A Review of Selected Presentations From the 2018 American Society of
Clinical Oncology Annual Meeting • June 1-5, 2018 • Chicago, Illinois
Phase 2 CAPTIVATE Results of Ibrutinib Plus Venetoclax in First-Line Chronic Lymphocytic Leukemia
Ibrutinib is an oral inhibitor of Bruton’s tyrosine kinase approved for the first-line treatment of relapsed or refractory chronic lymphocytic leukemia (CLL), including patients with the 17p deletion (del[17p]). In the CLL setting, single-agent ibrutinib has been shown to elicit high response rates and durable responses. However, the majority of patients achieve only partial responses, with evidence of residual disease in the blood or bone marrow.1-3 Venetoclax is an oral BCL-2 inhibitor that has shown strong activity in CLL.4 It is approved as therapy for previously treated patients with CLL who have del(17p). The combination of ibrutinib plus venetoclax is of interest for several reasons. Preclinical and ongoing clinical studies have shown synergistic and complementary activities.5-7 The all-oral combination could provide deeper remissions and might allow ibrutinib treatment holidays.8,9 In addition, the risk of tumor lysis syndrome could potentially be reduced by incorporating an ibrutinib lead-in treatment for initial debulking.10
The randomized phase 2 CAPTIVATE study (PCYC-1142; Ibrutinib Plus Venetoclax in Subjects With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) investigated 12 cycles of ibrutinib plus venetoclax in treatment-naive patients with CLL or small lymphocytic leukemia (SLL).11 Eligible patients had active disease requiring treatment (based on criteria from the International Workshop on Chronic Lymphocytic Leukemia [iwCLL]), were younger than 70 years, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.12 All patients received three 28-day cycles of ibrutinib (420 mg, once daily) as lead-in treatment, followed by 12 cycles of ibrutinib plus venetoclax. The latter therapy was escalated to 400 mg once daily. Patients were then randomly assigned to receive ibrutinib plus either venetoclax or placebo. Measures were taken to reduce the risk of tumor lysis syndrome based on the venetoclax prescribing information. Minimal residual disease (MRD) was assessed in peripheral blood after 6 cycles of combination treatment. MRD and bone marrow responses were assessed after 12 cycles of combination treatment. Confirmed, undetectable MRD was defined as 2 consecutive blood analyses separated by 3 treatment cycles. Confirmation of undetectable bone marrow MRD was also required. The study included an MRD cohort and a fixed duration cohort. Results from the fixed duration cohort will be presented at a later date.
The primary objectives for the MRD cohort were to assess drug exposure and safety. A preplanned interim analysis of 164 patients in the MRD cohort included blood MRD for the first 30 patients who received 6 cycles of combination treatment, and bone marrow MRD for the first 14 patients who received 12 cycles of combination treatment. Patients underwent disease assessment at baseline and prior to initiation of venetoclax treatment. MRD assessments were made after treatment cycles 9, 12, and 15. Imaging was performed after cycles 9 and 15, and the full assessment of response, including bone marrow examination, was performed following cycle 15.
In the entire MRD cohort, the median age was 58 years (range, 28-69 years), and 32% of patients had Rai stage III/IV disease. Fifteen percent of patients had del(17p), 18% had del(11q), and 60% had an unmutated immunoglobulin heavy chain variable region gene (IGHV). For the 30 patients in the blood MRD cohort, the median age was 57 years (range, 28-69 years), and 40% of patients had Rai stage III/IV disease. Twenty-three percent of patients had del(17p), and 23% of patients had del(11q). IGHV was unmutated in 67%. In the entire MRD cohort, the median treatment duration was 8.7 months (range, 0.5-15.2 months) with ibrutinib and 6.0 months (range, 0.8-12.0 months) with venetoclax. Ibrutinib treatment was discontinued in 1 patient (1%) owing to progressive disease and in 7 patients (4%) owing to adverse events (AEs). An AE led to discontinuation of venetoclax in 3 patients (2%). In the blood MRD cohort, the median treatment duration was 10.4 months (range, 10.0-15.2 months) with ibrutinib and 7.6 months (range, 7.0-12.0 months) with venetoclax. None of these patients discontinued treatment with ibrutinib or venetoclax.
Treatment with 3 cycles of ibrutinib lead-in therapy reduced the risk of tumor lysis syndrome. Among the entire MRD population of 164 patients, 24% had a high risk of tumor lysis syndrome at baseline vs 3% after ibrutinib lead-in, and the proportion of low-risk patients increased from 12% to 29%. Lymph node bulk was also reduced.
No unexpected ibrutinib-related toxicities were observed during the lead-in treatment. After a median of 6 months of exposure to combination treatment (range, 0.8-12.0 months), neutropenia was the only grade 4 AE. A treatment-related grade 3/4 AE occurred in 45% of patients, and 16% experienced an AE that required a dose reduction. An AE led 5% of patients to discontinue treatment. A serious AE occurred in 21% of patients, and 11% experienced a treatment-related serious AE. Two patients (1%) developed laboratory tumor lysis syndrome, but no cases of clinical tumor lysis syndrome were observed. No patients died during the study.
