of patients in the AVR cohort vs 58% in the AVO cohort. Other baseline characteristics were generally similar for the patient groups. The median follow-up was 27.7 months for the AVR cohort vs 26.0 months for the AVO cohort.

After 16 treatment cycles, the ORR was 92% (95% CI, 62%-100%) in patients who were previously treated at baseline and 100% (95% CI, 74%-100%) in treatment-naive patients. In each cohort, 50% of patients achieved a CR or CR with incomplete hematologic recovery (CRi). The median duration of response, PFS, and overall survival were not reached in either cohort. The estimated 18-month rates of PFS and overall survival were 100% for both cohorts. Pharmacokinetic findings with acalabrutinib, its active metabolite, and venetoclax were similar to those observed with monotherapy. The rate of undetectable MRD (≤0.01%) for both cohorts combined was 71% (Figure 4). By day 1 of cycle 10 and/or day 1 of cycle 16, only 1 of 12 patients (8%) remained MRD-positive in the peripheral blood in both cohorts.

The most common AEs of any grade included headache, nausea, and diarrhea in the AVR cohort and diarrhea, upper respiratory tract infection, and headache in the AVO cohort. Nine patients overall had grade 1/2 infusion-related reactions. Decreased neutrophil counts of grade 3 or higher were observed in 1 patient (8%) with relapsed or refractory disease at baseline and in 6 patients (50%) with treatment-naive disease at baseline. No cases of ventricular arrhythmia, Richter transformation, or death were reported.

Serious AEs of grade 3 or higher were noted in 2 patients (17%) in the AVR cohort and 4 patients (33%) in the AVO cohort. Infections of grade 3 or higher were observed among 3 patients (25%) in the AVO cohort. No cases of tumor lysis syndrome were observed in either cohort.

References

1. Woyach JA, Blachly JS, Rogers KA, et al. Acalabrutinib plus obinutuzumab in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia. Cancer Discov. 2020;10(3):394-405.

2. Woyach JA, Blachly JS, Rogers KA, et al. Acalabrutinib in combination with venetoclax and obinutuzumab or rituximab in patients with treatment-naïve or relapsed/refractory chronic lymphocytic leukemia [ASH abstract 1312]. Blood. 2020;136(suppl 1).

 

LOXO-305, A Next-Generation, Highly Selective, Non-Covalent BTK Inhibitor in Previously Treated CLL/SLL: Results From the Phase 1/2 BRUIN Study

Among patients with CLL, treatment with BTK inhibi tors  might be discontinued not only because of AEs, but also because acquired mutations in BTK or PLCG2 may lead to drug resistance. Genetic analysis of CLL patients treated with ibrutinib in 4 prospective studies showed a discontinuation rate of 54% among patients with relapsed or refractory disease at study entry, and resistance mutations were common among patients who relapsed after treatment with ibrutinib.1 Mutations in BTK residue C481 attenuate the activity of covalent BTK inhibitors, and C481 mutations are the most common reason for CLL progression after treatment with a covalent BTK inhibitor.1-8

LOXO-305 is a reversible BTK inhibitor with nanomolar potency against both wild-type and C481-mutated BTK in cell and enzyme assays.9,10 The phase 1/2 BRUIN study evaluated LOXO-305 in previously treated patients with advanced B-cell malignancies.11 The phase 1 portion of the trial evaluated LOXO-305 dose escalation, using a 3+3 design. The LOXO-305 dose ranged from 25 mg daily to 300 mg daily. The safety population of the study included 170 CLL/SLL patients, with a median age of 69 years (range, 36-88 years). Patients had received a median of 3 prior treatments (range, 1-11), and 86% had received prior therapy with a BTK inhibitor. Among the latter group, 67% had discontinued prior BTK therapy owing to progressive disease, and 33% did so owing to toxicity or other reasons. At baseline, 27% of patients had a BTK C481 mutation, and 4% had a PLCG2 mutation. Molecular characteristics consistent with high-risk disease included unmutated IGHV in 88%, TP53 mutation in 30%, 17p deletion (del[17p]) in 25%, and 11q deletion in 19%. Plasma exposure of LOXO-305 exceeded the BTK IC90 throughout the dosing interval at doses of 100 mg daily or higher, and plasma concentrations were dose-dependent and linear.

The ORR in 139 patients with CLL/SLL was 63%, including PRs in 50% and PRs with lymphocytosis in 14%. Among 121 patients who had received prior therapy with a BTK inhibitor, the ORR was 62%, including a PR rate of 47% and a PR with lymphocytosis rate of 15%. The ORR increased over time (Figure 5). After a median follow-up of 6 months (range, 0.6-17.8+ months), 94% of responding patients continued to show a response. Four patients discontinued treatment after disease progression, and 1 patient who achieved a PR discontinued therapy in order to undergo stem cell transplant. LOXO-305 yielded response rates of 50% or higher in patients with prior BTK exposure and in those with a C481 mutation.

Among 323 patients treated at all dose levels of LOXO-305, the most common AEs of any grade were fatigue (20%) and diarrhea (17%). AEs of special interest were mostly grade 1/2 and included bruising (16%), rash (11%), arthralgia (5%), hemorrhage (5%), hypertension (5%), and atrial fibrillation/flutter (<1%). One patient (<1%) experienced grade 3 hemorrhage, and 4 patients (1%) developed grade 3 hypertension. No dose-limiting toxicities were reported, and the maximum tolerated dose was not reached. Five patients (1.5%) discontinued therapy owing to treatment-related AEs. The 200-mg daily dose of LOXO-305 was selected as the recommended phase 2 dose.

