Augmented Hyper-CVAD (AHCVAD), a Pediatric Inspired Regimen for Adults Younger Than 50 Years of Age with Acute Lymphoblastic Leukemia (ALL), Yields High Rates of MRD Negativity, Favorable 3-Year Overall Survival Regardless of Allogeneic Stem Cell Transplant (ASCT): A Single Center Experience
Authors: Gill Sarvarinder Kaur , Lee Geeny , Rubin Joelle , Wang Shuqi , Koprivnikar Jamie , Linder Katherine , McCloskey James 
Published: December 2024

Background: Adult patients (pts) with ALL have inferior outcomes compared to children with a higher relapse rate and shorter disease-free survival. Numerous randomized studies have demonstrated significantly improved survival in adolescents and young adults (AYA) with ALL 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 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 ph- ALL.

Methods: Pts were identified by retrospective review. 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 (HCVAD) regimen is well established and has been described in the past (Kantarjian et al: Cancer 2004). The AHCVAD regimen uses the HCVAD backbone with four modifications: pts receive 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 cycle 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 18 of cycles 1 to 8. Pts with CD20+ 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 HCVAD.

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 January 2017 and March 2024, 44 consecutive pts treated with AHCVAD were identified. Median age was 29 yrs (20 to 47); 18 pts were more than 30 yrs old. The diagnosis was B-ALL in 77% (34/44) and T-ALL in 23%. CR was achieved in 97% (43/44), with 80% (35/44) of these becoming MRD negative. Those who didn't achieve MRD negativity after 2 cycles were switched to blinatumomab or inotuzumab ozogamicin. The median time to CR was 26(23.5 - 29.5) days with 40 pts (90%) achieving CR following cycle 1 and an additional 3 pts achieving a CR following cycle 2. Pts received a median of 4 cycles and pts who proceeded to ASCT received a median of 2 cycles. 17 pts (39%) proceeded to ASCT. The median PFS was not reached (95% CI 2.55-NR) and median OS was 4.56 yrs (95% CI 2.83-NR). At 36 months the PFS was 59% and the OS was 61.4%. Median OS was not influenced by age (2.47 yrs (1.69-NR) for pts &lt;/=30 yrs and NR (3.06-NR) for pts &gt;30, p=.255). There was no significant difference in OS and PFS for pts who did or did not undergo transplantation (OS= NR for pts transplanted vs 3.06 yrs for not transplanted, p=0.303 and PFS= NR for both pts transplanted and not transplanted, p=0.588).

Age was not a factor for early mortality (only 1 death after C2) or thrombotic toxicities. There were no deaths during the first 30 days of treatment. There was one treatment related death from disseminated fungal infection while in CR during cycle 2 of AHCVAD. 8 pts (18%) were transitioned to standard HCVAD due to toxicities. Most common reported toxicities that prompted a reduction in treatment intensity were infectious complications and thrombosis. There were 3 (7%) thrombotic events reported while on treatment. 4 pts experienced hemorrhagic complications. Osteonecrosis occurred in one patient. 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.

Conclusion: AHCVAD is an effective regimen for pts &lt; 50 yrs with newly diagnosed ALL with a high rate of CR, MRD negativity, and low relapse rate compares favorably with other “pediatric inspired” regimens. The augmentation of the hyper-CVAD backbone in this fashion may be more feasible in the community setting than other pediatric protocols. However, intensive monitoring with appropriate antibiotic, antiviral prophylaxis and growth factor support is required given significant toxicities observed.