Role of Allogeneic Stem Cell Transplant (ASCT) in Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab (Blina): Results from a Phase 2 Study

Background:

The combination of low intensity therapy with mini-hyper-CVD and INO with or without Blina has led to significant improvement in survival and outcomes of pts with R-R ALL. ASCT following salvage therapy is considered standard of care in pts with R-R ALL. The aim of this study is to compare the outcomes of pts with R-R ALL treated with this combination followed by ASCT to those who did not receive subsequent ASCT.

Methods:

The chemotherapy was lower in intensity than conventional hyper-CVAD and referred to as mini-hyper-CVD (details in a separate abstract). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m² for course 1 followed by 1.3-1.0 mg/m² for subsequent courses. Following the enrollment of 67 pts, INO was reduced and fractionated into biweekly doses (0.6 mg/m² and 0.3 mg/m² during course 1 and 0.3 mg/m² and 0.3 mg/m² during subsequent courses), and Blina was added for up to 4 courses after INO therapy. The decision to proceed with ASCT was at the discretion of the treating physician and after discussion with the pt. Median time to ASCT was 4 months (range, 2 to 10 months). We performed a landmark analysis at 4 months and compared survival of pts on protocol who received ASCT and those who did not. We used a prognostic model to stratify pts into 2 categories: high- vs low-risk. This model relies on cytogenetics and CD22 expression to predict survival (detailed in another abstract). Pts with CD22 expression ≥70% and cytogenetics without KMT2A rearrangements, or low-hypodiploidy / near triploidy were considered low-risk disease. We compared the survival of pts who received ASCT to those who did not among each risk category.

Results:

Ninety-six pts with R-R ALL were treated. Forty-four pts (46%) with a median age of 34 years (range, 18 to 64 years) underwent ASCT (13 related donors; 16 match unrelated donors, 13 haploidentical, 2 cord stem cells). Of them, 35 (79%) underwent ASCT in Salvage 1 (S1). At the time of ASCT, all 44 pts were morphologic response (39 CR, 5 CRp), 38 among them (86%) in negative MRD status. To date, 19/44 pts (43%) remain alive in remission following ASCT [17 complete response (CR); 2 alive after relapse]. The remaining 25 pts (57%) died of vaso-occlusive disease (VOD; 2 pts), relapse (17 pts) or ASCT complications (6 pts). The median time from start of therapy to ASCT was 18 weeks (range 8 to 44 weeks); this median was 15 weeks (range: 8-44 weeks) for pts who received the original combination and 18 weeks (range: 9-31 weeks) for pts who received the weekly lower dose of INO followed by Blina. In a landmark analysis, the median OS for pts who received ASCT and those who did not was 35 months and 17 months, respectively. The 3-year OS rates were 48% (95% CI, 32%-63%) and 37% (95% CI, 19%-55%), respectively (p=0.4) (Figure 1). In pts who received ASCT in S1, the 3-year OS rate was 55.2% (95% CI, 36.7%-70.4%) with a median OS of 47 months. In univariate analysis of factors predicting survival, ASCT as a time-dependent variable was not associated with better survival [HR 0.775; 95% CI, 0.430-1.396; p=0.396].

VOD was observed in 7/44 pts (16%) who received subsequent ASCT versus 3/52 pts (6%) who did not and in 9/67 pts (13%; 22/67 received subsequent ASCT) treated with mini-hyper-CVD-INO compared with 1/29 pts (3%) treated with mini-hyper-CVD-INO-Blina (15/29 received a subsequent ASCT). This may be the result of lower dose schedules and distancing ASCT from last course of INO.

For risk stratification, 82 pts were evaluable; 30 were considered high-risk. In low-risk pts, there was no difference in OS whether or not pts received ASCT (p=0.777). With a 4-month landmark analysis, the 3-year OS rates were 62% and 60% for pts who received ASCT and those who did not, respectively. Among the high-risk pts, the 1-year OS rates were 25% and 11% (p=0.14), respectively (Figure 2).

Conclusions:

The combination of mini-hyper-CVD and INO with or without Blina is very effective in pts with R-R ALL. ASCT ASCT should be potentially considered in pts with high-risk disease (KMT2A rearrangement, low-hypodiploidy / near triploidy, CD22 expression <70%). Further improvement of outcome might be achieved with the administration of more courses of inotuzumab and blinatumomab, optimal selection of the transplant preparative regimen to minimize further hepatotoxicity, and the use of VOD-preventive measures (e.g. ursodiol, defibrotide).