ASH 2018 | CAR-T and ibrutinib combination for the treatment of R/R CLL

On Sunday 2 December 2018, Oral Session 642 took place at the 60^th American Society of Hematology (ASH) Annual Meeting, San Diego, CA. During that session, two different studies were presented that investigated the efficacy and safety of CAR-T therapy in combination with ibrutinib in chronic lymphocytic leukemia (CLL) patients. Abstract #298 was presented by Saar Gill from the University of Pennsylvania (UPenn), PA, USA. Abstract #299 was presented by Jordan Gauthier from the Fred Hutchinson Cancer Research Center (FHCRC), WA, USA.

Both the pilot UPenn trial and the phase I/II FHCRC study, administered CD19 CAR-T cells in relapsed or refractory (R/R) CLL patients with or without concomitant ibrutinib treatment. The primary endpoints of both studies were efficacy and safety.

Study designs & baseline characteristics

UPenn study

• N = 19 R/R CLL and small lymphocytic lymphoma (SLL) patients in partial response (PR) or stable disease (SD) on ibrutinib (at least six months of ibrutinib monotherapy before CAR-T infusion)
• CTL119 CAR-T cells at a target dose of 1−5 x 10⁸ cells/kg (10%, 30% and 60% of the target dose over 3 days)
• All patients received at least 2 CTL119 doses; 14 patients received all 3 and 5 received 2 doses
• Median number of CART cells given (range): 5.3 x 10⁶ (2.0−5) cells/kg
• Median patient age (range): 62 (42−76) years
• Median number of prior lines (range): 2 (1−16)
• Three patients had received prior CTL019 CAR-T infusion without ibrutinib

FHCRC study

• N = 43 R/R CLL patients after prior failure of ibrutinib monotherapy received CAR-T infusion
• Single JCAR014 CAR-T cell infusion at three different dose levels (DL):
  • DL1: 2 x 10⁵ cells/kg
  • DL2: 2 x 10⁶ cells/kg
  • DL3: 2 x 10⁷ cells/kg
• Nineteen out of 43 patients were concomitantly treated with ibrutinib (420 mg daily) from at least 3 weeks prior to leukapheresis to minimum 3 months after CAR-T infusion
• Lymphodepletion regimen: fludarabine and cyclophosphamide
• In the CAR-T + ibrutinib arm the median number of prior lines was 5 (range, 4−7)

Key results

UPenn study

• As of July 2018, n = 18 out of 19 patients were alive (95%)
• Median follow-up (range): 18.5 (8−28) months
• At month 3 post infusion, per iwCLL criteria:
  • Complete response (CR) was achieved in n = 6 out of 14 evaluable patients (43%)
  • PR was achieved by n = 4 out of 14 evaluable patients (29%)
  • Stable disease was observed in n = 3 out of 14 evaluable patients (17%)
• At month 12 post infusion, per iwCLL criteria:
  • CR was sustained in n = 2 out of 7 evaluable patients (29%)
  • PR was achieved by n = 5 out of 7 evaluable patients (71%)
  • SD was not observed in any of the evaluable patients at this time point

FHCRC study

• Median follow-up: 98 days (CAR-T + ibrutinib arm)
• In the CAR-T + ibrutinib arm, at 4 weeks post infusion and per iwCLL criteria:
  • CR, CRi and PR was achieved by n = 15 out of 18 evaluable patients (83%)
• Better CD4⁺ CAR-T cell expansion was observed in the CAR-T + ibrutinib group than the patients infused with CAR-T cells alone (P = 0.03)
• The CAR-T + ibrutinib cohort was associated with a higher probability of response by iwCLL criteria

Safety

UPenn study

• Eighteen out of 19 patients (95%) experienced cytokine release syndrome (CRS) of any grade:
  • Grade 1−2 CRS: n = 15
  • Grade 3−4 CRS: n = 3
  • Grade 5 CRS: none
• Two patients received tocilizumab for CRS management
• CAR-T related encephalopathy syndrome (CRES) of any grade developed in five out of 19 patients (26%):
  • Grade 1 CRES: n = 2
  • Grade 2 CRES: n = 2
  • Grade 3 CRES: none
  • Grade 4 CRES: n = 1
• One patient died on Day 14 from cardiac arrhythmia during severe neurotoxicity after CRS resolution
• Six patients discontinued ibrutinib at a median of 8 months (range, 3−12) due to toxicity (n = 2) or patient choice (n = 4)

FHCRC study

• In the CAR-T + ibrutinib arm, 14 out of 19 patients (74%) experienced CRS of any grade:
  • CRS Grade ≥ 3: none
• Neurotoxicity (NT) of any grade developed in 6 out of 19 patients (32%):
  • NT Grade ≥ 3: n = 5 (26%)
  • NT Grade 5: n = 1 (presumed ibrutinib-related cardiac arrhythmia)
• Concurrent ibrutinib administration did not affect NT frequency or severity
• Lower rates of CRS Grade ≥ 3 were seen in the CAR-T + ibrutinib arm compared to the CAR-T group (P = 0.03)
• Ibrutinib was reduced or discontinued in six patients (35%) at a median of 21 days after CAR-T infusion

Conclusions

These preliminary results from both studies indicate that concurrent ibrutinib and CAR-T infusion:

• Is feasible and tolerable for most R/R CLL patients
• Induced high response rates in R/R CLL patients
• Led to reduced rates of severe CRS in the FHCRC study
• CRS was common but mostly of mild/moderate grade
• Is a promising combination regimen for the treatment of R/R CLL and potentially SLL patients