Page 118 - Haematologica Vol. 107 - September 2022

ARTICLE - iLLUMINATE: final analysis
C. Moreno et al.
(n=11/113), 10% (n=10/98), 8% (n=7/84), and 9% (n=7/74) in years 0-1, 1-2, 2-3, and 3-4, respectively; the prevalence of grade ≥3 atrial fibrillation was 4% (n=5/113), 2% (n=2/98), 0%, and 1% (n=1/74), in years 0-1, 1-2, 2-3, and 3-4, respectively. Among 17 patients with atrial fibrillation of any grade, atrial fibrillation led to discontinuation of ibrutinib in one patient (a grade 3 event).
Seven major hemorrhagic adverse events (grade 1/2 for 2 events, grade 3 for 5 events, and no grade 4/5 events) oc- curred in five (4%) patients in the ibrutinib plus obinutu- zumab arm: catheter site hematoma, ecchymosis, hematemesis, hemoptysis, post-procedural hematoma, subdural hematoma, and traumatic hematoma. Major hemorrhage led to discontinuation of ibrutinib in one pa- tient (grade 2 hemoptysis).
Over a median duration of 42 months of ibrutinib therapy, the only adverse event leading to discontinuation of ibruti- nib in more than one patient was thrombocytopenia (n=2); all other adverse events leading to discontinuation of ibrutinib occurred in only one patient each. Of these, seven and six patients discontinued during the first 6 and 12 months of treatment, respectively. Four patients each discontinued at time intervals of >12‒≤24 months, >24‒≤36 months, and >36‒≤48 months.
In the ibrutinib plus obinutuzumab arm, 17 (15%) patients experienced a total of 32 adverse events (including 18 grade ≥3 events) that led to ibrutinib dose reduction, most commonly due to neutropenia (6 [5%] patients) (Online Supplementary Figure S7). Most (28/32 [88%]) of these ad- verse events resolved or recovered with dose reduction, including 94% (17/18) of grade ≥3 events.
At the time of final analysis, 14 and three patients had died from treatment-emergent adverse events in the ibrutinib plus obinutuzumab and chlorambucil plus obinutuzumab arms, respectively (Online Supplementary Table S4). Of the five deaths that occurred in the ibrutinib plus obinutuzu- mab arm with the additional follow-up, four were due to adverse events (1 each due to respiratory tract infection, pneumonia, septic shock and one death was due to an un- known cause after the adverse event reporting period). In the chlorambucil plus obinutuzumab arm, an additional two deaths occurred since the primary analysis, after crossover to the ibrutinib plus obinutuzumab arm. One was due to sepsis, the other was due to progressive dis- ease.
Outcomes after discontinuation of ibrutinib
Thirty-eight patients discontinued ibrutinib after a median of 15.5 months (range, 0.1-43.7) of treatment for reasons other than progression or death at any time on study, 25 patients discontinued due to adverse events (Table 1). Among patients who discontinued ibrutinib for reasons other than progressive disease or death, eight patients had achieved a CR or CRi, 22 patients had PR or nPR, and
one patient had stable disease; seven patients had no op- portunity for response assessment. With a median follow- up of 17 months (range, 0.03-42) after ibrutinib discontinuation, 18-month PFS in these 38 patients who discontinued for reasons other than progression or death was 73.8% (95% CI: 55.4-85.5).
Discussion
Results from the final analysis of the iLLUMINATE study with up to 52 months of follow-up (median: 45 months) confirmed the durable efficacy of ibrutinib plus obinutu- zumab in previously untreated patients with CLL. Ibrutinib plus obinutuzumab resulted in sustained PFS compared to chlorambucil plus obinutuzumab, with median PFS not reached after a median follow-up of 45 months and the risk of disease progression or death reduced by 75%. No- tably, durable PFS was also seen in the high-risk patient population (i.e., with del[17p], TP53 mutation, del[11q], or unmutated IGHV) treated with ibrutinib plus obinutuzu- mab, confirming earlier observations from the primary analysis of iLLUMINATE.3 At 42 months, the PFS estimates among patients with del(17p), TP53, unmutated IGHV or del(11q) mutations were significantly higher in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obi- nutuzumab arm. Importantly, the benefit in PFS was ob- served regardless of high-risk features.3 A similar benefit was observed in the CLL14 trial for the venetoclax plus obinutuzumab regimen in patients with unmutated and mutated IGHV.12 These results support current global con- sensus guidelines,13,14 noting ibrutinib as a preferred thera- peutic regimen for older patients and/or those with comorbidities regardless of the presence of del(17p)/TP53 mutations and unmutated CLL. The follow-up for other, similarly recommended novel treatment options is more limited.
With this extended follow-up, as has been observed con- sistently across several large, randomized phase III studies of ibrutinib in previously untreated15 and relapsed/refrac- tory patients with CLL/SLL,16,17 highly durable PFS and OS have been confirmed even in patients with high-risk dis- ease characteristics.
In line with the results of the iLLUMINATE trial, other phase III studies have also reported the superiority of ibrutinib-based regimens over chemoimmunotherapy in the first-line treatment of CLL. Concurrently, in the phase III ALLIANCE 041202 study in patients with CLL aged ≥65 years (median follow-up: 38 months), first-line single- agent ibrutinib or ibrutinib plus rituximab significantly prolonged PFS compared with bendamustine plus rituxi- mab; estimated 2-year PFS rates were 87% and 88% ver- sus 74%, respectively.6 In patients aged ≤70 years, the phase III ECOG1912 study (median follow-up: 34 months)
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