Asparaginase rechallenge after pancreatitis: pain or gain? Free

In this issue of Blood, Chen et al¹ provide clinical, disease, and outcome data on nearly 300 pediatric patients with acute lymphoblastic leukemia (ALL) experiencing asparaginase-associated pancreatitis (AAP), providing valuable new insight.

Asparaginase is a unique drug, whose antileukemic effects are mainly due to a distinct lack of the enzyme, asparagine synthetase, in leukemic lymphoblasts, rendering them incapable of producing asparagine. Hydrolyzation of free asparagine by asparaginase deprives the lymphoblasts of this essential amino acid, halting protein production, and leading to cell death. In 1966 the first in-human use of asparaginase was reported when an 8-year-old boy with relapsed ALL was treated with partially-purified l-asparaginase isolated from guinea pig serum. The response was remarkable with a dramatic reduction in leukemic burden. However, the side effects including fever, hypotension, and hemorrhagic diarrhea were so severe, treatment was terminated prematurely.² Subsequently, the incorporation of highly purified bacteria-derived asparaginase into ALL therapy beginning in the 1970s markedly improved outcomes, and asparaginase quickly became a cornerstone of ALL therapy.

With its distinct mechanism of action, asparaginase is not associated with many of the adverse effects of most traditional antileukemic agents such as myelosuppression, mucositis, or hair loss; yet carries its own unique toxicity profile. As a foreign-derived protein, antibody-mediated hypersensitive reactions are relatively common. Impacts on proteins of the coagulation cascade result in bleeding and clotting risk. Direct hyperbilirubinemia, hypertriglyceridemia, and hyperglycemia can also occur. But of the known toxicities, pancreatitis may be the most peculiar with unclear mechanisms, erratic behavior, and management conundrums. Although relatively rare, when it occurs, AAP can be life-threatening and for some, fatal. The timing is unpredictable varying from a few days to weeks after the asparaginase dose. Further, unlike liver toxicity, which is most likely with the first asparaginase dose, and hypersensitivity occurring most often with the second or third dose, pancreatitis does not seem to preferentially occur with any particular dose. Additionally, there is a lack of clarity and consensus regarding who should get more asparaginase after an episode of AAP and who would be better off having all further doses omitted.

Previously, the Ponte di Legno (PdL) group (a collaborative effort of several pediatric oncology consortia to study rare ALL patient populations), reported on ∼500 pediatric patients with ALL with AAP, shedding important light on the topic including risk factors and clinical features.³ Perhaps most importantly, of patients who were rechallenged, about half had a recurrence of pancreatitis, but the second event was not likely to be more severe than the first. The authors concluded that the decision of whether to rechallenge should therefore be based on the risk of relapse. This is particularly critical as data support that omitting doses of asparaginase leads to inferior outcomes, particularly for higher-risk patients.^4-6 Although helpful, the PdL report was limited by heterogeneity with patients treated over 2 decades using several different chemotherapy regimens with differences in the timing and number of asparaginase doses, varied asparaginase preparations, and nonstandardized guidance on pancreatitis management. Thus, important questions, including the impact of AAP on outcomes, remained unresolved.

Chen et al leveraged data from 298 pediatric patients with ALL treated from 2015 to 2019 under one contemporary protocol to fill some of the residual data gaps. Their work confirmed that older age is a risk factor as was risk group, but asparaginase product did not appear to be associated with risk. Importantly, as patients were uniformly treated, the authors were able to evaluate disease outcome, finding that event-free survival (EFS) and overall survival (OS) were inferior in patients experiencing an AAP event compared to those without AAP. Outcome was impacted by rechallenge, as the EFS of the 92 patients with AAP who were rechallenged, was significantly better than patients with AAP who were not rechallenged. Additionally, in this cohort, only 30.4% of rechallenged patients had a recurrence. Like was reported by PdL, second events were no more severe than the initial event. This study supports that most patients can be successfully rechallenged with asparaginase after an AAP event, avoiding prognosis-impacting asparaginase omissions.

Interestingly, although omission of asparaginase has been associated with increased relapse risk, relapses in patients with AAP reported by Chen et al were surprisingly not increased. Some of the outcome difference was due to toxic death including from pancreatitis (6/298 AAP events were grade 5). Removal from protocol therapy was counted as an event and was perhaps higher among patients who had AAP (17/298). Additionally, although relapses were not more likely, as AAP was more likely in higher-risk patients, the difference in OS may be partly due to enrichment among AAP patient for those more difficult to salvage after relapse. Overall, additional investigations are needed to define the impact of AAP on outcome.

Although how to manage AAP was not dictated by the protocol, Chen et al collected data on asparaginase products used for rechallenging. This was particularly important as an often-asked question is if use of short-acting asparaginases might mitigate subsequent toxicity risk. The data presented by Chen et al do not support this practice, as several patients receiving a short-acting asparaginase including Erwinia asparaginase for their rechallenge had recurrent AAP, although the numbers were too small to apply statistical testing.

Lastly, there remains an important question that cannot be addressed by this or any retrospective data set to date: will omission of asparaginase be as prognostically relevant in B-ALL treatment regimens that include the immunotherapy blinatumomab? Blinatumomab is now widely considered a standard component of therapy for most newly-diagnosed patients with B-ALL^7-9 but was not used in the PdL or Chen et al cohorts. Historically defined prognostic factors like cytogenetics and minimal residual disease may be partially neutralized by the addition of blinatumomab to therapy.^7-9 Furthermore, reports indicate that blinatumomab may overcome some of the risk associated with omitted components of chemotherapy.¹⁰ So, like all factors identified as prognostic in the context of traditional chemotherapy regimens, the impact of AAP and asparaginase omission on outcome will have to be studied in patients treated with blinatumomab.

Conflict-of-interest disclosure: R.E.R. reports advisory board participation for Jazz Pharmaceuticals and Servier; honorarium and travel for Jazz Pharmaceuticals; and honoraria for Amgen.