This ad hoc analysis of data from 2 clinical trials examines factors that may predict complete response in patients with chronic lymphocytic leukemia or small lymphocytic leukemia treated with ibrutinib.
Key Points
Question
What are the baseline features in patients with chronic lymphocytic leukemia that predict complete response to treatment with ibrutinib?
Findings
In this analysis of pooled data of 327 patients from 2 clinical trials, those who had chronic lymphocytic leukemia with no previous therapies (vs those with ≥1 previous therapy) and those without bulky disease (vs those with bulky disease [lymph nodes ≥5 cm]) at baseline had an increased likelihood of achieving a complete response with ibrutinib therapy.
Meaning
Patients with chronic lymphocytic leukemia who receive ibrutinib as a first-line therapy or do not have bulky disease have a better chance of complete response to this treatment.
Abstract
Importance
Ibrutinib, a first-in-class Bruton tyrosine kinase inhibitor taken once daily, is approved in the United States for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma and allows for treatment without chemotherapy. Extended treatment with ibrutinib has demonstrated increased complete response (CR) rates over time.
Objective
To analyze baseline factors that predict CR in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma treated with ibrutinib.
Design, Setting, and Participants
Univariate and multivariate analyses of pooled data from 2 clinical trials were used to assess the prognostic value of baseline factors associated with CR in 327 patients from the PCYC-1102 and PCYC-1112 studies treated with single-agent ibrutinib. Participants were followed up in academic and community medical centers in the United States, the United Kingdom, Australia, France, Italy, Ireland, Poland, Spain, and Austria.
Main Outcomes and Measures
Odds ratio (OR) of CR rate.
Results
The 327 patients included in this analysis had a median age of 67 years (range, 30-86 years) and 227 (69.4%) were male. At baseline, 185 patients (56.6%) had bulky disease (lymph node ≥5 cm), 184 (56.3%) had advanced-stage disease, and 182 (55.7%) had an Eastern Cooperative Oncology Group performance status of 1 or higher. Thirty-one patients (9.5%) were in the first-line setting; 38 (11.6%) had undergone 1 previous therapy, 81 (24.8%) had undergone 2, and 177 (54.1%) had undergone 3 or more; patients with relapsed/refractory disease had undergone a median of 3 (range, 0-12) previous therapies. Median time on study was 26.4 months (range, 0.3-55.6 months). Thirty-two of the 327 patients (9.8%) treated with ibrutinib had a CR (PCYC-1102: relapsed/refractory, 12 of 101 [11.9%]; treatment-naive, 8 of 31 [25.8%]; and PCYC-1112: 12 of 195 [6.2%]). The median time to CR for these patients was 14.7 months (range, 4.6-47.1 months). Univariate analysis of baseline factors showed that bulky disease, clinical stage, number of previous therapies, and β2-microglobulin concentration had a significant effect on the odds of CR. The final multivariate model showed that patients with no previous therapy vs patients with at least 1 previous therapy (OR, 2.65; 95% CI, 1.01-6.95; P = .047) and patients without bulky disease (lymph node <5 cm) vs those with bulky disease (lymph node ≥5 cm [OR, 4.97; 95% CI, 1.91-12.91; P = .001]) had an increased likelihood of CR.
Conclusions and Relevance
Patients receiving ibrutinib as a first-line therapy for chronic lymphocytic leukemia and those without bulky disease had a better likelihood of CR to treatment. The CR rate with continued longer-term ibrutinib treatment was higher than in previous reports.