In the blood MRD cohort, flow cytometry analysis of the leukocyte population showed that 93% of patients had at least 1.0% CLL cells. The value was between 0.01% and less than 1.0% in 3% of patients. After 3 cycles of ibrutinib lead-in and 6 cycles of combination treatment, 77% of patients had less than 0.01% CLL cells (ie, undetectable peripheral blood MRD), 13% had between 0.01% and less than 1.0%, and 10% had greater than 10%. The proportion of patients with undetectable MRD increased to 86% (12 of 14 patients) after the ninth cycle of combination treatment and to 93% after the final treatment cycle (13 of 14 patients; Figure 1). After the 3 cycles of ibrutinib monotherapy and 12 cycles of combination therapy, 86% of patients (12 of 14) had undetectable bone marrow MRD.
Among the 11 patients who completed 12 cycles of combination treatment, 36% experienced a complete response (CR), 36% had a partial response (PR), 18% had a CR with incomplete blood count recovery (iCR), and 9% had a nodular PR. All 6 of the patients who achieved a CR or iCR and 3 of the patients who achieved a PR or nodular PR also had undetectable MRD. Among all patients in the blood MRD cohort, lymphadenopathy target lesions decreased in bulk by more than 60% to 100% (Figure 2). A reduction in splenomegaly of approximately 35% to 100% was observed among all 24 patients who had spleen enlargement at baseline. The combination of ibrutinib plus venetoclax will be evaluated in a phase 3 study as a fixed-duration regimen in treatment-naive patients with CLL.13
References
1. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437.
2. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.
3. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
4. Perini GF, Ribeiro GN, Pinto Neto JV, Campos LT, Hamerschlak N. BCL-2 as therapeutic target for hematological malignancies. J Hematol Oncol. 2018;11(1):65.
5. 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.
6. 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.
7. Tam CS, Anderson MA, Pott C, et al. Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma. N Engl J Med. 2018;378(13):1211-1223.
8. Olin JL, Griffiths CL, Smith MB. Venetoclax: a novel B-cell lymphoma-2 inhibitor for chronic lymphocytic leukemia and other hematologic malignancies [published online January 1, 2017]. J Oncol Pharm Pract. doi:10.1177/1078155217718383.
9. Venclexta [package insert]. North Chicago, IL: AbbVie, Inc; 2016.
10. Wierda W, Byrd JC, O’Brien S, et al. Tumor de-bulking and reduction in tumor lysis syndrome risk: analyses from single-agent ibrutinib studies. Presented at: the XVII International Workshop on Chronic Lymphocytic Leukemia; New York, NY; May 12-15, 2017. Abstract 106.
11. Wierda WG, Siddiqi T, Flinn IW, et al. Phase 2 CAPTIVATE results of ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia [ASCO abstract 7502]. J Clin Oncol. 2018;36(15 suppl).
12. 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.
13. 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 June 24, 2018.
Durability of Response to Venetoclax in Patients With CLL Relapsed/Refractory to Ibrutinib and/or Idelalisib
Ibrutinib and idelalisib are inhibitors of the B-cell receptor pathway, and both agents have yielded high objective response rates (ORRs) in treatment-naive patients with CLL.1 They are less effective, however, in patients with relapsed or refractory disease, and other treatment options are limited.2,3 Venetoclax monotherapy has demonstrated activity in heavily pretreated patients with CLL, including those who had received a B-cell receptor pathway inhibitor.4-6 An open-label, multicenter phase 2 trial evaluated venetoclax monotherapy in patients with CLL who had refractory disease or had progressed after discontinuation of ibrutinib and/or idelalisib.7 The trial assessed the durability of response to venetoclax monotherapy, and evaluated levels of MRD. Eligible patients had an ECOG performance status of 0 to 2, with adequate bone marrow function and creatinine clearance. The washout period following the most recent prior treatment was 7 days for patients enrolled in the initial cohort and 3 days for the expansion cohort. Venetoclax treatment was initiated at 20 mg daily for 1 week and escalated weekly to reach the target dose of 500 mg daily by week 5. Because tumor lysis syndrome is a concern with this class of drugs, patients received prophylactic treatment starting at least 72 hours before the first dose of study drug. Laboratory monitoring was risk-based. Disease assessments occurred at screening, at weeks 8 and 24, and every 12 weeks thereafter. Responses were evaluated based on 2008 iwCLL criteria.8 MRD was assessed at a central laboratory using 6-color flow cytometry. Peripheral blood MRD was assessed at week 24 for all patients. Bone marrow MRD was assessed 8 weeks after demonstration of a CR, iCR, or PR, and/or after 2 consecutive negative MRD results in the peripheral blood.
The 127 enrolled patients had a median age of 66 years (range, 28-85 years) and had received a median of 4 prior therapies (range, 1-15). Prior therapies inhibiting the B-cell receptor included single-agent ibrutinib in 61%, single-agent idelalisib in 20%, and both treatments combined in 19%. IGHV was unmutated in 78% of patients, 40% had del(17p), and 28% had a TP53 mutation. The median duration of venetoclax treatment was 17.3 months (range, 0.1-35.5 months). Sixty-four patients discontinued study treatment, most commonly owing to disease progression (35%), AEs (8%), Richter transformation (6%), and stem cell transplant (6%).