References

1. Woyach JA, Ruppert AS, Guinn D, et al. BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443.

2. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.

3. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332.

4. Hershkovitz-Rokah O, Pulver D, Lenz G, Shpilberg O. Ibrutinib resistance in mantle cell lymphoma: clinical, molecular and treatment aspects. Br J Haematol. 2018;181(3):306-319.

5. Lampson BL, Brown JR. Are BTK and PLCG2 mutations necessary and sufficient for ibrutinib resistance in chronic lymphocytic leukemia? Expert Rev Hematol. 2018;11(3):185-194.

6. Woyach J, Huang Y, Rogers K, et al. Resistance to acalabrutinib in CLL is mediated primarily by BTK mutations [ASH abstract 504]. Blood. 2019;134(suppl 1).

7. 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.

8. Xu L, Tsakmaklis N, Yang G, et al. Acquired mutations associated with ibrutinib resistance in Waldenström macroglobulinemia. Blood. 2017;129(18):2519-2525.

9. Mato A, 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).

10. Brandhuber B, Gomez E, Smith S, et al. LOXO-305, a next generation reversible BTK inhibitor, for overcoming acquired resistance to irreversible BTK inhibitors [SHO abstract S216]. Clin Lymphoma Myeloma Leuk. 2018;18(suppl 1).

11. Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study [ASH abstract 542]. Blood. 2020;136(suppl 1).

 

Acalabrutinib vs Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: ASCEND Final Results

The multicenter, randomized phase 3 ASCEND study compared acalabrutinib monotherapy vs standard of care in patients with relapsed or refractory CLL.1,2 Prior to randomization, eligible patients were stratified by del(17p) status, ECOG performance status, and number of prior lines of therapy. Patients had received a median of 2 prior therapies (range, 1-10). Patients in the standard-of-care arm received the investigator’s choice of either idelalisib plus rituximab or bendamustine plus rituximab. Responses were evaluated by independent review based on iwCLL 2008 criteria, and the primary endpoint was PFS.3 The trial assigned 154 patients to treatment with acalabrutinib. In the control arms, 118 patients received idelalisib plus rituximab and 35 received bendamustine plus rituximab. The median duration of treatment exposure was 21.9 months with acalabrutinib, 11.5 months with idelalisib plus rituximab, and 5.6 months with bendamustine plus rituximab. The relative dose intensity was at least 90% for all 3 regimens. The rate of treatment discontinuation was 27% in the acalabrutinib arm, 77% in the idelalisib arm, and 19% in the bendamustine arm.

In updated results based on a median of 22 months of follow-up, the estimated 18-month PFS was 82% with acalabrutinib vs 48% with the standard of care (HR, 0.27; 95% CI, 0.18-0.40; P<.0001), confirming previous reports. In the acalabrutinib arm, the median PFS was not reached (Figure 6). Acalabrutinib was superior to the other regimens in patients with del(17p) and TP53 mutations (HR, 0.11; 95% CI, 0.04-0.34; Figure 7) and in patients without these characteristics (HR, 0.29; 95% CI, 0.19-0.45). Acalabrutinib was also superior to the standard-of-care regimens in patients with unmutated IGHV (HR, 0.28; 95% CI, 0.18-0.43) or mutated IGHV (HR, 0.30; 95% CI, 0.12-0.76). The median overall survival was not reached. The median duration of response was superior with acalabrutinib (not reached vs 18 months; HR, 0.19; 95% CI, 0.11-0.33), as was the estimated 18-month duration of response rate (85.4% vs 49.4%).

The safety profile of acalabrutinib was similar to that of bendamustine plus rituximab and superior to that of the idelalisib combination in terms of AEs of grade 3 or higher (55% vs 90% with idelalisib/rituximab), serious AEs (33% vs 56%), and treatment-related AEs (70% vs 95%). AEs led to drug discontinuation in 14% of the acalabrutinib arm, 59% of the idelalisib arm, and 17% of the bendamustine arm. Grade 3 or higher AEs included infections (20% with acalabrutinib vs 25% in the control arm).

References

1. Ghia P, Pluta A, Wach M, et al. Acalabrutinib vs idelalisib plus rituximab or bendamustine plus rituximab in relapsed/refractory chronic lymphocytic leukemia: ascend final results [ASH abstract 3140]. Blood. 2020;136(suppl 1).

2. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861.

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.

 

Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: 1-Year Disease-Free Survival Results From the MRD Cohort of the Phase 2 CAPTIVATE Study

The BTK inhibitor ibrutinib is associated with a significant improvement in overall survival as first-line treatment for CLL in phase 3 trials.1,2 Venetoclax inhibits Bcl-2 and induces apoptosis in CLL cells, thus providing a complementary function to that of ibrutinib.3

The international, phase 2 CAPTIVATE study evaluated the combination of ibrutinib plus venetoclax as first-line therapy for CLL. The chemotherapy-free regimen was administered either as a fixed-duration treatment or a schedule based on MRD.4 The study enrolled treatment-naive CLL patients with active disease who required treatment based on iwCLL 2008 criteria.5 Patients were younger than 70 years and had an ECOG performance status of 0 or 1. All patients received 3 cycles of ibrutinib lead-in treatment followed by 12 cycles of ibrutinib plus venetoclax, at which point they were evaluated for MRD. Ibrutinib was administered at 420 mg daily, and the venetoclax dose was ramped up to 400 mg daily.