Trial Registration
clinicaltrials.gov Identifiers: NCT01105247 and NCT01578707
Introduction
Chronic lymphocytic leukemia (CLL) follows a heterogeneous clinical course, with many patients experiencing relapse after an initial response to treatment.1 Complete response (CR) in CLL is associated with improved progression-free and overall survival for some therapies,1 and several prognostic factors can predict treatment outcomes.2 Ibrutinib, a first-in-class inhibitor of Bruton tyrosine kinase that is taken once daily, is approved in the United States for the treatment of patients with CLL/small lymphocytic lymphoma (SLL) and allows for treatment without chemotherapy. Extended treatment with ibrutinib leads to an increase in the CR rate over time.3,4,5 In 31 patients with CLL in the first-line setting who received single-agent ibrutinib, the CR rate increased from 13% at primary analysis with a median follow-up of 22.1 months (interquartile range, 18.4-23.2) to 29% with an extended follow-up of approximately 5 years.5,6 In 30 patients with relapsed/refractory (R/R) CLL treated with ibrutinib and bendamustine hydrochloride plus rituximab, the CR rate increased from 17% at primary analysis with a median follow-up of 15.8 months to 40% with longer median follow-up of 37 months.3 In the phase 3 study of bendamustine plus rituximab and ibrutinib in 289 patients with R/R CLL/SLL without del17p, the CR and CRi (CR with incomplete bone marrow recovery) rate with addition of ibrutinib was 33% vs 7.2% with bendamustine plus rituximab alone after a median follow-up of 25 months.7 The present ad hoc analysis examines baseline factors predictive of CR in patients with CLL/SLL treated with ibrutinib in clinical trials.
Methods
Univariate and multivariate analyses were performed on data from patients with treatment-naive and R/R CLL in studies PCYC-11025,8 and PCYC-11129 who received single-agent ibrutinib. Participants were followed up in academic and community medical centers in the United States, the United Kingdom, Australia, France, Italy, Ireland, Poland, Spain, and Austria. Participants in PCYC-1102 were enrolled from May 2010 through December 2012 for treatment-naive patients and from May 2010 through August 2011 for patients with relapsed/refractory disease.8 The primary objective of PCYC-1102 was safety, and the secondary objectives were preliminary efficacy and long-term safety. Participants in PCYC-1112 were enrolled from June 2012 through April 2013; the primary objective was progression-free survival of ibrutinib compared with ofatumumab by independent review committee.9 Secondary objectives included overall survival, overall response rate (ORR), patient-reported outcomes, hematologic improvement, and safety. Response rate was included among the primary or secondary end points of both studies. (The ClinicalTrials.gov trial number for PCYC-1102 is NCT01105247 and for PCYC-1112 is NCT01578707.) The present ad hoc analysis was approved by the institutional review boards of all participating sites (eAppendix in the Supplement); all participants provided written informed consent.
Complete response was confirmed according to XVI International Workshop Criteria on measurements representative of CLL (lymphocyte count, <4000/μL [to convert to ×109/L, multiply by 0.001]; no lymphadenopathy, hepatomegaly, or splenomegaly) and bone marrow confirmation.10,11 A hematologic response was defined as a platelet count greater than 100 × 103/μL (to convert to ×109/L, multiply by 1.0); absolute neutrophil count greater than 15 × 103/μL (to convert to ×109/L, multiply by 0.001); hemoglobin concentration greater than 11.0 g/dL (to convert to grams per liter, multiply by 10.0); and absolute lymphocyte count less than 4000/μL (to convert to ×109/L, multiply by 0.001), irrespective of nodal or bone marrow response. Patients with CRi (meeting CR criteria except for persistent anemia, thrombocytopenia, or neutropenia) were considered as having a CR for analysis. Complete response was confirmed only if no residual bone marrow disease was present. A logistic regression model of CR rate against each prognostic factor was fit in the univariate model. Statistical analyses performed in this study are all 2-sided. Factors with P < .10 (2-sided) were selected. A multivariate model with these selected factors was simultaneously tested in stepwise selection with an α-to-enter significance level of .1 and an α-to-remove significance level of .05. Two-sided P values were derived using the Wald χ2 test. SAS 9.3 software (SAS Institute Inc) was used for statistical analyses.