The ORR was 66% (84/127) per investigator assessment and 70% (89/127) per independent review. Investigator-assessed response rates included CRs in 6%, iCRs in 5%, PRs in 54%, and nodular PRs in 2%. After a median follow-up of 16 months, the median progression-free survival (PFS) based on investigator assessment was 24.7 months. Kaplan-Meier estimates showed a PFS rate of 52% (95% CI, 40%-62%) at 24 months (Figure 3). The median duration of response (Figure 4) and median overall survival were not reached. Kaplan-Meier estimates yielded a 24-month duration of response of 57% (95% CI, 41%-71%), and a 24-month overall survival of 76% (95% CI, 65%-84%). Among 77 patients assessed for MRD, 32 (42%) had undetectable MRD in the peripheral blood (using a cutoff of 10-4 CLL cells). Among the latter, bone marrow was MRD-negative in 9 and MRD-positive in 7. (Status was unknown in 16 patients.) Investigator-assessed median PFS was not reached in patients with undetectable MRD in the peripheral blood vs 21.9 months for patients with detectable levels (hazard ratio [HR], 0.148; 95% CI, 0.04-0.49; P=.0019). The most common grade 3/4 AEs were neutropenia (52%), thrombocytopenia (29%), and anemia (25%). A serious AE was reported in 51% of patients, and included febrile neutropenia in 9% and pneumonia in 6%. Seven patients died during the study from an AE. Two patients developed laboratory tumor lysis syndrome.
References
1. Maharaj K, Sahakian E, Pinilla-Ibarz J. Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia. Blood Adv. 2017;1(21):1867-1875.
2. Jain P, Keating M, Wierda W, et al. Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood. 2015;125(13):2062-2067.
3. Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128(18):2199-2205.
4. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704-1711.
5. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75.
6. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-778.
7. Byrd JC, Wierda WG, Davids MS, et al. Durability of response to venetoclax in patients with CLL relapsed/refractory to ibrutinib and/or idelalisib [ASCO abstract 7512]. J Clin Oncol. 2018;36(15 suppl).
8. 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.
High, Durable Minimal Residual Disease Negativity With Venetoclax + Rituximab in Relapsed/Refractory CLL: MRD Kinetics From the Phase 3 MURANO Study
In patients with CLL, undetectable MRD after treatment with chemotherapy, with or without rituximab, is associated with prolonged PFS and overall survival.1 The use of CR as an endpoint in trials of CLL is limited by the subjectivity in measuring lymph node size and by the need for multiple computed tomography scans.2 Undetectable MRD may provide a more objective endpoint. The open-label phase 3 MURANO study (A Study to Evaluate the Benefit of Venetoclax Plus Rituximab Compared With Bendamustine Plus Rituximab in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia) compared the combination of venetoclax plus rituximab vs bendamustine plus rituximab in patients with relapsed or refractory CLL. The recently published results demonstrated a superior PFS with the venetoclax combination.3 At the 2018 American Society of Clinical Oncology meeting, Dr Peter Hillmen reported results of the MRD analysis.4 The study enrolled 389 patients, who were stratified based on del(17p), responsiveness to prior therapy, and geographic region. The population included 17 pediatric patients, who were stratified between the 2 treatment arms. Patients were randomly assigned to receive either venetoclax or bendamustine in combination with rituximab. Rituximab was administered on day 1 of each cycle, starting at 375 mg/m2 in cycle 1 and followed by 500 mg/m2 in cycles 2 to 6. Bendamustine was administered at 70 mg/m2 on days 1 and 2 for all 6 treatment cycles. The venetoclax dose was escalated throughout 5 weeks to a dose of 400 mg daily, starting on day 1 of cycle 1. After completion of 6 cycles of venetoclax plus rituximab, venetoclax monotherapy was administered for a maximum of 2 years. Bone marrow MRD was evaluated at baseline and at 3 months after completion of treatment. Peripheral blood MRD was evaluated at baseline, on day 1 of cycle 4, at 3 months after the end of treatment, and every 3 months thereafter. MRD was defined as less than 1 CLL cell in 10,000 leukocytes for peripheral blood and bone marrow and was centrally assessed by allele-specific oligonucleotide polymerase chain reaction and/or multicolor flow cytometry.5,6 MRD status was reported as positive if either method showed a positive result. Missing MRD data and assay failures were reported as MRD-positive. The primary endpoint was investigator-assessed PFS, and the secondary endpoint was MRD in the peripheral blood at the end of combination treatment.
The analysis was conducted in the intent-to-treat population. After a median follow-up of 23.8 months, the 1-year PFS was 92.7% for the venetoclax combination vs 72.5% for the bendamustine combination. The 2-year PFS was 84.9% vs 36.3%, respectively (HR, 0.17; 95% CI, 0.11-0.25; P<.0001). A consistent benefit with the venetoclax combination was observed in all subgroups. The PFS benefit for venetoclax plus rituximab was confirmed by an independent review committee (HR, 0.19; 95% CI, 0.13-0.28; P<.0001). A high level of concordance was observed among patients who were evaluated for MRD in both the peripheral blood and the bone marrow.4
In the venetoclax combination arm, the paired bone marrow MRD result did not confirm the peripheral blood result in 10 of 68 patients (14.7%; Figure 5). A similar rate of discordance was observed in the bendamustine combination arm (7/40; 17.5%). Among the patients who were MRD-positive according to peripheral blood analysis, discordant results were seen in 38.5% in the venetoclax arm and no patients in the bendamustine arm. Among patients who achieved MRD negativity, the rates of discordance were 10% in the venetoclax arm (5/50) vs 70% in the bendamustine arm (7/10). Based on these results, peripheral blood analysis was considered a reasonable method for determining MRD.