Patients with undetectable MRD that was not confirmed were randomly assigned to receive treatment with open-label ibrutinib monotherapy or ibrutinib plus venetoclax. Patients with confirmed undetectable MRD were randomly assigned to receive placebo or ibrutinib in a double-blind fashion. Undetectable MRD was defined as a malignant cell count in the peripheral blood and bone marrow below 10-4 as assessed by 8-color flow cytometry serially throughout 3 or more treatment cycles.

The primary endpoint was the 1-year rate of disease-free survival in patients with confirmed undetectable MRD after 12 cycles of combination therapy who were randomly assigned to placebo vs ibrutinib after induction therapy. Disease-free survival was defined as freedom from MRD relapse of more than 10-2 malignant cells, confirmed on 2 separate occasions, in the absence of disease progression or death.

The trial enrolled 164 patients. Their median age was 58 years (range, 28-69 years). Fifty-three patients (32%) had Rai stage III/IV disease, and 53 patients (32%) had a lymph node diameter of 5 cm or larger. High-risk features included unmutated IGHV in 60%, del(17p)/TP53 mutation in 20%, complex karyotype in 19%, and del(11q) in 17%. A cytopenia was reported in 36% of patients, and 32% had an enlarged lymph node (≥5 cm). Administration of 3 cycles of ibrutinib lead-in therapy reduced the risk of tumor lysis syndrome and hospitalization.

After 12 cycles of ibrutinib plus venetoclax, the rate of undetectable MRD was 75% (95% CI, 69%-82%) in peripheral blood and 72% (95% CI, 65%-79%) in bone marrow. Among the patients who had matched peripheral blood and bone marrow samples at cycle 16, 93% had undetectable MRD in both sample types.

Among 164 patients in the entire study population, 149 were randomly assigned to treatment. Eighty-six of these patients (58%) achieved confirmed undetectable MRD. A trend toward an increased likelihood of having high-risk features was observed among patients who achieved confirmed undetectable MRD as compared with patients who did not. For example, unmutated IGHV was reported in 70% vs 46%, respectively, and del(11q) was reported in 21% vs 8%.

At a median follow-up of 16.6 months after randomization, the 1-year rate of disease-free survival was 100% with ibrutinib monotherapy vs 95.3% with placebo, a difference that did not reach statistical significance (P=.1475; Figure 8). At a median on-study follow-up of 31.3 months, the 30-month PFS was 95.3% for the 164 enrolled patients. The 30-month PFS rates were higher than 95% across all 4 randomized arms. Among the 63 patients with unconfirmed undetectable MRD, the rates of undetectable bone marrow MRD increased from 32% to 42% with ibrutinib alone and from 31% to 66% with ibrutinib plus venetoclax. Rates of undetectable MRD in peripheral blood remained at 45% with ibrutinib monotherapy and increased from 50% to 69% with further ibrutinib plus venetoclax. These increases in undetectable MRD were higher than those seen in patients with confirmed undetectable MRD prior to randomization.

Rates of AEs generally decreased after the first 6 months of combination therapy, regardless of subsequent therapy. AEs of grade 3 or higher were infrequent across all randomized arms. No new safety signals were observed.

References

1. Burger JA, Barr PM, Robak T, et al. Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study. Leukemia. 2020;34(3):787-798.

2. 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.

3. Awan FT, Al-Sawaf O, Fischer K, Woyach JA. Current perspectives on therapy for chronic lymphocytic leukemia. Am Soc Clin Oncol Educ Book. 2020;40:1-10.

4. Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ib4) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study [ASH abstract 123]. Blood. 2020;136(suppl 1).

5. 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.

 

Umbralisib Plus Ublituximab (U2) Is Superior to Obinutuzumab Plus Chlorambucil (O+Chl) in Patients With Treatment-Naive and Relapsed/Refractory Chronic Lymphocytic Leukemia: Results From the Phase 3 UNITY-CLL Study

Umbralisib is a dual inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ) and casein kinase-1ε.1 With high selectivity for the δ form of PI3K, umbralisib is associated with low rates of immune-mediated toxicity and treatment discontinuation owing to AEs. Ublituximab is a novel anti-CD20 antibody that targets a unique epitope on CD20.2 This antibody was glycoengineered to enhance antibody-dependent cellular cytotoxicity. The randomized phase 3 UNITY-CLL study compared the combination of umbralisib and ublituximab (U2) vs obinutuzumab and chlorambucil among patients with CLL.3 Enrolled patients had treatment-naive or previously treated CLL that required treatment based on iwCLL criteria, as well as an ECOG performance status of 0 to 2 and adequate organ function. Patients were stratified for randomization based on del(17p) status and receipt of prior treatment. Patients were initially randomly assigned into 4 treatment arms to receive U2, obinutuzumab and chlorambucil, umbra­lisib monotherapy, or ublituximab monotherapy.

After the contribution of the single agents to the U2 combination was established, the 2 monotherapy arms were closed, and additional patients were randomly assigned into the U2 arm and the obinutuzumab/chlorambucil arm. Each treatment cycle was 28 days. Umbralisib (800 mg) was administered once daily. Ublituximab (900 mg) was administered with a split dose on days 1 and 2, followed by the full dose on days 8 and 15 of cycle 1, day 1 of cycles 2 to 6, and on day 1 every 3 cycles after cycle 6. Obinutuzumab (1000 mg) was administered with a split dose on days 1 and 2, followed by the full dose on days 8 and 15 of cycle 1 and on day 1 of cycles 2 to 6. Chlorambucil (0.5 mg/kg) was administered on days 1 and 15 of cycles 1 to 6. The primary endpoint was PFS for U2 vs obinutuzumab and chlorambucil based on independent review.