Results
Baseline Characteristics
Three hundred twenty-seven ibrutinib-treated patients were evaluated, 31 (9.5%) with CLL in the first-line setting and 296 (90.5%) with R/R CLL. Patients with R/R CLL had received a median of 3 (range, 0-12) previous therapies; 38 patients (11.6%) had 1 previous therapy, 81 patients (24.8%) had 2, and 177 patients (54.1%) had 3 or more previous therapies. Median age was 67 years (range, 30-86 years) and 227 (69.4%) were male. In all, 185 patients (56.6%) had bulky disease (lymph node ≥5 cm), 184 (56.3%) had advanced-stage disease, 182 (55.7%) had an Eastern Cooperative Oncology Group performance status12 of 1 or higher, and 194 (59.3%) had β2-microglobulin levels greater than 3.5 mg/L. Del11q was observed in 99 patients (30.3%), del17p was observed in 96 (29.4%), and unmutated IGVH (OMIM 151400) was observed in 192 (58.7%).
Efficacy Outcomes
With up to 55.6 months of follow-up and a median time on study of 26.4 months (range, 0.3-55.6 months), the overall population (N = 327) had an ORR of 89.6% from 21 months onward, including 32 patients (9.8%) with CR and a time-dependent improvement in rate of CR with continued once-daily ibrutinib therapy (Table 1 and Figure). One hundred ninety-one of 327 patients (58.4%) achieved a hematologic response. Median time to first response (including partial response with lymphocytosis) was 2.5 months (range, 0-49.9), whereas median time to CR was 14.7 months (range, 4.6-47.1 months) for those patients achieving CR. Median treatment duration for patients with CR at this long-term follow-up was 35.5 months (range, 13-55 months). At the time of analysis, there were no deaths or disease progression among the 32 patients who achieved CR. The faster time to CR and lower CR rate in PCYC-1112 are likely related to relatively shorter follow-up times, as CR and CRi rates with ibrutinib increase over time.
Table 1. CR and ORR Among Patients With Chronic Lymphocytic Leukemia Treated With Ibrutinib in 2 Clinical Trials.
| Outcome | PCYC-1102 | PCYC-1112 (n = 195) | Total (N = 327) | |
|---|---|---|---|---|
| R/R CLL Group (n = 101) | TN CLL Group (n = 31) | |||
| CR, No. (%) | 12 (11.9) | 8 (25.8) | 12 (6.2) | 32 (9.8) |
| ORR, No. (%) | 90 (89.1) | 26 (83.9) | 177 (90.8) | 293 (89.6) |
| Time on study, median (range), mo | 45.7 (0.7-55.6) | 24.8 (0.3-32.0) | 26.4 (0.3-55.6) | |
| Time to CR, median (range), mo | 28.5 (4.6-46.0) | 23.2 (7.1-47.1) | 11.0 (5.3-17.4) | 14.7 (4.6-47.1) |
| Patients continuing to receive therapy, No. (%) | 42 (41.6) | 24 (77.4) | 130 (66.7) | 196 (59.9) |
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; ORR, overall response rate; R/R, relapsed/refractory; TN, treatment-naive.
Figure. Overall Response Rate (ORR) and Complete Response (CR) Rate Over Time in 327 Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) Treated With Ibrutinib.
At up to 48 months of follow-up, patients with CLL/SLL (N = 327) had an 89.6% ORR from 21 months onward and a time-dependent improvement in CR rate with continued once-daily ibrutinib therapy. CRi indicates CR with incomplete bone marrow recovery.
Univariate and Multivariate Analyses of Prognostic Factors
In the overall patient population by univariate analysis, the odds of achieving CR were significantly increased for patients who at baseline had no bulky disease (lymph node <5 cm vs ≥5 cm), Rai stage 0 to II vs stage III to IV disease,13 no previous therapy vs 1 or more previous therapies or vs 2 or more previous therapies, and a β2-microglobulin level of 3.5 mg/L or less vs greater than 3.5 mg/L (Table 2). In the patients with R/R disease, univariate analysis showed that bulky disease (lymph node <5 cm vs ≥5 cm), number of previous therapies (0 vs ≥1 or 0 vs ≥2), and β2-microglobulin levels (≤3.5 vs >3.5 mg/L) were baseline factors that had a significant association with the odds of achieving CR.