Peripheral blood analysis at 3 months after the end of treatment yielded an MRD-negative rate of 62% (121/194) in the venetoclax-plus-rituximab arm vs 13% (26/195) in the bendamustine-plus-rituximab arm (P<.0001). Among the subset of patients with del(17p) and/or the TP53 mutation, the rate of MRD negativity was 57% (41/72) with the venetoclax combination vs 5% (4/75) with the bendamustine combination. Among patients without either mutation, rates of MRD negativity were 66% (70/106) and 20% (19/95), respectively. The venetoclax combination was superior regardless of the patient’s IGHV status. Superior rates of MRD negativity in the peripheral blood were observed across all subgroups, including age, sex, 11q deletion, levels of ß2 microglobulin, bulky disease, and number of prior regimens. Rapid responses were observed among patients treated with the venetoclax combination, and the responses tended to be durable. Among 15 patients in the venetoclax combination arm, the response converted from MRD-negative to MRD-positive. Most of these patients still showed relatively low levels of CLL cells, ranging between 10-4 and 10-2, and 11 of them remained progression-free at the time of the study report.
References
1. Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012;30(9):980-988.
2. 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.
3. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120.
4. Hillmen P, Kater AP, Seymour JF, et al. High, durable minimal residual disease negativity with venetoclax + rituximab in relapsed/refractory CLL: MRD kinetics from phase 3 MURANO study [ASCO abstract 7508]. J Clin Oncol. 2018;36(15 suppl).
5. Rawstron AC, Böttcher S, Letestu R, et al; European Research Initiative in CLL. Improving efficiency and sensitivity: European Research Initiative in CLL (ERIC) update on the international harmonised approach for flow cytometric residual disease monitoring in CLL. Leukemia. 2013;27(1):142-149.
6. van der Velden VH, Cazzaniga G, Schrauder A, et al; European Study Group on MRD detection in ALL (ESG-MRD-ALL). Analysis of minimal residual disease by Ig/TCR gene rearrangements: guidelines for interpretation of real-time quantitative PCR data. Leukemia. 2007;21(4):604-611.
Depth of Response and Progression-Free Survival in CLL Patients on Ibrutinib
Among patients with CLL, a CR after treatment with chemoimmunotherapy corres-ponds to a longer PFS.1,2 A similar relationship, however, has not been demonstrated after treatment with ibrutinib.1,2 A retrospective study evaluated the association between depth of response and PFS in patients with CLL treated with ibrutinib.3 The study included patients enrolled in 4 sequential clinical trials of ibrutinib alone or in combination with ofatumumab conducted at Ohio State University. Two independent investigators evaluated responses using iwCLL 2008 guidelines.4 For patients without bone marrow analyses, clinical response was used instead. Landmark analysis was performed based on response assessment at 12 ±2 months, and PFS was calculated based on this response. The 237 patients in the analysis had a median age of 65 years (range, 27-89 years), and 70% were male. The Rai stage was low in 4%, intermediate in 31%, and high in 64%. The median number of prior therapies was 3 (range, 0-13). Eighty-two percent of patients had unmutated IGHV, 54% had a complex karyotype, 27% had del(11q), and 36% had del(17p).
At the 12-month assessment, 5% of patients had a CR, 3% had an iCR, 77% had a PR, 12% had a PR with lymphocytosis, and 3% had stable disease. A lymph node size of less than 3 cm was seen in 61% of patients with a PR and 79% of those with a PR with lymphocytosis. After a median follow-up of 48 months, the median PFS was 52 months (95% CI, 42-70 months), and no significant difference was observed among the response groups (P=.32; Figure 6). However, in a multivariable Cox model, the median PFS was significantly prolonged in patients with lymph nodes smaller than 3 cm (P=.01; Figure 7).
References
1. Byrd JC, Furman RR, Coutre SE, et al. Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood. 2015;125(16):2497-2506.
2. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42.
3. Sigmund A, Huang Y, Ruppert AS, et al. Depth of response and progression-free survival in CLL patients on ibrutinib (ASCO abstract 7514). J Clin Oncol. 2018;36(15 suppl).
4. 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.
A Phase 2 Study to Assess the Safety and Efficacy of Umbralisib (TGR-1202) in Patients With CLL Who Are Intolerant to Prior BTK or PI3Kδ Inhibitor Therapy
Ibrutinib and other kinase inhibitors are generally well-tolerated in CLL. However, drug intolerance accounts for approximately 50% of discontinuations.1,2 Interruptions in the administration of ibrutinib lasting 8 days or more are associated with a reduced PFS.3 Patients who show poor tolerance to one kinase inhibitor can often be successfully treated with a different one. Umbralisib is a novel inhibitor of phosphoinositide 3-kinase delta (PI3Kδ). In an early study, the safety profile of umbralisib differed from that of other drugs in the same class; no cases of grade 3/4 transaminitis, pneumonitis, diarrhea, or colitis were reported.4 The drug has a half-life compatible with once-daily administration and is highly selective for the δ isoform of PI3K. It also binds to casein kinase-1ε, which may inhibit the function of regulatory
T cells.
Umbralisib monotherapy at a dose of 800 mg daily was evaluated in a multicenter, single-arm trial in patients with CLL who were intolerant to prior kinase inhibitor therapy.5 Eligible patients had received prior treatment with a Bruton’s tyrosine kinase inhibitor, such as ibrutinib or acalabrutinib, or a PI3Kδ inhibitor, such as idelalisib or duvelisib. A key eligibility requirement was that the prior kinase inhibitor was discontinued owing to intolerance within 12 months of day 1 of the first cycle. The study enrolled patients who had discontinued prior kinase inhibitor treatment for at least 14 days and showed no disease progression. Resolution of all toxicities to grade 1 or lower was required before initiation of umbralisib.