The study randomly assigned 421 patients to treatment with U2 or obinutuzumab plus chlorambucil. The baseline characteristics were well balanced between the 2 arms. The patients’ median age was 67 years (range, 36-91 years). Fifty-seven percent of patients were treatment-naive. High-risk genomic features included unmutated IGHV in 56%, del(11q) in 20%, and del(17p) in 10%.

The median treatment exposure was 21.1 months (range, 0.03-46.3 months) for ublituximab, 20.5 months (range, 0.03-47.2 months) for umbra­lisib, 4.7 months (range, 0.03-7.4 months) for obinutuzumab, and 5.1 months (range, 0.03-7.4 months) for chlorambucil. After a median follow-up of 36.7 months, the median PFS was 31.9 months (95% CI, 28.2-35.8 months) in the U2 arm vs 17.9 months (95% CI, 16.1-22.6 months) in the control arm (HR, 0.546; 95% CI, 0.413-0.720; P<.0001; Figure 9). The estimated 2-year PFS rates were 60.8 months vs 40.4 months, respectively. The median PFS in previously treated patients was 19.5 months with the U2 regimen vs 12.9 months with the control (HR, 0.601; 95% CI, 0.415-0.869; P<.01). The estimated 2-year PFS rates were 41.3% vs 24.8%, respectively.

The ORR was 83.3% with U2 vs 68.7% with obinutuzumab plus chlorambucil (P<.001; Figure 10). Most subgroups benefited from U2 compared with obinutuzumab plus chlorambucil. U2 yielded a superior ORR in treatment-naive patients (84% vs 78%), previously treated patients (82% vs 57%), and those with prior exposure to a BTK inhibitor (57% vs 25%). Durable responses were observed, with 62% of patients maintaining their response at 2 years.

Serious AEs were observed in 46.1% of the U2 arm vs 23.5% of the control arm. AEs of grade 3 or higher were observed in 82.0% vs 66.0%, respectively, and grade 5 AEs occurred in 3.9% vs 2.5%. More patients in the U2 arm discontinued study treatment owing to an AE (16.5% vs 7.6%). The most common grade 3/4 AEs in the U2 arm were neutropenia (31%) and diarrhea (12%, all grade 3), followed by infusion-related reactions (1.9%) and fatigue (1.9%). In the U2 arm, the most common grade 3 or higher AEs of clinical interest were alanine transaminase elevation (8.5%), opportunistic infections (5.8%), and aspartate transaminase elevation (5.3%).

References

1. Burris 3rd HA, Flinn IW, Patel MR, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ε inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol. 2018;19(4):486-496.

2. Sawas A, Farber CM, Schreeder MT, et al. A phase 1/2 trial of ublituximab, a novel anti-CD20 monoclonal antibody, in patients with B-cell non-Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab. Br J Haematol. 2017;177(2):243-253.

3. Gribben J, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 UNITY-CLL study [ASH abstract 543]. Blood. 2020;136(suppl 1).

 

TRANSCEND CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel in Combination With Ibrutinib for Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Lisocabtagene maraleucel is an autologous chimeric antigen receptor (CAR) T-cell therapy directed at CD19.1 The T-cell product is administered by delivering equal doses of engineered CD8-positive and CD4-positive T cells. The TRANSCEND CLL 004 study evaluated lisocabtagene maraleucel in patients with relapsed or refractory CLL/SLL.2-4 Enrolled patients were ineligible for treatment with a BTK inhibitor or had not responded to previous treatment. The trial enrolled patients with high-risk disease who had an inadequate response to 2 or more prior therapies and patients with standard-risk disease who had an inadequate response to at least 3 prior therapies. Bridging therapy was allowed. The phase 1 portion of the trial investigated 2 dose levels of CAR T-cell therapy: 50 × 106 CAR-positive T cells and 100 × 106 CAR-positive T cells. Dose-limiting toxicities were evaluated for 28 days after the lisocabtagene maraleucel infusion, and responses were assessed based on iwCLL 2018 criteria.5

Twenty-three patients in the trial received lisocabtagene maraleucel monotherapy.3 The patients’ median age was 66 years (range, 50-80 years), and the median time since diagnosis was 87.5 months (range, 30-209 months). Eight patients (35%) had bulky disease. Fifteen patients (65%) had Rai stage III/IV disease, and 19 (83%) had a high-risk genetic feature. Patients had received a median of 4 prior lines of therapy (range, 2-11). Two dose-limiting toxicities were reported at the higher dose level of lisocabtagene maraleucel therapy. Common grade 3/4 treatment-emergent AEs included anemia, thrombocytopenia, and neutropenia, observed in 70% to 74% of patients, and leukopenia in 43%. Cytokine release syndrome of any grade was observed in 74% of patients, including 2 patients (9%) with grade 3 cases. Neurologic events of any grade were observed in 9 patients (39%), with neurologic AEs of grade 3 or higher observed in 5 patients (22%).