Table 2. Univariate and Multivariate Models of Prognostic Factors for Complete Response to Ibrutinib in Patients With Chronic Lymphocytic Leukemia.
| Prognostic Factor | No. of Patients | CR, No. (%) | Baseline Factor Effect | |
|---|---|---|---|---|
| OR (95% CI) | P Valuea | |||
| Univariate Model | ||||
| Age <65 y | 128 | 11 (8.6) | 0.80 (0.37-1.71) | .56 |
| Age ≥65 y | 199 | 21 (10.6) | ||
| Male | 227 | 25 (11.0) | 1.64 (0.69-3.94) | .26 |
| Female | 100 | 7 (7.0) | ||
| ECOG PSb | ||||
| 0 | 145 | 19 (13.1) | 1.96 (0.93-4.12) | .08 |
| ≥1 | 182 | 13 (7.1) | ||
| Del11q | ||||
| No | 218 | 21 (9.6) | 1.07 (0.47-2.42) | .88 |
| Yes | 99 | 9 (9.1) | ||
| Del17p | ||||
| No | 226 | 23 (10.2) | 1.44 (0.60-3.48) | .42 |
| Yes | 96 | 7 (7.3) | ||
| IGVH | ||||
| Mutated | 67 | 4 (6.0) | 0.41 (0.14-1.21) | .10 |
| Unmutated | 192 | 26 (13.5) | ||
| Rai stage 0-II disease | 137 | 19 (13.9) | 2.31 (1.08-4.93) | .03 |
| Rai stage III or IV disease | 184 | 12 (6.5) | ||
| No bulky disease | 142 | 24 (16.9) | 4.50 (1.96-10.35) | <.001 |
| Bulky disease ≥5 cm | 185 | 8 (4.3) | ||
| Previous lines of therapyc | ||||
| 0 | 31 | 8 (25.8) | 0-1 vs 2: 1.35 (0.54-3.39) | .12 |
| 0-1 | 69 | 11 (15.9) | 0-1 vs 3: 2.72 (0.72-10.34) | .12 |
| ≥2 | 258 | 21 (8.1) | 0 vs ≥1: 3.94 (1.59-9.76) | .003 |
| ≥1 | 296 | 24 (8.1) | 0 vs ≥2: 3.93 (1.56-9.85) | .01 |
| β2-Microglobulin level, mg/L | ||||
| ≤3.5 | 113 | 18 (15.9) | 2.87 (1.33-6.22) | .007 |
| >3.5 | 194 | 12 (6.2) | ||
| Multivariate Model | ||||
| No bulky diseased | 142 | 24 (16.9) | 4.97 (1.91-12.91) | .001 |
| Bulky disease ≥5 cmd | 185 | 8 (4.3) | ||
| Prior therapies, No. | ||||
| 0 | 31 | 8 (25.8) | 2.65 (1.01-6.95) | .047 |
| ≥1 | 296 | 24 (8.1) | ||
Abbreviations: CR, complete response; del11q, deletion of chromosome 11q; del17p, deletion of chromosome 17p; ECOG PS, Eastern Cooperative Oncology Group performance status; IGVH, immunoglobulin heavy chain variable region gene; OR, odds ratio.
The P value to test the global null hypothesis β = 0 using a likelihood ratio test.
The ECOG PS ranges from 0 (fully active) to 5 (dead), with 4 meaning fully disabled.12
Coefficient (0-1, 2, and ≥3); OR, −0.53; 95% CI, −0.96 to −0.10; P = .02.
Bulky disease was defined as a lymph node of 5 cm or larger.
In the overall patient population, multivariate analysis showed that the odds of achieving a CR increased for patients who had no previous treatment (odds ratio [OR], 2.65; 95% CI, 1.01-6.95; P = .047) and lacked bulky disease (lymph node <5 cm vs ≥5 cm) (OR, 4.97; 95% CI, 1.91-12.91; P = .001; Table 2). In patients with R/R disease, multivariate analysis indicated that only having no bulky disease (lymph node <5 cm vs ≥5 cm) (OR, 4.18; 95% CI, 1.68-10.42; P = .002) at baseline was significantly associated with the odds of achieving a CR.
CR Characteristics Across Prognostic Factors
The CR rate was notably higher in patients receiving ibrutinib as their first-line treatment (8 of 31 patients [25.8%]) and those without bulky disease (24 of 142 patients [16.9%]) (Table 2). For those patients who were treatment naive and had no bulky disease, the rate of CR was 28.0% (7 of 25 patients). Factors such as del11q, del17p, and unmutated IGHV were not found to be associated with CR.
