ASH 2018 | Late CAR-T effects in R/R NHL and CLL patients

On Saturday 1 December 2018, Oral Session 626 took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session, Abstract #223 was presented by Ana Cordeiro from the Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

The investigator presented data on the long-term safety of CD19 CAR-T infusion in relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) patients (NCT01865617). These results provide important information on the late effects of the recently approved CAR-T therapies in NHL and CLL.

Study design and baseline characteristics

• N = 60 R/R NHL (n = 43; 71%) and CLL (n = 17; 29%) patients
• Patients included in the study:
  • Survived more than a year
  • Had at least one-year follow-up data after the first infusion
• Median age at CAR-T infusion (range): 60 (34−73) years
• Median number of prior lines (range): 4(1−8)
• Twenty-four patients had received prior autologous stem cell transplantation (ASCT) and nine received allogeneic SCT (allo-SCT)
• Thirty-five patients (59%) received one CD19 CAR-T infusion and n = 22 (37%) received two infusions and n = 2 (3%) patients received three infusions
  • n = 3 (5%) patients received a maximum cell dose of 2 x 10⁵/kg
  • n = 40 (68%) patients received a maximum dose of 2 x 10⁶/kg
  • n = 16 (27%) patients received a maximum dose of 2 x 10⁷/kg
• Median follow-up (range): 25 (12.6−62.6) months

Results

• At two months after the CAR-T infusion:
  • Complete response (CR) was achieved by n = 29 (48%) patients
  • Partial response (PR) was achieved by n = 21 (35%) patients
  • Disease progression (PD) occurred in n = 6 (10%) patients
  • Stable disease (SD) was observed in n = 4 (7%) patients
• During the follow-up period:
  • PD was observed in 25% of patients
    • n = 29 (49%) received salvage therapy
    • n = 8 (14%) received allo-SCT
  • Seventy-eight percent of the patients were alive

Safety

• All reported adverse events (AEs) occurred or persisted 90 days after the last CAR-T infusion
• n = 65 (76%) infusions were followed with cyclophosphamide and fludarabine
• Cytokine release syndrome (CRS) Grade 1/2 occurred in n = 38 (63%) patients
• CRS Grade 3 occurred in n = 4 (7%) patients
• No Grade 4 CRS was reported
• Acute neurotoxicity (NT) occurred in n = 20 (34%) patients
• Five out of 25 (20%) patients who did not receive additional therapy after last CAR-T cell infusion experienced ongoing cytopenia requiring additional managment beyond 90 days after infusion
• Patients diagnosed with subsequent malignancies (n = 8 [14%]):
  • Myelodysplasia: n = 3 (5%)
  • Non-melanoma skin cancer: n = 4 (7%)
  • Non-invasive bladder cancer: n = 1
• Neuropsychiatric disorders were documented in n = 5 (8%) patients:
  • Major depression
  • Suicidal attempt
  • Myoclonic seizures
  • Transient ischemic attack
• Cardiovascular events occurred in n = 5 (8%) patients, renal dysfunction in n = 4 (7%) and respiratory disorders in n = 3 (5%) patients
• One patient had gastrointestinal bleeding
• Of the patients who had undergone allo-SCT, one (11%) developed graft-versus-host disease (GvHD) flare
• Severe hypogammaglobulinemia (IgG < 400 mg/dL) or IgG replacement beyond day 90 after last CAR-T cell infusion (and before SCT if applicable) were documented in n = 29 (60%) patients
• Out of 54 patients who were included in the infection analysis, infections were observed in n = 40 (74%) patients, with the following most common occurrences:
  • Upper respiratory infections (51%)
  • Lower respiratory infections (26%)
• Hospitalization due to infection was required in 20% of the cases, with 2% being admitted to the intensive care unit (ICU)
• Three patients died of non-relapse causes
  • n = 2 due to infection after allo-SCT
  • n = 1 due to duodenal ulcer and gut perforation

Conclusions

• The majority of late events were mild and could have been related to prior or subsequent therapies
• CD19 CAR-T were relatively well tolerated in this study
• Further systematic follow-up is needed to understand the potential long-term effects of CAR-T therapy