International reference analysis of outcomes in adults with B-precursor Ph-negative relapsed/refractory acute lymphoblastic leukemia

Abstract

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612.

Trial registration: ClinicalTrials.gov NCT02003612.

Figure 1.

Flow chart of patients and patient records analysed. Patients with more than one line of salvage in the dataset could contribute multiple records; the numbers in the bottom row correspond to the number of records available for each line of salvage. There were 11 patients without survival information that were included in the analysis: 10 had CR information only and 1 had HSCT information only. The total number of patients (who met eligibility criteria and had outcome data available) was 1706. Overall survival data was missing from 11 patients. Two study group databases did not collect information on CR (n = 590 patients); CR data was missing from a further 140 patients. HSCT data were missing from 290 patients.

Figure 2.

(A) Overall survival from time of first salvage among adult Ph-negative relapsed/refractory B-precursor ALL patients. (B) Overall survival from time of first salvage among adult Ph-negative relapsed/refractory B-precursor ALL patients, by disease status at the time of salvage. (C) Overall survival from time of first salvage among adult Ph-negative relapsed B-precursor ALL patients without prior HSCT, by time to relapse (refractory patients excluded). (D) Overall survival from time of salvage among adult Ph-negative relapsed/refractory B-precursor ALL patients, by line of salvage (all disease statuses included).

Figure 3.

Overall survival by CR status among adult Ph-negative relapsed/refractory B-precursor ALL patients in first salvage. The CR survival curve includes only those patients who achieved CR with the first salvage therapy. Patients who achieved CR but for whom no date of CR was available were excluded from the analysis. Survival between groups is assessed beginning at 36 days after the start of first salvage (the median time to CR) and therefore patients who died or whose data were censored before 36 days are not included in the comparison. At 36 days, 137 patients had achieved CR with first salvage and 563 patients had not. Thirty patients who achieved CR with first salvage and 17 patients who did not remained alive and uncensored at 4 years.

Figure 4.

Overall survival among adult R/R ALL patients by receipt of HSCT during first salvage. The HSCT survival curve includes only those patients who received HSCT following first salvage and before any subsequent salvage treatment. Patients who received HSCT but for whom no date of HSCT was available were excluded from the analysis. Survival between groups is assessed beginning at 110 days after the start of first salvage (the median time to HSCT); therefore, patients who died or whose data were censored before 110 days are not included in the comparison. At 110 days, 67 patients had received HSCT following first salvage and 581 patients had not. Twenty-two patients who received HSCT following first salvage and 40 patients who did not remained alive and uncensored at 4 years.