Discussion
These data show that patients without previous therapy or bulky disease at baseline have a better likelihood of attaining CR to treatment with ibrutinib. Initial responses to ibrutinib were achieved early (median, 2.5 months), with median time to CR of more than 1 year (14.7 months). Ninety percent of patients responded to therapy and demonstrated sustained response, including patients with bulky disease and those who had received previous therapy. With continued once-daily ibrutinib therapy, the depth of response increased, leading to higher CR rates than for those observed in earlier reports.5,8,14
In patients with treatment-naive or R/R CLL, attainment of CR has historically been associated with superior progression-free and overall survival outcomes with chemoimmunotherapy regimens.15 The achievement of CR with ibrutinib therapy at the time of this analysis allowed patients to remain in follow-up for a median of 26.4 months with no deaths or disease progression. Owing to the extended time observed to reach CR (Table 1), the depth of response may improve further. A better understanding of the dynamics and associated clinical attributes of CR may offer an opportunity to explore concepts, such as discontinuation of ibrutinib therapy once a depth of response is achieved.
Conclusions
Data support continued treatment with ibrutinib until disease progression is experienced or unacceptable toxic effects occur. Assessing the durability of CR with continued ibrutinib therapy and its association with long-term outcomes will require longer follow-up.
eAppendix. Institutional Review Boards That Approved the Study
References
- 1.Hallek M, Pflug N. Chronic lymphocytic leukemia. Ann Oncol. 2010;21(suppl 7):vii154-vii164. [DOI] [PubMed] [Google Scholar]
- 2.Santacruz R, Villamor N, Aymerich M, et al. The prognostic impact of minimal residual disease in patients with chronic lymphocytic leukemia requiring first-line therapy. Haematologica. 2014;99(5):873-880. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Brown JR, Barrientos JC, Barr PM, et al. The Bruton tyrosine kinase inhibitor ibrutinib with chemoimmunotherapy in patients with chronic lymphocytic leukemia. Blood. 2015;125(19):2915-2922. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.O’Brien SM, Furman RR, Coutre SE, et al. Five-year experience with single-agent ibrutinib in patients with previously untreated and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic leukemia [ASH annual meeting abstract 233]. Blood. 2016;128(22):233. [Google Scholar]
- 7.Fraser G, Cramer P, Demirkan F, et al. Ibrutinib (I) plus bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): a 2-year follow-up of the HELIOS study. J Clin Oncol. 2016;34(15)(suppl):7525. doi: 10.1200/JCO.2016.34.15_suppl.7525 [DOI] [Google Scholar]
- 8.Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. New Engl J Med. 2013;369(1):32-42. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Byrd JC, Brown JR, O’Brien S, et al. ; RESONATE Investigators . Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. New Engl J Med. 2014;371:213-223. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.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. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Hallek M, Cheson B, Catovsky D, et al. Response assessment in chronic lymphocytic leukemia treated with novel agents causing an increase in peripheral blood lymphocytes [letter]. Blood. 2012;119(23):5348. [Google Scholar]
- 12.Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. [PubMed] [Google Scholar]
- 13.Rai KR, Sawitsky A, Cronkite EP, Chanana AD, Levy RN, Pasternack BS. Clinical staging of chronic lymphocytic leukemia. Blood. 1975;46(2):219-234. [DOI] [PubMed] [Google Scholar]
- 14.Cramer P, Chanan-Khan A, Fraser G, et al. Improvement of quality of response with ibrutinib plus bendamustine/rituximab vs placebo plus bendamustine/rituximab for previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Blood. 2015;126(23):2938 http://www.bloodjournal.org/content/126/23/2938. Accessed January 7, 2018. [Google Scholar]
- 15.Thompson PA, Wierda WG. Eliminating minimal residual disease as a therapeutic end point: working toward cure for patients with CLL. Blood. 2016;127(3):279-286. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
eAppendix. Institutional Review Boards That Approved the Study