After a median follow-up of 24 months, the ORR was 82%, including a CR/CRi rate of 46%. Six patients (27%) experienced a deepening of response. Fifty percent of patients (11/22) continued to demonstrate a response at 12 months, and 2 of these patients progressed after 12 months. Among 15 patients with a CR or PR and undetectable MRD in the peripheral blood, 4 patients had progressed, including 3 owing to Richter transformation. The median duration of response was not reached (95% CI, 4.8 months to not reached; Figure 11), and the median PFS was 18 months (95% CI, 3.0 months to not reached). In the subgroup of 11 patients who had previously progressed on a BTK inhibitor and venetoclax, the median duration of response was 17 months (95% CI, 1.9 months to not reached), and the median PFS was 13 months (95% CI, 2.8 months to not reached). The lisocabtagene maraleucel product was detected in 50% of patients (6/12) at 12 months and in 18% of patients (2/11) at 18 months.

The TRANSCEND NHL 004 study contained a second arm in which 19 patients with relapsed or refractory CLL received the lisocabtagene maraleucel transfusion (at either dose level) plus ibrutinib (420 mg daily). These patients had a median age of 61 years (range, 50-77 years), with a median time since diagnosis of 121 months (range, 21-252 months). Forty-seven percent of patients had Rai stage III/IV disease. Ninety-five percent had a high-risk feature, such as complex karyotype in 42%, del(17p) in 42%, and mutated TP53 in 32%. The median number of prior lines of therapy was 4 (range, 1-10). Common grade 3/4 treatment-emergent AEs included neutropenia (89%), anemia (47%), and febrile neutropenia (26%). Fourteen patients (74%) experienced any-grade cytokine release syndrome, including 1 patient (5%) with grade 3 cytokine release syndrome. Neurologic events of any grade were observed in 6 patients (32%), including 3 patients with grade 3 events (16%). Ibrutinib therapy was discontinued owing to an AE in 4 patients (21%). After 10 months of follow-up, the ORR was 95% (18/19), including a CR/CRi rate of 63%. Eighty-nine percent of patients (11/19) achieved undetectable MRD, with 1 patient later progressing owing to Richter transformation. The lisocabtagene maraleucel product was detected in 38% of patients (6/16) at 6 months and in 20% of patients (1/5) at 12 months.

References

1. Li R, Ma C, Cai H, Chen W. The CAR T-cell mechanoimmunology at a glance. Adv Sci (Weinh). 2020;7(24):2002628.

2. Siddiqi T, Soumerai JD, Dorritie KA, et al. Rapid undetectable mrd (uMRD) responses in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T cell product: updated results from TRANSCEND CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib [ASH abstract 503]. Blood. 2019;134 (suppl 1).

3. Siddiqi T, Soumerai JD, Dorritie KA, et al. Updated follow-up of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma treated with lisocabtagene maraleucel in the phase 1 monotherapy cohort of TRANSCEND CLL 004, including high-risk and ibrutinib-treated patients [ASH abstract 546]. Blood. 2020;136(suppl 1).

4. Wierda WG, Dorritie KA, Munoz J, et al. TRANSCEND CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [ASH abstract 544]. Blood. 2020;136(suppl 1).

5. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760.

 

Continued Long-Term Responses to Ibrutinib + Venetoclax Treatment for Relapsed/Refractory CLL in the Blood Cancer UK TAP CLARITY Trial

The phase 2 Blood Cancer UK TAP CLARITY trial evaluated the combination of ibrutinib plus venetoclax among patients with relapsed or refractory CLL.1,2 The trial design incorporated a plan to stop therapy early if undetectable MRD (<0.01%) was achieved in the peripheral blood and bone marrow. After 2 months of treatment with ibrutinib monotherapy, venetoclax was added first at a daily dose of 10 mg or 20 mg, then escalated weekly to a final daily dose of 400 mg. Paired samples of peripheral blood and bone marrow were evaluated at months 8, 14, and 26. Longitudinal samples of peripheral blood were obtained at multiple time points. An updated analysis provided data regarding long-term responses.2

The trial enrolled 54 patients. Most patients (69%) were male, and their median age was 64 years. Their median number of prior therapies was 1 (range, 1-6). Bulky lymph nodes (≥5 cm) were reported in 8%. High-risk genetic factors included del(17p) in 20%, del(11q) in 25%, and unmutated IGHV in 75%. During the first 8 weeks of ibrutinib monotherapy, 4 patients discontinued treatment after developing treatment-related adverse events. The trial recruited 50 patients to the combination portion, and all were successfully treated through the venetoclax dose-escalation phase.

Therapy was halted after confirmation of a CR based on iwCLL 2008 criteria and MRD reduction to below 10-4 CLL cells in the peripheral blood and bone marrow (MRD4). Among patients with MRD4 at month 8, treatment with ibrutinib and venetoclax was stopped at month 14. Among those with MRD4 at month 14 and/or month 26, ibrutinib and venetoclax were stopped at month 26. When MRD was detectable at month 26, venetoclax was stopped, but ibrutinib was continued until disease progression or toxicity. The trial protocol was amended to permit patients without an MRD4 at month 26 to receive 12 months of venetoclax in addition to ibrutinib.

