Select Abstracts on Chronic Lymphocytic Leukemia (CLL)
ASH 2014 Abstract 330. Second Interim Analysis of a Phase 3 Study of Idelalisib (ZYDELIG®) Plus Rituximab (R) for Relapsed Chronic Lymphocytic Leukemia (CLL): Efficacy Analysis in Patient Subpopulations with Del(17p) and Other Adverse Prognostic Factors
Jeff P. Sharman, MD et al.
Background: There is high unmet need in frail pts with relapsed CLL, particularly in those characterized by adverse prognostic factors such as presence of del(17p) and/or TP53 mutations. Idelalisib is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kd recently approved for the treatment of relapsed CLL in combination with R. This report describes results from the 2nd interim analysis (IA) of a Phase 3 study evaluating IDELA in combination with R in relapsed CLL with focus on various risk subgroups of pts.
Results: 220 pts (110/group) with median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1‑12) were randomized. 43% had del(17p)/TP53 mutation and 84% hadunmutated IGHV. At the time of data cut‑off, the median (range) exposure was 5 (0-17) mos on IDELA+R and 4 (0-15) mos on PBO+R. 76% of pts on IDELA+R and 46% of pts on PBO+R were continuing on study. Median PFS was not reached for pts on IDELA+R and was 5.5 mos for pts on the comparator arm. At 12 months, the PFS rates for pts on IDELA treatment was 66% compared to 13% for pts on PBO+R. PFS strongly favored IDELA+R in all risk‑subgroups, including those with genetic risk factors such as del(17p)/TP53 mutations, del(11q) (FIGURE 1) orunmutated IGHV as well as with disease-related risk factors like advance Rai stage or high levels of β2-microglobulin. Adverse events (any Gr/Gr ≥3) occurring in ≥20% of pts on IDELA treatment were: pyrexia (IDELA+R 35%/3%; PBO+R 17%/1%), fatigue (IDELA+R 28%/3%; PBO+R 27%/2%), nausea (IDELA+R 26%/0%; PBO+R 21/0%), chills (IDELA+R 21%/2%; PBO+R 16%/0%), diarrhea/colitis (IDELA+R 21%/5%; PBO+R 15%/0%). ALT/AST elevation (any Gr/Gr ≥3) occurred in 40%/8% of pts on IDELA+R and in 20%/1% of pts on PBO+R. At the time of this analysis, 19 total deaths had occurred on the primary study: 6 on IDELA+R and 13 on PBO+R.
TABLE 1: Summary of efficacy in various risk subgroups, and safety.
a) Number of patients on both arms evaluable at the time of analysis
b) Number of patients on both arms with respective test result. Note: Distribution of risk features on both arms was balanced.
c) Includes 16 preferred terms
FIGURE 1: KM estimates of PFS in pts with del(17p) or TP53mutation or del(11q) vs pts without any of these factors. IDELA+R without these risk factors: median PFS 12.1 mos (74% at 12 mos); IDELA+R with these risk factors: median PFS not reached (62% at 12 mos); PBO+R without these risk factors: median PFS 8.2 mos (19% at 12 mos); and PBO+R with these risk factors: median PFS 4 mos (8% at 12 mos). Curve comparison: Pts with these risk factors: HR = 0.16 (95% CI: 0.08, 0.32); Pts without these risk factors: HR = 0.24 (95% CI: 0.09, 0.66).
Conclusions: IDELA+R demonstrated statistically significant improvement over PBO+R in PFS, ORR, and OS with an acceptable safety profile in these frail pts with relapsed CLL. These results confirm the 1st interim analysis of comparable efficacy of IDELA+R across all risk groups, including those with high-risk genomic markers like del(17p), TP53mutations, and del(11q).
ASH 2014 Abstract 327. Efficacy and Safety of Ibrutinib in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Leukemia with 17p Deletion: Results from the Phase II RESONATE™-17 Trial
Susan O'Brien, MD et al.
Background: Patients with chronic lymphocytic leukemia (CLL) with deletion of the short arm of chromosome 17 (del 17p) follow an aggressive clinical course and demonstrate a median survival of less than 2 years in the relapsed/refractory (R/R) setting. Ibrutinib (ImbruvicaTM), a first-in-class Bruton's tyrosine kinase (BTK) inhibitor, has been approved for previously treated patients with CLL and for patients with del 17p CLL. We report results from the primary analysis of the Phase II RESONATETM-17 (PCYC-1117-CA) study, designed to evaluate the efficacy and safety of single-agent ibrutinib for treatment of patients with R/R del 17p CLL or small lymphocytic leukemia (SLL).
