A Phase II Study of Mini-Hyper-CVD Plus Inotuzumab Ozogamicin, with or without Blinatumomab, in Older Adults with Newly Diagnosed Philadelphia Chromosome-Negative B-Cell Acute Lymphoblastic Leukemia: Updated Results and Predictors for Outcomes

Abstract

Background: Inotuzumab ozogamicin (INO) and blinatumomab are superior to chemotherapy for relapsed/refractory B-cell acute lymphoblastic leukemia (ALL). Incorporation of these agents in the frontline setting could improve remission durations and OS in older adults with newly diagnosed B-cell ALL. Methods: Patients (pts) ≥60 years of age with newly diagnosed Philadelphia chromosome (Ph)-negative pre-B-cell ALL were eligible. Pts were required to have a performance status of ≤3, total bilirubin ≤1.5 mg/dl, AST/ALT ≤3x ULN and creatinine ≤2 mg/dl. Pts received mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses) for up to 8 cycles. INO was given at a dose of 1.3-1.8mg/m2 on day 3 of cycle 1 and 0.8-1.3mg/m2 on day 3 of cycles 2-4. Rituximab (if CD20+) and prophylactic IT chemotherapy were given for the first 4 cycles. Responding pts received POMP maintenance for up to 3 years. To decrease the risk of veno-occlusive disease (VOD), the protocol was amended in 3/2017 (pts 50+) to give INO in fractionated doses each cycle (0.6 mg/m2 on day 2 and 0.3 mg/m2 on day 8 of cycle 1; 0.3 mg/m2 on day 2 and 8 of cycles 2-4) and to administer 4 cycles of blinatumomab following 4 cycles of hyper-CVD plus INO, followed by maintenance with 12 cycles of POMP and 4 cycles of blinatumomab (1 cycle of blinatumomab after every 3 cycles of POMP). The cumulative dose of INO given before and after this most recent amendment was 4.3 mg/m2 and 2.7 mg/m2, respectively. Results: To date, 80 pts have been treated. Six pts were in complete remission (CR) at the time of enrollment. Baseline characteristics are shown in Table 1. The median age was 68 years (range, 60-87 years); 30 pts (39%) were ≥70 years. From all pts, 39% were positive for TP53 mutation and 24% had an adverse-risk karyotype. Among 74 pts evaluable for morphologic response, 73 (99%) responded (CR, n=66; CRp, n=6; CRi, n=1). MRD negativity by flow cytometry was achieved in 61/76 pts (80%) after 1 cycle and 74/79 pts (94%) overall. The 30-day and 60-day mortality rates were 0% and 3%, respectively. Among 79 pts who achieved remission, 11 (14%) relapsed, 4 (5%) underwent allogeneic SCT in first remission (1 of whom subsequently relapsed), 32 (40%) are alive in remission without SCT, and 32 (40%) died in remission. Among the 32 deaths in remission, 9 were from sepsis, 3 from VOD, 9 from development of MDS or AML; the rest from miscellaneous causes. Overall, 9 pts (11%) developed MDS/AML after a median of 33 months (range 3-66); 7 of these pts had a detectable TP53 mutation in the myeloid malignancy. Notably, 6 pts (8%) developed VOD, 1 after subsequent allogeneic SCT. With a median follow-up of 61 months (range, 7-123 months), the 5-year CR and OS rates were 76% and 46%, respectively. Outcomes were superior in pts who were 60-69 years old versus those who were ≥70 years (5-year OS rates: 57% and 28%, respectively; P=0.05) and for those without poor-risk cytogenetics (e.g. KMT2A-rearranged, low hypodiploidy/near triploidy, complex cytogenetics) versus poor-risk cytogenetics (5-year OS rates: 55% and 21%, respectively; P=0.005). The 5-year OS for pts with and without TP53 mutation were 35% and 47%, respectively (P=0.34). The 5-year OS for pts age 60-64 was 65%, for those age 65-69 was 50%, and for those age ≥70 was 28%. The 3-year OS for patients with and without CRLF2+ ALL were 25% and 60%, respectively (P=0.12). Pts ≥70 years of age were more likely to die in remission (19/30 [63%]) and those who were 60-69 years of age (15/50 [30%]) (P=0.004), which was a major driver of the poor survival in this age group. Outcomes were favorable for pts age 60-69 years with poor risk cytogenetics (5-year OS 70%), intermediate for pts age 60-69 with poor risk cytogenetics (5-year OS 31%) or those age ≥70 with low risk cytogenetics (5-year OS 36%), and were very poor for pts age ≥70 with poor risk cytogenetics (5-year OS 0%) (Figure 1). Conclusion: Low-intensity chemotherapy with hyper-CVD plus INO, with or without blinatumomab, in older adults with newly diagnosed Ph-negative ALL resulted in very high rates of response (99%), including an MRD-negative response rate of 94%. This led to a 5-year OS rate of 46%. Despite the reduced intensity of this regimen, a substantial proportion of pts >70 years of age died in remission. Ongoing efforts are evaluated for INO and blinatumomab without chemotherapy for these pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal