Minimal Residual Disease Status Predicts Outcome in Patients With Previously Untreated Follicular Lymphoma: A Prospective Analysis of the Phase III GALLIUM Study.

PURPOSE: We report an analysis of minimal residual/detectable disease (MRD) as a predictor of outcome in previously untreated patients with follicular lymphoma (FL) from the randomized, multicenter GALLIUM (ClinicalTrials.gov identifier: NCT01332968) trial. PATIENTS AND METHODS: Patients received induction with obinutuzumab (G) or rituximab (R) plus bendamustine, or cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or cyclophosphamide, vincristine, prednisone (CVP) chemotherapy, followed by maintenance with the same antibody in responders. MRD status was assessed at predefined time points (mid-induction [MI], end of induction [EOI], and at 4-6 monthly intervals during maintenance and follow-up). Patients with evaluable biomarker data at diagnosis were included in the survival analysis. RESULTS: MRD positivity was associated with inferior progression-free survival (PFS) at MI (hazard ratio [HR], 3.03 [95% CI, 2.07 to 4.45]; P < .0001) and EOI (HR, 2.25 [95% CI, 1.53 to 3.32]; P < .0001). MRD response was higher after G- versus R-chemotherapy at MI (94.2% v 88.9%; P = .013) and at EOI (93.1% v 86.7%; P = .0077). Late responders (MI-positive/EOI-negative) had a significantly poorer PFS than early responders (MI-negative/EOI-negative; HR, 3.11 [95% CI, 1.75 to 5.52]; P = .00011). The smallest proportion of MRD positivity was observed in patients receiving bendamustine at MI (4.8% v 16.0% in those receiving CHOP; P < .0001). G appeared to compensate for less effective chemotherapy regimens, with similar MRD response rates observed across the G-chemo groups. During the maintenance period, more patients treated with R than with G were MRD-positive (R-CHOP, 20.7% v G-CHOP, 7.0%; R-CVP, 21.7% v G-CVP, 9.4%). Throughout maintenance, MRD positivity was associated with clinical relapse. CONCLUSION: MRD status can determine outcome after induction and during maintenance, and MRD negativity is a prerequisite for long-term disease control in FL. The higher MRD responses after G- versus R-based treatment confirm more effective tumor cell clearance.

Ibrutinib and rituximab versus fludarabine, cyclophosphamide, and rituximab for patients with previously untreated chronic lymphocytic leukaemia (FLAIR): interim analysis of a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival. METHODS: This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m2 on day 1 of cycle 1 and at 500 mg/m2 on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m2 per day orally on day 1-5, cyclophosphamide 150 mg/m2 per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete. FINDINGS: Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0·44 [95% CI 0·32-0·60]; p<0·0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group. INTERPRETATION: Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder. FUNDING: Cancer Research UK and Janssen.

Haematopoietic stem cell transplantation for acquired aplastic anaemia.

PURPOSE OF REVIEW: Survival outcomes from haematopoietic stem cell transplantation (HSCT) in severe aplastic anaemia (SAA) have improved steadily over the past decades, largely reflecting progress in supportive care and conditioning regimens. Here we review recently published data that highlight the improvements and current issues. RECENT FINDINGS: Human leukocyte antigen (HLA)-matched sibling donor (MSD) HSCT remains the gold standard for SAA patients younger than 40-50 years, with HLA-matched unrelated donor (MUD) HSCT for second line after failure to respond to immunosuppressive therapy (IST). The use of alternative donor sources for aplastic anaemia patients remains limited and problematic, but novel conditioning regimens, particularly in the haploidentical setting, justify further evaluation. In recent studies when comparing alemtuzumab-based conditioning with standard antithymocyte globulin conditioning regimens, lower rates of acute and chronic graft-versus-host disease and better tolerance in older patients are seen. SUMMARY: Improving outcomes may lead to an expanded frontline HSCT role in the future. In children lacking a MSD, increasingly MUD HSCT is being considered as first-line treatment and is also being considered more for young adults. Further research is needed to advance our understanding of the role HSCT has to play in SAA with particular emphasis on alternative donor sources and identifying optimal conditioning regimens.