The study evaluated 47 patients for safety, 46 for PFS, and 22 for response. The patients’ median age was 71 years (range, 52-96 years), and 57% were male. Del(17p) was observed in 15% of patients and del(11q) in 17%. IGHV was unmutated in 53%, and 43% had bulky disease. Patients had experienced a total of 37 prior grade 2 AEs, 26 grade 3 AEs, and 5 grade 4 AEs. The median number of prior therapies was 2 (range, 1-7). After a median follow-up of 9.5 months, the median PFS had not been reached. The changes in nodal lesion size are shown in Figure 8.
The most common AEs of any grade observed during umbralisib treatment were nausea (43%), diarrhea (40%), and thrombocytopenia (26%). The most common grade 3/4 AEs were neutropenia (15%), thrombocytopenia (9%), and diarrhea (6%). Dose reductions occurred in 3 patients (6%) owing to headache, neutropenia, or colitis. One patient developed colitis after 6 weeks of treatment. This patient recovered after a 2-week break from study treatment. Upon resumption of umbralisib therapy at 600 mg daily, the colitis did not recur, and the patient achieved a CR and continued on the study for more than 16 months. Thirteen percent of patients discontinued study treatment owing to an umbralisib-related AE, including pneumonia, pancreatitis, pneumonitis, dermatitis, and rash. Three patients developed the same AE that had led to intolerance of the prior kinase inhibitor therapy. One of these patients discontinued treatment with umbralisib. In the other 2, the AE was less severe than the first time, and treatment continued.
References
1. Mato AR, Hill BT, Lamanna N, et al. Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol. 2017;28(5):1050-1056.
2. Mato AR, Nabhan C, Barr PM, et al. Outcomes of CLL patients treated with sequential kinase inhibitor therapy: a real world experience. Blood. 2016;128(18):2199-2205.
3. Barr PM, Brown JR, Hillmen P, et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129(19):2612-2615.
4. Davids MS, Kim HT, Nicotra A, et al. Updated results of a multicenter phase I/Ib study of TGR-1202 in combination with ibrutinib in patients with relapsed or refractory MCL or CLL [ICML abstract 040]. Hematol Oncol. 2017;35(S2).
5. Mato AR, Schuster SJ, Lamanna N, et al. A phase 2 study to assess the safety and efficacy of umbralisib (TGR-1202) in pts with CLL who are intolerant to prior BTK or PI3Kδ inhibitor therapy [ASCO abstract 7530]. J Clin Oncol. 2018;36(15 suppl).
Change in Tumor Lysis Syndrome Risk After Lead-In Treatment in a Phase 1b/2 Study of Obinutuzumab, Ibrutinib, and Venetoclax for Chronic Lymphocytic Leukemia
Venetoclax is associated with tumor lysis syndrome, thereby increasing treatment burden and limiting administration to settings that offer appropriate monitoring and management. The risk for tumor lysis syndrome is closely related to CLL tumor burden, which is defined by the absolute lymphocyte count and the largest lymph node diameter observed by cross-sectional imaging. During venetoclax dose ramp-up, monitoring for tumor lysis syndrome is required for all patients, and patients at high risk are hospitalized. Additional strategies to reduce the risk for tumor lysis syndrome and avoid hospitalization are needed.
A retrospective study was conducted to determine whether treatment with lead-in obinutuzumab and ibrutinib prior to venetoclax therapy reduced the risk for tumor lysis syndrome.1 The analysis included all patients who completed treatment through day 1 of cycle 3. Treatment with each of the 3 drugs was initiated sequentially throughout the first 3 cycles. Obinutuzumab was administered at 100 mg on day 1, 900 mg on day 2, and 1000 mg on days 8 and 15 during cycle 1. Afterward, the drug was administered at 1000 mg on day 1 of each subsequent cycle. Ibrutinib (420 mg daily) was initiated on day 1 of cycle 2. Venetoclax ramp-up was initiated on day 1 of cycle 3. Lymph node diameter was assessed by computed tomography, and the risk of tumor lysis syndrome was calculated as specified in the venetoclax prescribing information.
Sixty-one patients were included in the study. The patients’ median age was 61 years (range, 26-79 years), and 67% were male. Fifty-nine percent had relapsed or refractory disease, and 41% were treatment-naive. IGHV was unmutated in 78% of patients, ZAP-70 was methylated in 42%, and 35% had the complex CLL karyotype. The most common chromosomal abnormalities were del(11q) in 36% and del(13q) in 21%.
From the initiation of study treatment through day 1 of cycle 3, the median absolute lymphocyte count decreased significantly, with a median change of –56.5 k/µL (P<.001; Figure 9). From day 1 of cycle 1 through day 1 of cycle 3, the median absolute lymphocyte count increased by a median of 2.1 k/µL (P<.001), reflecting the initiation of treatment with ibrutinib. As measured by the sum of the products of the greatest perpendicular diameters, the lymph node volume decreased after every cycle (P<.001). The median change in lymph node volume from day 1 of cycle 1 to day 1 of cycle 3 was –11.8 cm2. During this time, 7 patients (11%) remained high risk, 13 (21%) went from high to medium risk, 9 (15%) remained at medium risk, 24 (39%) went from medium to low risk, and 8 (13%) remained low risk. At the start of venetoclax treatment, 52% of patients were at low risk of experiencing tumor lysis syndrome. No incidents of laboratory or clinical tumor lysis syndrome were observed.
Reference
1. Rogers KA, Huang Y, Ruppert AS, et al. Change in tumor lysis syndrome risk after lead-in treatment in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax for chronic lymphocytic leukemia [ASCO abstract 7528]. J Clin Oncol. 2018;36(15 suppl).
