Curing CLL: Long-Term Outcomes of Chronic Lymphocytic Leukemia Patients with at Least One Year of Response to CART-19 Therapy

Background: While outcomes have improved, relapsed or refractory chronic lymphocytic leukemia (R/R CLL) remains incurable with standard therapies and has a poor prognosis. We and others have reported remarkably durable responses to chimeric antigen receptor T cell (CART) therapy, with several patients remaining disease free without additional treatment for over 10 years (Nature 2022 Feb: 503-9). However, long-term outcomes after CART cells are available for a limited number of patients. Here, with a median follow-up of over 6.5 years, we report long-term outcomes of a large cohort of R/R CLL patients treated in two clinical trials of CART therapy.

Methods: Treatment protocols were previously published (J Clin Oncol. 202 Sep:2862-71; Blood Adv. 2022 Nov:5774-85). Briefly, patients on NCT01747486 (n=38) had R/R CLL with at least two prior treatments and received murine anti-human CD19 directed CART monotherapy. Patients on NCT02640209 (n = 19) had R/R CLL with at least one prior treatment and at least six months of ibrutinib, which was continued during and after human anti-human CD19 directed CART infusion. We conducted a landmark analysis of the 31 patients from these trials (14 from NCT01747486, 17 from NCT02640209) who had achieved at least partial response without progression at one year. Endpoints included overall survival (OS) and progression free survival (PFS), and we evaluated the association between these endpoints and complete response (CR; iwCLL) achieved within the first year of treatment.

Results: The median age at infusion was 62 (range 42 -78) years. Patients had received a median of 3 (range 1-17) prior lines of therapy, and 28 (90.3 %) patients had an adverse cytologic or molecular marker. The median bone marrow CLL burden was 30% (range 1-90%) prior to starting CART-19.

The median follow-up after infusion was 9.1 (range 1.2-13.4) years for patients treated with CART-19 alone, 6.1 (range 1.4-7.3) years for patients treated with concurrent ibrutinib, and 6.5 (range 1.2-13.4) years across all patients. At five years post-infusion, the PFS rate for patients who achieved one year of PR or better was 57.1% (95% CI 22.0-92.3) after CART-19 alone and 64.7% (95% CI 37.2-92.2%) with concurrent ibrutinib. Overall survival (OS) for these patients at five years post-infusion was 78.6% (95% CI 53.9%-100%) after CART-19 alone and 70.6% (95% CI 44.8-96.4%) with concurrent ibrutinib. Median PFS and OS were not reached for either group. Causes of death included CLL (n = 1), infection (n = 2), or new primary malignancy (n = 1). In total, 24 of 31 patients (77.4%) who reached one year without disease progression remained progression free at time of last follow-up, including 19 of 24 patients (79.1%) with follow-up >5 years. No relapses were observed in patients who were progression free at 4 years.

Of the 31 patients, 22 (71%) were in CR and 9 had less than a CR (29%) in the first year after infusion. Both OS and PFS were significantly higher for patients with CR than patients with less than CR (p = 0.014 and p = 0.046 respectively).

Hypogammaglobulinemia was common, with 28 patients (90.3%) receiving IVIG at least once, and 20 patients (64.5%) receiving monthly IVIG at time of last follow-up. B cells constituted <1% of total WBCs in 16 of 22 patients (72.7%) who had peripheral blood flow cytometry at least one year after infusion (range 1.02-10.7 years), suggestive of functional CART-19 persistence.

Of the 17 patients treated with concurrent ibrutinib, 11 (64.7%) discontinued ibrutinib while in clinical remission, 10 (91%) of whom remained in remission without further treatment. The median time to ibrutinib discontinuation was 1.2 (range 0.4-5.5) years after CART-19 infusion. Four patients (23.5%) remained on ibrutinib at time of last follow up, and two patients (11.85%) were transitioned to a different BTKi due to suspected side effects of ibrutinib (atrial fibrillation and joint pains).

Conclusion: We report long-term follow-up on a large cohort of CLL patients treated with CART-19. Most patients who reach one year of PFS after infusion remain progression free for more than 5 years without further treatment. Achieving CR within one year of infusion is associated with improved long-term PFS and OS, which underscores the significance of this benchmark. Despite the poor prognosis of these patients at time of treatment, these long-term follow-up data suggest a significant subset of patients have been cured of R/R CLL with CART-19.