The primary endpoint was MRD4 (<0.01%) in the bone marrow after 12 months of treatment with ibrutinib plus venetoclax. At month 14, 58% of patients were MRD-negative in the peripheral blood and 40% of patients were MRD-negative in the bone marrow. Levels of trephine were normal in 81%. Among patients who had relapsed after treatment with FCR or bendamustine plus rituximab, 70% were MRD-negative in the peripheral blood and 45% were MRD-negative in the bone marrow. These rates were 67% and 56%, respectively, among patients who had received previous treatment with idelalisib. The ORR was 100% at month 8, 98% at month 14, 92% at month 26, and 90% at month 38. The rates of CR were 40%, 50%, 64%, and 68%, respectively. Among patients receiving at least 1 treatment at the time of assessment, the ORR was 94% at month 25 and 85% at month 38, with CR rates of 59% and 65%, respectively. At month 38, rates of MRD4 negativity were 50% in the peripheral blood and 40% in the bone marrow among all evaluable patients. Responses correlated with the initial depletion rate. After treatment,  a sustained MRD of less than 0.01% was reported in 68% of patients with higher levels of depletion vs 20% among those with lower levels of depletion. The median PFS and overall survival were not reached. At month 36, the estimated rate of PFS was 95.9%, and the estimated rate of overall survival was 97.7%.

There were 6 cases of atrial fibrillation/flutter occurring in 5 patients. Three events were grade 1/2, and the other 3 were grade 3. No grade 4 events were reported. Any-grade febrile neutropenia occurred in 2 patients. There were 37 reports of a decrease in neutrophil count (occurring in 13 patients). Most events (24) were grade 3. There was a single case of tumor lysis syndrome, which occurred with the 200-mg dose of venetoclax. This case was managed by delaying treatment. The protocol included a recommendation to administer granulocyte colony–stimulating factor to maintain the neutrophil count above 1 × 109/L.

In conclusion, at a follow-up of 38 months, the response to ibrutinib plus venetoclax was sustained, despite planned treatment discontinuation among patients with MRD-negative disease. No new safety signals arose in this long-term follow-up analysis. Two patients had COVID-19 infection, and both recovered. The investigators found that the initial rate of disease depletion achieved during the first 2 months of treatment with ibrutinib plus venetoclax was highly predictive of longer-term response. Patients without rapid disease clearance who had persistent MRD after 12 months of combination treatment tended to have stable or slowly decreasing levels of disease similar to those reported with ibrutinib monotherapy.

References

1. Hillmen P, Rawstron AC, Brock K, et al. Ibrutinib plus venetoclax in relapsed/refractory chronic lymphocytic leukemia: the CLARITY study. J Clin Oncol. 2019;37(30):2722-2729.

2. Munir T, Boucher RH, Webster N, et al. Continued long term responses to ibrutinib + venetoclax treatment for relapsed/refractory CLL in the Blood Cancer UK TAP CLARITY trial [ASH abstract 124]. Blood. 2019;134 (suppl 1)

 

Highlights in Chronic Lymphocytic Leukemia From the 62nd American Society of Hematology Annual Meeting and Exposition: Commentary

Matthew S. Davids, MD, MMSc

Associate Professor of Medicine
Harvard Medical School
Director of Clinical Research
Division of Lymphoma
Dana-Farber Cancer Institute
Boston, Massachusetts

 

Several studies presented at the 62nd American Society of Hematology Annual (ASH) Meeting and Exposition provided insight into the management of patients with chronic lymphocytic leukemia (CLL). Some of the highlights to me were data presented on treatments such as the triplet regimens of BTK inhibitors with venetoclax and obinutuzumab; the doublet regimen of ibrutinib and venetoclax; LOXO-305; umbralisib plus ublituximab; and lisocabtagene maraleucel.

My colleagues and I presented the results of a phase 2 trial of acalabrutinib, venetoclax, and obinutuzumab (AVO) for the frontline treatment of patients with CLL.1 An interesting aspect of the study is that the population was enriched for high-risk patients with TP53-aberrant CLL; 38.6% of patients had deletion 17p or the TP53 mutation. The study showed very deep responses in terms of minimal residual disease (MRD). For example, the rate of undetectable bone marrow MRD was 76.5% on day 1 of cycle 16. The benefit was similar in patients with high-risk disease vs standard-risk, as this rate was 70.0% among patients with TP53-aberrant disease. Another notable aspect of the AVO study is the favorable safety profile. Although the regimen consisted of 3 drugs, the rates of severe cytopenias, atrial fibrillation, and infection were low. Grade 3 or higher infection, atrial fibrillation, and infusion-related reactions were reported in 2% of patients each. No major bleeding issues occurred. The study explored the use of a shorter 4-week venetoclax dose ramp-up instead of the usual 5 weeks. This more convenient dosing strategy was enabled by the effective reduction in disease burden among patients who received acalabrutinib and obinutuzumab. There were no reports of tumor lysis syndrome associated with starting venetoclax.

Dr William Wierda presented results from the MRD cohort of the phase 2 CAPTIVATE trial, an important study of the doublet regimen of ibrutinib and venetoclax in the frontline setting.2 According to the study design, patients could be randomly assigned to additional therapy after separation into cohorts with or without confirmed undetectable MRD. Overall, this early report suggested that ibrutinib and venetoclax was an effective combination in the frontline setting. The rate of undetectable MRD in the bone marrow was 72% among evaluable patients. At this point in the analysis, among patients with confirmed undetectable MRD who completed the initial 15 months of therapy, similar rates of disease-free survival at 1 year were reported in patients who received an additional year of ibrutinib vs placebo (100.0% vs 95.3%, respectively; P=.1475). It is reassuring that 1 year of treatment with ibrutinib plus venetoclax provided good durability, and this observation raises the prospect that such patients may do well without the need for continuous BTK inhibitor therapy. However, longer follow-up and phase 3 data are needed before the results with this regimen can be considered practice-changing.