Prognostic Role of Beta-2 Microglobulin in Relapsed/Refractory Chronic Lymphocytic Leukemia Patients Treated With Ibrutinib
Patients with CLL often have elevated levels of ß2 microglobulin, and both disease stage and tumor burden correlate with ß2 microglobulin levels. In patients with CLL who received ibrutinib-containing treatment, normalization of ß2 microglobulin levels was associated with a longer PFS.1 Multivariable analysis identified a reduced PFS (HR, 16.9; P=.031) among patients with an abnormal level of ß2 microglobulin at 6 months of treatment. A retrospective study investigated the correlation between ß2 microglobulin status and PFS in patients with relapsed or refractory CLL who enrolled in 2 open-label clinical trials that included treatment with ibrutinib monotherapy.2-4 The time of ß2 microglobulin normalization was defined as the first time the level decreased below the upper limit of normal as defined by the central laboratory used in each trial.
The analysis included 339 patients. Most patients (55%) were 65 years or older, and two-thirds were male. Rai stage III/IV disease was present in 59%, and 58% had bulky disease. Nearly half of patients (47%) had received 3 or more prior lines of therapy. Del(17p) was observed in 61% of patients, del(11q) was observed in 15%, and 77% had unmutated IGHV. The creatinine clearance rate was less than 60 mL/min in 25%. The median ß2 microglobulin level was 5.4 mg/L (range, 1.8-20.2 mg/L), and 83% of patients had a ß2 microglobulin level of at least 3.5 mg/L.
In the overall study population, the median ß2 microglobulin level decreased from 5.4 mg/L at baseline to 3.05 mg/L at 3 months (Figure 10). The median ß2 microglobulin level remained low thereafter. ß2 microglobulin levels normalized during ibrutinib treatment in half of the 312 patients who had an abnormally high ß2 microglobulin level at baseline. After a median follow-up of 41.5 months, the median time to ß2 microglobulin normalization was 17 months. The median time to ß2 microglobulin normalization was 14 months in patients with del(17p) vs 26 months in those without this deletion, but this difference was not statistically significant (P=.220). Based on multivariate analysis, a baseline ß2 microglobulin level of less than 3.5 mg/mL and a creatinine clearance rate of 60 mL/min or higher were independently associated with normalization of ß2 microglobulin at 6 months. A creatinine clearance rate of at least 60 mL/min was independently associated with ß2 microglobulin normalization at 9 months. PFS was not impacted by normalization of ß2 microglobulin levels by 6 months (HR, 0.699; 95% CI, 0.452-1.080; P=.105) At 9 months, however, PFS was significantly improved among patients with normalized levels (HR, 0.579; 95% CI, 0.366-0.915; P=.018). These results contrasted with those from a prior report showing that ß2 microglobulin status at 6 months was a prognostic factor for PFS.1
References
1. Thompson PA, O’Brien SM, Xiao L, et al. β2-microglobulin normalization within 6 months of ibrutinib-based treatment is associated with superior progression-free survival in patients with chronic lymphocytic leukemia. Cancer. 2016;122(4):565-573.
2. Wierda WG, Brown JR, Stilgenbauer S, et al. Prognostic role of beta-2 microglobulin in relapsed/refractory chronic lymphocytic leukemia patients treated with ibrutinib [ASCO abstract 7521]. J Clin Oncol. 2018;36(15 suppl).
3. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
4. O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17(10):1409-1418.
The Efficacy of Duvelisib Monotherapy Following Disease Progression on Ofatumumab Monotherapy in Patients With Relapsed/Refractory CLL or SLL in the DUO Crossover Extension Study
Duvelisib is an oral inhibitor of both PI3Kδ and PI3Kγ.1 The drug is in development for patients with relapsed or refractory CLL/SLL, as well as other hematologic malignancies. The phase 3 DUO trial (A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL) evaluated duvelisib monotherapy in patients with relapsed or refractory CLL/SLL. The study randomly assigned 319 patients to receive duvelisib (25 mg twice daily) or ofatumumab (300 mg infusion on day 1, then 2000 mg weekly for 7 treatments, then 2000 mg each month for 4 months). The study met its primary endpoint, demonstrating a significant improvement in median PFS with duvelisib (13.3 vs 9.9 months; HR, 0.52; P<.0001).2 The ORR was 74% in the duvelisib arm vs 45% in the ofatumumab arm.
Study IPI-145-12 included 89 patients from DUO who voluntarily crossed over after developing radiologically confirmed disease progression on ofatumumab.3 Duvelisib (25 mg twice daily) was administered until disease progression, death, or study withdrawal. Patients had a median age of 68 years (range, 39-90 years), and 63% were male. Patients had received a median of 3 prior therapies (range, 2-8), and 61% had received 3 or more prior lines of therapy. Del(17p) was reported in 20% of patients. The median number of years from the initial diagnosis was 7 (range, 0.5-22.0), and half of patients had Rai stage III/IV disease at the beginning of the crossover study. The median lymphocyte count at baseline was 13.96 × 109/L. The median exposure to duvelisib during the crossover study was 32 weeks.
