Outcomes with Augmented Hyper-CVAD (AHCVAD), a Pediatric Inspired HCVAD-Based Regimen, for Adults Younger Than 50 Years of Age with Newly Diagnosed Acute Lymphoblastic Leukemia (ALL)

Background: Numerous randomized studies in adolescents and young adults (AYA) with ALL have demonstrated significantly improved survival when therapy is intensified compared to standard dose adult protocols. However, little agreement exists as to the upper age limit where the benefits of pediatric-inspired regimens outweigh toxicity concerns. Similar to pediatric regimens, AHCVAD uses intensified doses of vincristine, dexamethasone, and pegaspargase and shows activity in relapsed patients (pts) with ALL (Faderl S et al: Clin Lymphoma Myel Leuk 2011). Here we evaluate the efficacy and safety of AHCVAD in younger adult pts with newly diagnosed ALL.

Methods: Eligible were pts between ages 18 to 49 years with newly diagnosed adult B- or T-cell ALL. Excluded were pts with BCR-ABL-positive disease and Burkitt's leukemia. The hyper-CVAD regimen is well established and has been described in the past (Kantarjian et al: Cancer 2004). The AHCVAD regimen uses the hyper-CVAD backbone with four modifications: pts receive an intensified dose-schedule of vincristine 1.4 mg/m2 IV on days 1, 8, 15, 22 during cycle 1 and on days 1, 8, and 15 during cycles 3, 5, and 7; Dexamethasone is administered at 80 mg PO or IV on days 1-4 and 15-18 during cycles 1 and 40 mg PO or IV cycle 3, 5, and 7, and Pegaspargase 2500 units/m2 (capped at 3750 units) IV is given on day 4, and later changed to day 18 of cycles 1 to 8. Pts with CD20-positive ALL also received Rituximab at 375 mg/m2 on days 1 and15 of cycles 1 to 4. In pts with T-ALL, two cycles of nelarabine were given following AHCVAD cycles 4 and 5, respectively, and repeated during maintenance cycles 12 and 24. CNS prophylaxis was standard as published for hyper-CVAD.

Prophylactic Enoxaparin 40 mg subcutaneously daily unless platelets < 30,000 was given to all pts treated after December 2016. Minimal residual disease (MRD) was assessed from marrow or blood by multiparameter flow cytometry after cycle 1, and subsequent cycles until negative, and every 4 months until the completion of maintenance, then every 6 months.

Results: Between March 2014 and May 2017, 27 consecutive pts were enrolled. Median age was 29 yrs (19 to 49); 9 pts were more than 30 years old. The diagnosis was B-ALL in 66% and T-ALL in 33%. CR was achieved in 81% (22/27), with 84% (21/25) of these becoming MRD negative. The median time to CR was 0.85 months (mo) with 19 pts (70%) achieving CR following cycle 1 and an additional 3 pts achieving a CR following cycle 2. Pts received a median of 4 cycles. Fifteen pts (55%) proceeded to allogeneic stem cell transplantation. The median EFS and OS were not met with a median follow up of 16.6 months. At 36 months the EFS was 73% and OS was 77%. (Figure 1). Age was not a factor for early mortality (only 1 death during first 4 cycles) or thrombotic toxicities. Median OS survival was not influenced by age (20.6 mo for pts <30 yrs and 13.7 mo for pts >30 at 36 mo, p=.316). There were no deaths during the first 30 days of treatment.

There was one treatment related death from septic shock while in CR during cycle 4 of consolidation. Five pts (18%) were transitioned to standard Hyper-CVAD due to toxicities. Most common reported toxicities that prompted a reduction in treatment intensity were infectious complications (n=4) and thrombosis (n=1). One pt experienced Grade 2 pancreatitis during cycle 2 that resolved with conservative management. There were 14 thrombotic events reported while on treatment (53%). The most common event was DVT (n=10). Two pts experienced pulmonary embolism and 1 pt experienced a grade 4 CNS thrombosis. Three pts experienced hemorrhagic complications. Ten of the pts received thrombosis prophylaxis. There was no significant difference in the rate of thrombosis or hemorrhage for pts based on cycle number, age or the use of prophylactic anticoagulation. There was no significant difference in the rate of complications observed in those pts receiving pegaspargase on day 4 vs day 18, but analysis was limited by sample size.

Conclusion: AHCVAD is an active regimen for adults < 50 yrs with newly diagnosed ALL with a high rate of CR, MRD negativity, and low relapse rate. However significant toxicities were observed including hemorrhage, thrombosis and infection and intensive monitoring of these patients is required. Further exploration of this regimen appears warranted.

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