Results: Among 144 treated patients (137 with CLL, 7 with SLL), the median age was 64 (48% 65 years or older) and all had del 17p. Baseline characteristics included 63% of patients with Rai Stage III or IV disease, 49% with bulky lymphadenopathy of at least 5 cm, and 10% with lymphadenopathy of least 10 cm. The median baseline absolute lymphocyte count (ALC) was 32.9 x 109/L with 57% of patients with a baseline ALC at least 25.0 x 109/L. Baseline beta-2 microglobulin levels were at least 3.5 mg/L in 78% of patients (range 1.8-19.8 mg/L), and lactate dehydrogenase levels were at least 350 U/L in 24% of patients (range 127-1979 U/L). A median of 2 prior therapies (range 1-7) was reported. Investigator-assessed ORR was 82.6% including 17.4% partial response with lymphocytosis (PR-L). Complete response (CR)/complete response with incomplete bone marrow recovery (CRi) were reported in 3 patients. IRC-assessed ORR is pending. At a median follow up of 13.0 months (range 0.5-16.7 months), the median PFS (Figure 1) and DOR by investigator determination had not been reached. At 12 months, 79.3% were alive and progression-free, and 88.3% of responders were progression-free. Progressive disease was reported in 20 patients (13.9%). Richter transformation was reported in 11 of these patients (7.6%), 7 of the cases occurring within the first 24 weeks of treatment. Prolymphocytic leukemia was reported in 1 patient. The most frequently reported adverse events (AE) of any grade were diarrhea (36%; 2% Grade 3-4), fatigue (30%; 1% Grade 3-4), cough (24%; 1% Grade 3-4), and arthralgia (22%; 1% Grade 3-4). Atrial fibrillation of any grade was reported in 11 patients (7.6%; 3.5% Grade 3-4). Seven patients reported basal or squamous cell skin cancer and 1 patient had plasma cell myeloma. Most frequently reported Grade 3-4 AEs were neutropenia (14%), anemia (8%), pneumonia (8%), and hypertension (8%). Major hemorrhage was reported in 7 patients (4.9%, all Grade 2 or 3). Study treatment was discontinued in 16 patients (11.1%) due to AEs with 8 eventually having fatal events (pneumonia, sepsis, myocardial or renal infarction, health deterioration). At the time of data cut, the median treatment duration was 11.1 months, and 101 of 144 patients (70%) continued treatment with ibrutinib.
Conclusions: In the largest prospective trial dedicated to the study of del 17p CLL/SLL, ibrutinib demonstrated marked efficacy in terms of ORR, DOR, and PFS, with a favorable risk-benefit profile. At a median follow up of 13 months, the median DOR had not yet been reached; 79.3% of patients remained progression-free at 12 months, consistent with efficacy observed in earlier studies (Byrd, NEJM 2013;369:32-42). The PFS in this previously treated population compares favorably to that of treatment-naïve del 17p CLL patients receiving fludarabine, cyclophosphamide, and rituximab (FCR) (Hallek, Lancet 2010;376:1164-74) or alemtuzumab (Hillmen, J Clin Oncol 2007;10:5616-23) with median PFS of 11 months. The AEs are consistent with those previously reported for ibrutinib (Byrd, NEJM 2014;371:213-23). These results support ibrutinib as an effective therapy for patients with del 17p CLL/SLL.
CARE Faculty Canadian Perspective:
Idelalisib and Ibrutinib are clearly important drugs in the management of relapsed/refractory CLL. In these updates of previously presented studies, it is encouraging to see that preliminary results continue to have durable findings with additional follow-up.
The randomized Idelalisib study demonstrated improved OS and PFS for the Idelalsib+Rituximab arm over rituximab and placebo and these results extend to the high risk, 17p- population with the median PFS for this subgroup not yet reached which is similar to the other prognostic subgroups. Similarly, the Ibrutinib phase 2 data reports a 1 year PFS of approximately 80% at 12 months which is encouraging data in the 17p- population.
The value of Ibrutinib and Idelalisib is clear in patients with high risk CLL. Hopefully these agents will be broadly available to Canadian patients soon who remain in need of treatment options in this disease.