The 89 patients who crossed over to duvelisib had an ORR of 73% (95% CI, 64%-82%), and all responses were PRs. In contrast, the ORR for the same patients during ofatumumab treatment in the DUO study was 28%. Among the 20 patients with del(17p), the ORR was 80% (95% CI, 63%-98%). PFS was significantly longer with duvelisib (15 months) compared with the prior ofatumumab treatment (9 months). Among 87 evaluable
patients, a reduction in target nodal lesions of greater than 50% was observed in 28% of patients treated with ofatumumab vs 83% of patients treated with duvelisib after crossover. The most common grade 3/4 AEs were neutropenia (22%), diarrhea (17%), colitis (9%), and pneumonia (9%). Three patients experienced severe opportunistic infections. Two patients had pneumocystis jirovecii pneumonia, including 1 patient who died and whose death was considered related to treatment with duvelisib. The other severe opportunistic infection was cytomegalovirus pneumonia.
References
1. Vangapandu HV, Jain N, Gandhi V. Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia. Expert Opin Investig Drugs. 2017;26(5):625-632.
2. Flinn IW, Hillmen P, Montillo M, et al. Results from the phase 3 DUO study of duvelisib vs ofatumumab in relapsed/refractory CLL/SLL [ASH abstract 493]. Blood. 2017;130.
3. Kuss BJ, Davids MS, Hillmen P, et al. The efficacy of duvelisib monotherapy following disease progression on ofatumumab monotherapy in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study [ASCO abstract 7533]. J Clin Oncol. 2018;36(15 suppl).
Highlights in Chronic Lymphocytic Leukemia From the 2018 American Society of Clinical Oncology Annual Meeting: Commentary
Susan M. O’Brien, MD
Studies in chronic lymphocytic leukemia (CLL) at the 2018 American Society of Clinical Oncology meeting evaluated several new management approaches for these patients. The CAPTIVATE trial (PCYC-1142; Ibrutinib Plus Venetoclax in Subjects With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma) provided important data on ibrutinib and venetoclax in the frontline setting. Other studies of venetoclax evaluated the duration of response in patients previously treated with ibrutinib or idelalisib, and how lead-in therapy can reduce the risk of tumor lysis syndrome. Studies of the novel therapies duvelisib and umbralisib showed promising results.
Ibrutinib and Venetoclax
The CAPTIVATE trial evaluated 2 small molecules, ibrutinib and venetoclax, in the frontline setting.1 Several presentations at the 2017 American Society of Hematology (ASH) meeting studied similar regimens, with or without antibodies.2,3 The CAPTIVATE trial did not include an antibody. The results were consistent with those presented at the ASH meeting. The combination of ibrutinib plus venetoclax produced very high response rates. Of even more interest, this combination produced high levels of minimal residual disease (MRD) negativity, which is exciting because it raises the possibility of finite therapy. We can presume that deep remissions will be durable in patients who are MRD-negative. This association has been confirmed in the chemotherapy setting and will likely be seen with small molecules when long-term data are available. It may therefore be possible to stop therapy in some patients.
Venetoclax After Ibrutinib or Idelalisib
Dr John Byrd and colleagues examined the durability of response to venetoclax in patients who developed relapsed/refractory disease after ibrutinib or idelalisib.4 A 2016 phase 1 trial of venetoclax published in the New England Journal of Medicine showed that venetoclax had very good response rates and durable remissions.5 However, none of the patients in this study had been treated with ibrutinib. This trial was performed predominantly in Australia and Asia, and it began before ibrutinib became available in those regions. Ibrutinib has now been available in the United States for several years, and it is a very effective drug. In current clinical practice, most of the patients who receive venetoclax were intolerant to ibrutinib or relapsed after treatment.
The study by Dr Byrd evaluated venetoclax in patients who had received treatment with ibrutinib or idelalisib. Results were recently published separately for patients previously treated with ibrutinib or idelalisib.6,7 The response rate was approximately 65% in both groups. These data are impressive because they were seen in patients who had been previously treated with multiple lines of chemotherapy, as well as small-molecule agents. In the ibrutinib group, patients had received a median of 4 prior regimens. As would be expected in a group that required treatment after chemotherapy and ibrutinib, 40% had a 17p deletion. The median progression-free survival (PFS) was 2 years, which is striking. Another interesting finding is that some patients were able to achieve MRD negativity. Among these patients, the median PFS was not reached at the time of the report. As would be expected, these deeper remissions will be even more durable.
Reducing Tumor Lysis Syndrome Associated With Venetoclax
Dr Kerry Rogers presented results of a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax, which examined whether lead-in treatment before venetoclax impacted the risk of tumor lysis syndrome.8 The treatment regimen consisted of obinutuzumab alone for the first month, followed by the addition of ibrutinib in the second month and venetoclax in the third month. In the CAPTIVATE trial, ibrutinib was given for 3 months before venetoclax. Most trials of venetoclax combination regimens include a lead-in therapy to debulk patients and decrease their risk for tumor lysis. Decreasing risk is especially important among patients at high risk. According to the package insert for venetoclax, all high-risk patients must be hospitalized during the initial dosing and then a week later during the ramp-up 50-mg dose.
The study by Dr Rogers assessed the risk for tumor lysis syndrome (based on the lymph node size and absolute lymphocyte count) with venetoclax if the patients were starting treatment with that agent, and then reassessed it after the 2-month lead-in with obinutuzumab and ibrutinib, when venetoclax was actually started. As in other trials, lead-in treatment markedly reduced the risk of tumor lysis syndrome.9 A helpful table in the package insert for venetoclax explains how to calculate whether a patient is at high, intermediate, or low risk. Importantly, the study found that lead-in treatment reduced the risk for tumor lysis syndrome among the initially high-risk population, which not only reduces risk but abrogates the need for hospitalization.
