Mini-hyper-CVD plus inotuzumab ozogamicin, with or without blinatumomab, in the subgroup of older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: long-term results of an open-label phase 2 trial

Summary

Background

The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients.

Methods

For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The induction chemotherapy consisted of mini-hyper-CVD and has been published before; inotuzumab ozogamicin was administered intravenously on day 3 of the first four cycles at a dose of 1·3–1·8 mg/m² in cycle 1, followed by 1·0–1·3 mg/m² in subsequent cycles (cycles 2–4). Maintenance therapy with dose-reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was given for 3 years. From patient 50 onwards, the study protocol was amended to fractionate inotuzumab ozogamicin to a maximum cumulative dose of 2·7 mg/m² (0·9 mg/m² during cycle 1 fractionated into 0·6 mg/m² on day 2 and 0·3 mg/m² on day 8 of cycle 1, and 0·6 mg/m² in cycles 2–4 fractionated into 0·3 mg/m² on day 2 and 0·3 mg/m² on day 8) followed by blinatumomab for four cycles (cycles 5–8). POMP maintenance was shortened to 12 cycles with one cycle of blinatumomab administered by continuous infusion after every three cycles of POMP. The primary endpoint was progression-free survival and was analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT01371630) and the present data is from the newly diagnosed, older subgroup of patients treated on the phase 2 portion of this trial; the trial is still enrolling patients.

Findings

Between Nov 11, 2011, and March 31, 2022, 80 patients were enrolled and treated (32 female and 48 male patients; median age 68 years [IQR 63–72]), 31 of whom were treated after the protocol amendment. With a median follow-up of 92·8 months (IQR 42·0–106·7), the 2-year progression-free survival was 58·2% (95% CI 46·7–68·2) and 5-year progression-free survival was 44·0% (31·2–54·3). At a median follow-up of 104·4 months (IQR 92·8–110·4) for the patients treated before the protocol amendment and 29·7 months (12·8–59·6) for those treated after the protocol amendment, median progression-free survival did not differ significantly between the two groups (34·7 months [95% CI 15·0–68·3] vs 56·4 months [11·3–69·7]; p=0·77). The most common grade 3–4 events were thrombocytopenia in 62 (78%) patients and febrile neutropenia in 26 (32%) patients. Six (8%) patients developed hepatic sinusoidal obstruction syndrome. There were eight (10%) deaths due to infectious complications, nine (11%) from complications related to secondary myeloid malignancy, and four (5%) from sinusoidal obstruction syndrome.

Interpretation

Inotuzumab ozogamicin with or without blinatumomab added to low-intensity chemotherapy showed promising activity in terms of progression-free survival in older patients with B-cell acute lymphocytic leukaemia. Further attenuation of the chemotherapy regimen might improve tolerability while maintaining efficacy in older patients.

Funding

Pfizer and Amgen.