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M.B. Geyer et al.
seven of 11 hepatotoxicity-associated deaths (OR 8.65, P<0.001). UKALL14 data suggest the combination of ima- tinib and pegaspargase may have been particularly toxic, though similarly severe toxicity was not observed in patients with Ph+ ALL receiving imatinib in combination with the USC regimen.7 In contrast, our study did not include patients with Ph+ ALL. Additionally, use of pegaspargase 1,000 IU/m2 on days 4 and 18 of induction (vs. 2,000 IU/m2 on day 15 in this regimen) may have resulted in different duration of asparagine depletion, and in the context of the UKALL14 regimen, weekly dosing of daunorubicin 60 mg/m2 (vs. 60 mg/m2 days 1-3 in this reg- imen) may have led to greater overlap of hepatoxicity from pegaspargase and intense myelosuppression from the anthracycline. Similarly, patients aged 46-60 years ver- sus 15-45 years treated on the GRAALL-2003 study tend- ed to have higher rates of grade 3-4 hepatotoxicity during induction (28% vs. 18%), received significantly lower median cumulative dose of L-asparaginase during induc- tion (36,000 IU/m2 vs. 48,000 IU/m2) and post-remission (29,000 IU/m2 vs. 81,000 IU/m2), experienced delays in consolidation initiation, and exhibited significantly increased risk of death during induction (13% vs. 4%) and cumulative incidence of death in first CR (15% vs. 2%).9 Administration of cyclophosphamide and daunorubicin in proximity to L-asparaginase during induction with the GRAALL-2003 regimen may also have contributed to tox- icity. Like other series, toxicities associated with pegas- pargase were common in our study, and grade 3-4 hyper- bilirubinemia was observed more commonly in patients aged 40-60 years versus 18-39 years, albeit without evi- dence of acute liver failure or long-term hepatic morbidi- ty. Notably, nearly all patients experiencing grade 3-4 hyperbilirubinemia were able to be re-challenged with the drug without recurrent severe toxicity, suggesting that a single episode of grade 3-4 hyperbilirubinemia does not necessitate pegaspargase discontinuation in adults with ALL, even in patients aged 40-60 years. We observed no deaths during induction chemotherapy, though two patients aged 40-60 years ultimately died in CR1 during post-remission therapy. The rate of thrombosis was low (3%), perhaps due in part to chance as routine antithrom- botic prophylaxis was not used (Online Supplementary Table S1); the USC regimen was associated with a 16% incidence of deep vein thrombosis, similar to other pedi- atric regimens studied in this age group.7,10 Our restrictive approach to fibrinogen repletion (<50 mg/dL or bleeding) may have limited thrombotic risk as well, consistent with other recent reports.30 This regimen may serve as an effec- tive option for patients aged 40-60 years, particularly for patients for whom an asparaginase-containing regimen may be especially desirable (e.g. T-ALL/LBL).15,31,32
Asparaginase activity levels measured at 7 days follow- ing a full dose of pegaspargase were uniformly in the range associated with asparagine depletion (>0.1 IU/mL, with minimum observed level 0.34 IU/mL herein) across all age groups. Mean asparaginase activity at 7 days post- dose was 0.601 IU/mL in our prior pharmacokinetic study of pegaspargase 2,000 IU/m2 during remission induction for younger adults with ALL, and in that series, 12 of 12 and nine of 11 patients exhibited asparagine depletion at 14 and 20 of 21 days post-pegaspargase, respectively.33 In this study, mean asparaginase activity at 7 days was 0.919 IU/mL (Table 3), suggesting at least similarly robust asparagine depletion, though activity levels were not
directly measured at 14 and 21 days post-dose. Of note, even in patients developing antibodies to pegaspargase, there was no evidence of silent inactivation, providing some reassurance against this phenomenon as a major mechanism of therapeutic resistance in the enrolled patients, despite prophylactic administration of hydrocor- tisone to all patients. Absence of silent inactivation fur- ther suggests routine monitoring of asparaginase activity following each pegaspargase may not be essential. Whether pegaspargase doses <2,000 IU/m2 might achieve similar enzymatic activity levels and asparagine depletion within the context of this regimen, while leading to lower rates of severe toxicity, remains unclear. However, among patients treated on the GMALL07/2003 protocol, pegas- pargase doses of 1,000 IU/m2 or 2,000 IU/m2 resulted in asparaginase activity targets achieved in 96% and 98% of patients in the second week post-dose, and 73 and 89% in the third week post-dose, respectively.34
As noted previously, CALGB 10403 demonstrated the safety and efficacy of a true pediatric regimen in patients up to the age of 39 years and is currently considered one of several standard-of-care options for AYAs with newly- diagnosed ALL/LBL.13 The regimen herein differs from the CALGB 10403 treatment plan in incorporating a two- phase induction (with induction II bearing similarities to the consolidation phase of CALGB 10403), HD-MTX ver- sus standard escalating (“Capizzi”) MTX, two sequential intensification/re-induction blocks of therapy (vs. one block of interim maintenance and one block of delayed re-induction), 3-years of maintenance chemotherapy for all patients (vs. a shorter 2-year maintenance period for women), a pegaspargase dose of 2,000 IU/m2 versus 2,500 IU/m2, and six total doses versus seven total doses of pegaspargase. While it is challenging to compare clinical results directly given differences in trial size, follow-up time, ages of patients enrolled (17-39 years vs. 18-60 years) and period during which patients were enrolled (2007-2012, CALGB 10403 vs. 2014-2017, study herein), the 3-year EFS observed herein (68% among all patients and 85% among patients aged 18-39 years vs. 59% on CALGB 10403) is encouraging. Long-term follow-up to assess durability of responses observed in this study will further inform interpretation of these results.
Most patients with ALL (83%) treated on this study exhibited MRD negativity by FACS following induction II. While achievement of MRD negativity following induction I herein did not predict superior long-term DFS and OS among patients with ALL, this study was not powered to perform such a comparison. Other studies have reported a significant difference in DFS/OS among patients achieving MRD negativity by one of several methods at the conclusion of induction phase I.13,35 The small number of patients with MRD positivity post- induction II does not allow for formal comparison of this group of patients with those who exhibited MRD nega- tivity post-induction II, and alloHCT was favored for patients with MRD positivity post-induction II. It remains unclear whether those patients achieving MRD negativity following two courses (vs. one course) of induction therapy using this approach have inferior long- term disease control or would benefit from earlier intro- duction of novel agents (e.g., blinatumomab for B-cell ALL), intensified chemotherapy (high-dose cytarabine, nelarabine), or alloHCT in CR1. Inotuzumab ozogamicin and blinatumomab are actively being investigated as
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haematologica | 2021; 106(8)