Umbralisib
A study by Dr Anthony Mato evaluated the safety and efficacy of umbralisib (TGR-1202) in patients who were intolerant to treatment with a small-molecule therapy, either ibrutinib or idelalisib.10 Umbralisib is a phosphoinositide 3-kinase (PI3K) δ inhibitor, like idelalisib, but it appears to have a much better safety profile.11 The incidences of pneumonitis, transaminitis, and colitis are markedly decreased with umbralisib as compared with idelalisib. The trial by Dr Mato showed that umbralisib was very tolerable in this setting. Once umbra-lisib is approved by the US Food and Drug Administration (FDA), it will provide a good option for patients who are intolerant to ibrutinib or idelalisib. This population is not an insignificant minority of patients.
Duvelisib
A trial from Dr Bryone Kuss evaluated duvelisib in patients with progressive disease after ofatumumab.12 This study stemmed from a randomized trial of duvelisib vs ofatumumab in relapsed CLL, known as DUO (A Phase 3 Study of Duvelisib Versus Ofatumumab in Patients With Relapsed or Refractory CLL/SLL).13 Duvelisib is different from idelalisib in that it inhibits both the δ and γ isoforms of PI3K. Idelalisib and umbralisib are both PI3Kδ inhibitors. The γ isoform may be important in T-cell lymphomas; a development program is moving forward with a clinical trial in T-cell lymphoma.14
The toxicity profile appears to be reduced with duvelisib vs idelalisib. The randomized trial was a registration trial, and it followed the design of the RESONATE trial (Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia; PCYC-1112), which led to the approval of ibrutinib.15 RESONATE compared ibrutinib vs ofatumumab in relapsed CLL, and the DUO study compared duvelisib vs ofatumumab. Presentation of the DUO data at the 2017 ASH meeting showed that the primary endpoint was met; progression-free survival was significantly better with duvelisib than ofatumumab.13 Based on this randomized trial, it is expected that duvelisib will be approved by the FDA in 2018.
The analysis presented by Dr Kuss evaluated the crossover population: patients who progressed on ofatumumab and were then treated with duvelisib.12 These patients did very well, with a median progression-free survival of approximately 17 months. Their response was similar to that of the patients treated with duvelisib initially. The approval of duvelisib will provide another option in the armamentarium of treatments for CLL.
Disclosure
Dr O’Brien is a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, and Alexion. She has received research support from Kite, Regeneron, and Acerta. She is a consultant and/or has received research support from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis.
References
1. Wierda WG, Siddiqi T, Flinn IW, et al. Phase 2 CAPTIVATE results of ibrutinib plus venetoclax in first-line chronic lymphocytic leukemia [ASCO abstract 7502]. J Clin Oncol. 2018;36(15 suppl).
2. Rogers KA, Huang Y, Stark A, et al. Initial results of the phase 2 treatment naive cohort in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax in chronic lymphocytic leukemia [ASH abstract 431]. Blood. 2017;130(suppl 1).
3. Jain N, Thompson PA, Ferrajoli A, et al. Combined venetoclax and ibrutinib for patients with previously untreated high-risk CLL, and relapsed/refractory CLL: a phase II trial [ASH abstract 429]. Blood. 2017;130(suppl 1).
4. Byrd JC, Wierda WG, Davids MS, et al. Durability of response to venetoclax in patients with CLL relapsed/refractory to ibrutinib and/or idelalisib [ASCO abstract 7512]. J Clin Oncol. 2018;36(15 suppl).
5. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322.
6. Coutre S, Choi M, Furman RR, et al. Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood. 2018;131(15):1704-1711.
7. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75.
8. Rogers KA, Huang Y, Ruppert AS, et al. Change in tumor lysis syndrome risk after lead-in treatment in a phase 1b/2 study of obinutuzumab, ibrutinib, and venetoclax for chronic lymphocytic leukemia [ASCO abstract 7528]. J Clin Oncol. 2018;36(15 suppl).
9. Kipps TJ, Wierda W, Byrd JC, et al. Tumor debulking and reduction in risk of tumor lysis syndrome with single-agent ibrutinib [Society of Hematology Oncology abstract CLL-171]. Clin Lymphoma Myeloma Leuk. 2017;17(suppl 2).
10. Mato AR, Schuster SJ, Lamanna N, et al. A phase 2 study to assess the safety and efficacy of umbralisib (TGR-1202) in pts with CLL who are intolerant to prior BTK or PI3Kδ inhibitor therapy [ASCO abstract 7530]. J Clin Oncol. 2018;36(15 suppl).
11. Davids MS, Kim HT, Nicotra A, et al. Updated results of a multicenter phase I/Ib study of TGR-1202 in combination with ibrutinib in patients with relapsed or refractory MCL or CLL [ICML abstract 040]. Hematol Oncol. 2017;35(S2).
12. Kuss BJ, Davids MS, Hillmen P, et al. The efficacy of duvelisib monotherapy following disease progression on ofatumumab monotherapy in patients with relapsed/refractory CLL or SLL in the DUO crossover extension study [ASCO abstract 7533]. J Clin Oncol. 2018;36(15 suppl).
13. Flinn IW, Hillmen P, Montillo M, et al. Results from the phase 3 DUO study of duvelisib vs ofatumumab in relapsed/refractory CLL/SLL [ASH abstract 493]. Blood. 2017;130(suppl 1).
14. Horwitz SM, Koch R, Porcu P, et al. Activity of the PI3K-δ,γ inhibitor duvelisib in a phase 1 trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-898.
15. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.