Page 63 - 2021_06-Haematologica-web

Pediatric-inspired ALL therapy in adults age 18-60
Discussion
In this phase II study, we sought to improve the toxici- ty profile of the regimen investigated at the University of Southern California (USC) and previously reported by members of our group, and to define rates of MRD nega- tivity associated with this approach.7 Specifically, we omitted two intensely myelosuppressive courses of con- solidation (cytarabine/teniposide) and incorporated stan- dardized post-pegaspargase laboratory monitoring to enhance the safety of this regimen, particularly for adults over the age of 40 years. We observed no deaths during induction chemotherapy and toxicities of pegaspargase were manageable, albeit common, in patients up to the age of 60 years as subsequently discussed. Removal of the cytarabine/teniposide consolidation blocks did not appear to result in inferior outcomes compared with our prior experience.7 However, two patients died during post-remission therapy, underscoring the Re-induction blocks’ associated risks of myelosuppression. Incidence of febrile neutropenia (ten patients, 26%) herein was com- parable to other pediatric regimens10,13 though not report- ed directly with the USC regimen. Further follow-up will be needed to assess whether longer duration of mainte- nance chemotherapy will be associated with lower risk of late relapse. Despite incorporation of higher-dose MTX in the updated regimen and 16 doses of intrathecal MTX
given throughout treatment in both regimens, three patients experienced CNS relapse (isolated or with mar- row relapse). Neither this regimen nor its USC predeces- sor incorporated cranial radiation; further follow-up and clinical experience will clarify long-term rates of CNS relapse associated with this regimen. This study also pro- vides further data on kinetics of MRD clearance in adults over the age of 40 treated with a pediatric-inspired regi- men, whereas much of the existing MRD data utilizing similar regimens reflects treatment of children, adoles- cents, and younger adults. OS and EFS compare favorably to outcomes historically observed in adults with ALL/LBL.
Others have also investigated incorporation of pegas- pargase into frontline treatment paradigms for adults with ALL. The UK National Cancer Research Institute UKALL14 trial evaluated pegaspargase 1,000 IU/m2 given on days 4 and 18 in combination with daunorubicin, vin- cristine, and dexamethasone, ± rituximab (B-cell ALL) and imatinib (Ph-positive), in patients aged 25-65 years with newly-diagnosed ALL.8 However, 16 of 90 patients succumbed to treatment-related mortality during induc- tion, with 11 deaths related to hepatotoxicity ± infection and associated with grade 3-4 hyperbilirubinemia in nine patients. However, while patients with Ph+ ALL account- ed for only 29% of study participants, those with Ph+ ALL accounted for 11 of 16 deaths during induction and
AB
CD
Figure 1. Survival outcomes among treated patients. (A) Event-free survival (EFS) (freedom from morphologic relapse, removal from study for refractory disease, or death) and (B) overall survival (OS) among all treated patients. (C) EFS and (D) OS among patients aged 18-39 years vs. 40-60 years at initiation of therapy (P=0.06 and P=0.03, respectively).
haematologica | 2021; 106(8)
2091