Time to next treatment in patients with chronic lymphocytic leukemia initiating first-line ibrutinib or acalabrutinib.

Aim: To investigate real-world time to next treatment in patients with chronic lymphocytic leukemia initiating first-line (1L) ibrutinib or acalabrutinib. Materials & methods: US specialty pharmacy electronic medical records (21/11/2018-30/4/2022) were used; patients initiated 1L on/after 21/11/2019 (acalabrutinib approval). Results: Among 710 patients receiving ibrutinib, 5.9% initiated next treatment (mean time to initiation = 9.2 months); among 373 patients receiving acalabrutinib, 7.5% initiated next treatment (mean time to initiation = 5.9 months). Adjusting for baseline characteristics, acalabrutinib-treated patients were 89% more likely to initiate next treatment (hazard ratio = 1.89; p = 0.016). Conclusion: This study addresses a need for real-world comparative effectiveness between 1L ibrutinib and acalabrutinib and shows that next treatment (a clinically meaningful measure for real-world progression) occurred less frequently with 1L ibrutinib.

Ibrutinib and acalabrutinib are oral medications taken once-daily and twice-daily, respectively. They are recommended as initial treatment for chronic lymphocytic leukemia (CLL). The goal of this study was to compare the efficacy of these treatments as initial treatment for CLL. To meet this goal, real-world US specialty pharmacy electronic medical records between 11/21/2018­4/30/2022 were used. Patients treated with ibrutinib or acalabrutinib as initial treatment for CLL were studied. Treatment had to be started on or after the date of acalabrutinib approval for CLL (11/21/2019). Time to next treatment was used to estimate real-world disease progression. It was defined as the time from the initiation of initial treatment with ibrutinib or acalabrutinib to the initiation of a next treatment. Study results showed that patients were observed for a median of up to 1.5 years. Over this period, next treatment was more likely for acalabrutinib (7.5%) compared with ibrutinib (5.9%). After adjusting for differences in patient characteristics, next treatment was 89% more likely with acalabrutinib than ibrutinib. This study addresses a need to compare the effectiveness of initial treatment with ibrutinib and acalabrutinib in the real-world. It helps better contextualize results from clinical trial data and shows that next treatment occurred less frequently with ibrutinib.

Treatment-free remission after dasatinib in patients with chronic myeloid leukaemia in chronic phase with deep molecular response: Final 5-year analysis of DASFREE.

Patients with chronic myeloid leukaemia in chronic phase (CML-CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment-free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2-year TFR rate after dasatinib discontinuation was 46%; here we present the 5-year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow-up of 60 months, in 84 patients discontinuing dasatinib, the 5-year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off-treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5-year final follow-up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long-term option in patients with CML-CP. The safety profile is consistent with the previous report.

Dasatinib discontinuation in patients with chronic-phase chronic myeloid leukemia and stable deep molecular response: the DASFREE study.

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p = .0051), line of therapy (first line; p = .0138), and age (>65 years; p = .0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond.

Benefits and risks of ponatinib versus bosutinib following treatment failure of two prior tyrosine kinase inhibitors in patients with chronic phase chronic myeloid leukemia: a matching-adjusted indirect comparison.

OBJECTIVE: Comparing the benefit-risk profiles of ponatinib vs. bosutinib in third-line (3L) treatment of chronic phase chronic myeloid leukemia (CP-CML) is challenging because their pivotal trials lacked comparator arms. To characterize the overall benefit-risk profile in 3L CP-CML patients treated with bosutinib vs. ponatinib, a matching-adjusted indirect comparison (MAIC) was performed to compare efficacy outcomes and treatment duration after adjusting for trial subjects' baseline characteristics, and tolerability was assessed with an unadjusted comparison of study-drug discontinuation. METHODS: The MAIC was performed using published data from the pivotal bosutinib trial and the most recent individual-patient-level data on file from the pivotal ponatinib trial. RESULTS: Responses were more frequent and durable with ponatinib (n = 70 MAIC-adjusted) than with bosutinib (n = 119) - complete cytogenetic response (CCyR): 61% vs. 26%; Kaplan-Meier estimate of maintaining CCyR at 4 years: 89% vs. 54%. Median treatment duration was longer with ponatinib than with bosutinib: 38.4 vs. 8.6 months. Only 9% of ponatinib patients (n = 97 unadjusted) vs. 42% of bosutinib patients discontinued due to death, disease progression or unsatisfactory response; 19% vs. 24% discontinued due to adverse events. CONCLUSIONS: Based on these surrogate measures of patient benefit-risk profiles, ponatinib appears to provide a net overall benefit vs. bosutinib in 3L CP-CML.

An Expanded Treatment Protocol of Panobinostat Plus Bortezomib and Dexamethasone in Patients With Previously Treated Myeloma.

BACKGROUND: Panobinostat was recently approved by the US Food and Drug Administration and European Commission in combination with bortezomib and dexamethasone for patients with multiple myeloma who have received ≥ 2 regimens, including bortezomib and an immunomodulatory drug. The PANEX (panobinostat expansion) treatment protocol provided access to panobinostat and gathered additional safety data before commercial availability. PATIENTS AND METHODS: In treatment phase 1, patients received panobinostat 20 mg 3 times per week plus bortezomib 1.3 mg/m2 twice weekly with dexamethasone 20 mg on the days of and after bortezomib treatment. Patients with no change or better in treatment phase 1 proceeded to treatment phase 2, when bortezomib was reduced to once weekly. Unlike in the phase III trial, PANORAMA-1 (panobinostat or placebo with bortezomib and dexamethasone in patients with relapsed multiple myeloma), bortezomib could be administered either subcutaneously or intravenously. RESULTS: Thirty-nine patients with a median number of previous treatments of 4 (range, 1-12) were enrolled; most received subcutaneous bortezomib (87%). The overall response rate (partial response or better) was 56%. Grade 3/4 adverse events included thrombocytopenia (47%), fatigue (31%), dehydration (26%), and diarrhea (18%). Among the patients who received subcutaneous bortezomib, relatively low rates of peripheral neuropathy (all grade, 15%) and notable grade 3/4 adverse events (thrombocytopenia, 47%; diarrhea, 12%) were observed. CONCLUSION: Overall, data from the PANEX trial support regulatory approval of panobinostat plus bortezomib and dexamethasone and suggest the potential tolerability benefits of subcutaneous bortezomib in this regimen.

Cyclophosphamide unmasks an antimetastatic effect of local tumor cryoablation.

Cryoablation of a solitary tumor mass releases intact tumor antigens and can induce protective antitumor immunity but has limited efficacy in the treatment of established metastatic cancer. Cyclophosphamide (Cy), an anticancer drug, selectively depletes regulatory T cells (T(reg)s) and attenuates suppression of antitumor immunity. We used a BALB/c mouse model of metastatic colon cancer to investigate the systemic antitumor effects of in situ cryotherapy alone or in combination with 200 mg/kg i.p. Cy. When combined with Cy, cryoablation was significantly more effective than either surgical excision or cautery at inducing systemic antitumor immunity, resulting in the cure of a fraction of animals with established metastatic disease and resistance to tumor rechallenge. Lymphocytes from cured animals contained an expanded population of tumor-specific, interferon-gamma producing T cells and transferred antitumor immunity to naive recipients. Depletion of CD8(+) cells significantly impaired the adoptive transfer of antitumor immunity. Furthermore, treatment with Cy and cryoablation was associated with a significant decrease in the ratio of regulatory to effector CD4(+) T cells. The combination of tumor cryoablation and Cy induces potent, systemic antitumor immunity in animals with established metastatic disease.