Dr Anthony Mato provided an updated analysis of a study of LOXO-305 in patients with CLL or small lymphocytic leukemia (SLL).3 Early data presented at the previous ASH meeting suggested that LOXO-305 might be a well-tolerated, highly effective Bruton tyrosine kinase (BTK) inhibitor, even for patients with the BTK C481 mutation.4 The updated data confirmed the previous results, but in much larger patient numbers. It is clear that LOXO-305 is an active drug for patients with both mutated and wild-type BTK. The overall response rate was 63%. Patients who had progressed on ibrutinib and venetoclax still responded to LOXO-305. This agent appears to have a safe toxicity profile, with no significant rates of atrial fibrillation or bleeding, which are typically seen with BTK inhibitors. These exciting early data will inform the design of phase 3 registrational trials to gain approval in CLL from the US Food and Drug Administration.

Dr John G. Gribben presented results from the phase 3 UNITY-CLL study, which compared umbralisib plus ublituximab (also known as U2) vs obinutuzumab plus chlorambucil in patients with CLL.5 Results from this registrational study are likely to lead to FDA approval of umbralisib and ublituximab, which would be the first approval for each of these drugs. This study provided helpful data regarding the safety and efficacy profile for the U2 regimen. The median progression-free survival was 31.9 months with the U2 regimen vs 17.9 months with obinutuzumab/ chlorambucil (P<.0001). Although obinutuzumab/chlorambucil was not the strongest comparator regimen, it was useful because it has recently been the control arm in several other studies, such as the CLL14 trial.6 Another study expected to read out soon is the GLOW trial, which is comparing ibrutinib plus venetoclax to obinutuzumab plus chlorambucil.7 Results are not yet available, but the common comparator arm in these studies should facilitate cross-study comparison. Results from the UNITY CLL study suggest that umbralisib is fairly well-tolerated, with a differentiated safety profile compared with other phosphatidylinositol 3 (PI3)-kinase inhibitors.5 For example, this study is the first to provide evidence that it is feasible from a safety perspective to use a PI3 kinase inhibitor for the frontline treatment of CLL. The combination of umbralisib plus ublituximab will have a role in the CLL treatment paradigm. This regimen may not necessarily displace BTK inhibitors or venetoclax-based therapy for the majority of patients, but it will provide an alternative for some patients, particularly those who have cardiovascular comorbidities or who may have difficulties with venetoclax dose ramp-up.

Two presentations provided analy­ses from the phase 1 TRANSCEND CLL 004 trial of lisocabtagene maraleucel, with or without ibrutinib, in patients with relapsed or refractory CLL or SLL.8,9 Dr Tanya Siddiqi provided an update of the data for lisocabtagene maraleucel monotherapy.8 At a median follow-up of 24 months, lisocabtagene maraleucel appeared to be active, even in patients with very high-risk CLL, including those who had progressed during treatment with ibrutinib and venetoclax. The rate of complete response with or without complete blood count recovery was 46%. Dr William Wierda presented new data for the cohort treated with ibrutinib plus lisocabtagene maraleucel.9 The rate of complete response with or without complete blood count recovery was 63%, and the rate of undetectable MRD in the bone marrow was 79%. These responses are notable in this heavily pretreated group of patients, although longer follow-up is needed to understand more about the durability of these responses. The combination of lisocabtagene maraleucel plus ibrutinib appeared to be tolerable from a safety perspective, with a similar or possibly even slightly better adverse event profile as lisocabtagene maraleucel alone. Clinicians who treat patients with CLL are curious about whether these strategies can be used to manipulate the immune system to enhance the activity of CAR T cells. This study is among the first to provide proof of principle that it may be possible.

Dr Arnon Kater presented a 5-year follow-up analysis of the MURANO study.10 This data set is important because the MURANO trial established venetoclax plus rituximab as a standard of care for patients with relapsed/refractory CLL. This update provided the first data for the median progression-free survival, which was 53.6 months for venetoclax plus rituximab vs 17.0 months for bendamustine plus rituximab (P<.0001). It is helpful to remember this duration as we counsel patients about what they are likely to expect during treatment with venetoclax plus rituximab. These data are promising because they suggest that with 2 years of treatment, the majority of patients can obtain a remission lasting at least 2 additional years while off all treatment. Data presented at the ASH meeting by Dr Rosemary Harrup and colleagues suggest that it is possible to successfully re-treat any of these patients with venetoclax, and that BTK inhibitors could be used after venetoclax-based therapy with good effect.11 This updated analysis of the MURANO study provides strong support for the utility of the venetoclax/rituximab regimen in patients with relapsed CLL.

This analysis also provided interesting data on the clonal dynamics of MRD recurrence among patients enrolled in the MURANO trial.10 This information is helpful when considering the patients who are more likely to quickly develop recurrent disease after completing therapy. The analysis showed that patients with 17p deletion, unmutated IGHV, or genomic complexity all seemed to have faster regrowth of disease after completion of therapy. This observation could help guide the approach to disease monitoring after therapy and predict when patients may need to initiate treatment again. The investigators carefully documented the median time to MRD recurrence, as well as the median time from MRD recurrence to clinical disease progression. These markers can provide insight as we counsel patients about their likely length of remission, and when additional treatment might be needed.

Dr Othman Al-Sawaf provided an updated analysis of the CLL14 trial, the study of time-limited venetoclax/obinutuzumab as frontline treatment for CLL.12 The analysis evaluated the clonal dynamics of patients treated with venetoclax during the study, with a focus on how the level of clones can evolve over time in patients with or without undetectable MRD. A current question in the field is whether 1 year is the optimal treatment duration for venetoclax plus obinutuzumab. This analysis compared the MRD change from halfway through the year of therapy vs after the year of therapy was completed. Among the patients who still had detectable MRD at the end of treatment, approximately half had increasing MRD during treatment with venetoclax. It might be expected that additional venetoclax would not be helpful in this group of patients. In contrast, in half the group, MRD decreased during the second 6-month period of treatment with venetoclax. This finding suggests that additional venetoclax therapy might be helpful for these patients. These results are not practice-changing but more hypothesis-generating, and should inspire a trial designed to determine the length of therapy based not only on single MRD tests, but also on serial MRD testing, to identify patterns of change over time.

This analysis of the CLL14 study also generated updated data regarding survival for patients treated with this 1-year venetoclax/obinutuzumab regimen. At 4 years, 74% of the patients were progression-free. The previous data set had reported a progression-free survival rate of 82% at 3 years.6 Therefore, only approximately 8% of patients developed progressive disease with an additional year of follow-up, and that was in patients who were off all therapy. These data reinforce the durability of response after 1 year of treatment with venetoclax plus obinutuzumab, particularly for those patients with mutated IGHV and other types of lower-risk disease. The report did not provide data comparing progression-free survival among patients with or without mutated IGHV, but this analysis is eagerly awaited.

Disclosure

Dr Davids reports receiving grant support, paid to his institution, and consulting fees from Ascentage Pharma, AstraZeneca, Genentech, MEI Pharma, Novartis, Pharmacyclics, TG Therapeutics, and Verastem. He has received grant support, paid to his institution, from BMS and Surface Oncology. He has received consulting fees from AbbVie, Adaptive Biotechnologies, BeiGene, Celgene, Eli Lilly, Janssen, MEI Pharma, Merck, Research to Practice, and Vera­stem.

References

1. Davids MS, Lampson BL, Tyekucheva S, et al. Updated safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab (AVO) for frontline treatment of chronic lymphocytic leukemia (CLL) [ASH abstract 2219]. Blood. 2020;136(suppl 1).

2. Wierda WG, Tam CS, Allan JN, et al. Ibrutinib (Ib4) plus venetoclax (Ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): 1-year disease-free survival (DFS) results from the MRD cohort of the phase 2 CAPTIVATE study [ASH abstract 123]. Blood. 2020;136(suppl 1).

3. Mato AR, Pagel JM, Coombs CC, et al. LOXO-305, a next generation, highly selective, non-covalent BTK inhibitor in previously treated CLL/SLL: results from the phase 1/2 BRUIN study [ASH abstract 542]. Blood. 2020;136(suppl 1).

4. Mato A, 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).

5. Gribben J, Jurczak W, Jacobs R, et al. Umbralisib plus ublituximab (U2) is superior to obinutuzumab plus chlorambucil (O+Chl) in patients with treatment naïve (TN) and relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): results from the phase 3 UNITY-CLL study [ASH abstract 543]. Blood. 2020;136(suppl 1).

6. Fischer K, Ritgen M, Al-Sawaf O, et al. Quantitative analysis of minimal residual disease (MRD) shows high rates of undetectable MRD after fixed-duration chemotherapy-free treatment and serves as surrogate marker for progression-free survival: a prospective analysis of the randomized CLL14 trial [ASH abstract 36]. Blood. 2019;134(suppl 1).

7. ClinicalTrials.gov. A study of the combination of ibrutinib plus venetoclax versus chlorambucil plus obinutuzumab for the first-line treatment of participants with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). https://clinicaltrials.gov/ct2/show/NCT03462719. Identifier: NCT03462719. Accessed January 17, 2021.

8. Siddiqi T, Soumerai JD, Dorritie KA, et al. Updated follow-up of patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma treated with lisocabtagene maraleucel in the phase 1 monotherapy cohort of TRANSCEND CLL 004, including high-risk and ibrutinib-treated patients [ASH abstract 546]. Blood. 2020;136(suppl 1).

9. Wierda WG, Dorritie KA, Munoz J, et al. TRANSCEND CLL 004: phase 1 cohort of lisocabtagene maraleucel (liso-cel) in combination with ibrutinib for patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) [ASH abstract 544]. Blood. 2020;136(suppl 1).

10. Kater AP, Kipps TJ, Eichhorst BF, et al. Five-year analysis of MURANO study demonstrates enduring undetectable minimal residual disease in a subset of relapsed/refractory chronic lymphocytic leukemia patients following fixed-duration venetoclax-rituximab therapy [ASH abstract 125]. Blood. 2020;136(suppl 1).

11. Harrup RA, Owen C, D’Rozario J, et al. Efficacy of subsequent novel targeted therapies, including repeated venetoclax-rituximab (venR), in patients (pts) with relapsed/refractory chronic lymphocytic leukemia (R/R CLL) previously treated with fixed-duration venR in the MURANO study [ASH abstract 3139]. Blood. 2020;136(suppl 1).

12. Al-Sawaf O, Zhang C, Robrecht S, et al. Clonal dynamics after venetoclax-obinutuzumab therapy: novel insights from the randomized, phase 3 CLL14 trial [ASH abstract 127]. Blood. 2020;136(suppl 1).