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A New Asparaginase for Acute Lymphoblastic Leukemia

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A New Asparaginase for Acute Lymphoblastic Leukemia Author Manuscript Published OnlineFirst on October 22, 2019; DOI: 10.1158/1078-0432.CCR-19-2975 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. TITLE Space for Calaspargase? A New Asparaginase for Acute Lymphoblastic Leukemia AUTHOR Glen Lew MD Associate Professor of Pediatrics Aflac Cancer & Blood Disorders Center Emory University / Children's Healthcare of Atlanta 5461 Meridian Mark Rd, Suite 400 Atlanta, GA 30342 USA (404) 785-3240 (404) 785-3510 - FAX [email protected] RUNNING TITLE Space for Calaspargase CONFLICTS OF INTEREST GL has received travel funding from Bristol-Myers-Squibb 1 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 22, 2019; DOI: 10.1158/1078-0432.CCR-19-2975 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. SUMMARY In December 2018, the FDA approved calaspargase pegol-mknl (Asperlas, Servier Pharmaceuticals, Boston MA, USA) for acute lymphoblastic leukemia in children and young adults up to age 21. Asparaginase is a critical component in the treatment of ALL, but the niche for calaspargase within current treatment protocols is unclear. MAIN TEXT In this issue of Clinical Cancer Research, Li and colleagues review the data leading to the FDA’s approval of calaspargase pegol-mknl (CALASP) for use in children and young adults with acute lymphoblastic leukemia (ALL). [1] The discovery and development of asparaginase for ALL has a history beginning over 60 years ago [FIGURE] and has been recently reviewed by Engler, Ahuja, and Matloub [2]. In the 1950’s it was observed that guinea pig serum inhibited lymphosarcoma xenografts in mice; asparaginase was isolated as the active agent. After researchers learned to isolate and produce asparaginase from bacteria such as E. coli, the first commercial E. coli asparaginase was approved by the FDA in 1978, marketed as Elspar (Merck, West Point PA, USA). L-ASP soon became an integral component of chemotherapy for childhood ALL due to improved remission rates and survival. To address both the short half-life and immunogenicity of L-ASP, L-ASP was conjugated to polyethylene glycol (PEG) by investigators, and ultimately pegaspargase was approved by the FDA in 1994 (Oncaspar, Enzon Pharmaceuticals, Bridgewater NJ, USA). Pegaspargase is the primary form of asparaginase in clinical use today, replacing E. coli L-ASP, which has not been manufactured since 2012. Additionally, another short acting asparaginase derived from Erwinia crysanthemi, crisantaspase (Erwinaze, Jazz Pharmaceuticals, 2 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 22, 2019; DOI: 10.1158/1078-0432.CCR-19-2975 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Palo Alto CA, USA), was approved by the FDA in 2011 for use in patients allergic to L- ASP or pegaspargase. Hypersensitivity is the most common adverse reaction associated with any asparaginase, occurring in up to one-third of patients who received E. coli L-ASP. Although conjugation to PEG theoretically might reduce the immunogenicity, allergic reactions remain common with pegaspargase. It was hypothesized that instability of the succinimidyl succinate (SS) linker between the PEG and L-ASP moieties and release of free L-ASP might be a cause for the continued high reaction rate, leading to the development of CALASP. CALSP uses a more stable succinimidyl carbamate (SC) linker [3], which results in longer serum asparaginase activity over pegaspargase with similar toxicities, and was approved by the FDA in December 2018 largely based upon results from the Dana Farber Cancer Institute (DFCI) protocol 11-001 [1]. Asparaginase is just one component within complicated multi-agent chemotherapy regimens used for childhood ALL – regimens which may contain 10 or more different chemotherapeutic agents. Although the majority of chemotherapy drugs used against ALL are identical worldwide, the combinations and sequences of those agents vary highly between different cooperative group protocols. DFCI protocols for childhood ALL are relatively unique in containing a prolonged Intensification phase of 20 to 30 weeks, whose goal is continuous asparagine depletion given in the context of 3- week cycles of multi-agent chemotherapy [4]. Earlier DFCI protocols used weekly intramuscular E. coli L-ASP during the Intensification phase, but DFCI 91-01 randomized weekly L-ASP versus pegaspargase every two weeks, and pegaspargase has become the standard in current DFCI protocols in subsequent trials. 3 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 22, 2019; DOI: 10.1158/1078-0432.CCR-19-2975 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. In DFCI 11-001, patients were randomized to either pegaspargase every two weeks versus CALASP every 3 weeks during Intensification. There were no significant differences in treatment outcomes or toxicities between the pegaspargase and CALASP arms, and PK data as expected showed more prolonged serum asparaginase activity after CALASP in the induction phase. However, in contrast to DFCI protocols, the Children’s Oncology Group’s (COG) protocols for ALL do not have a phase corresponding to the DFCI’s prolonged asparagine-depleting Intensification. COG therapy, which was adapted from Berlin- Frankfurt-Muenster (BFM) group protocols, contains rotating phases lasting one to two months from Induction through Delayed Intensification. Most patients with NCI standard-risk ALL receive pegaspargase only twice during their overall therapy – once in Induction, and once in Delayed Intensification. Patients with higher-risk of relapse receive additional pegaspargase (approximately once every four weeks) during Consolidation and Delayed Intensification in the context of multi-agent chemotherapy. COG protocol AALL07P4, like DFCI 11-001, randomized CALASP instead of pegaspargase but in the context of typical COG therapy for high risk ALL [3]. This study’s primary objective was to compare the pharmacokinetics of the two drugs. CALASP was given at 2500 IU/m2 at the study’s onset, equivalent to the pegaspargase dose, but because of the its prolonged half-life, the study was amended and the CALASP dose reduced to 2100 IU/m2 to achieve a more comparable pharmacokinetic profile to pegaspargase. However, AALL07P4 was ultimately closed when data safety monitoring committee interim analysis suggested inferior outcomes in the CALASP 4 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 22, 2019; DOI: 10.1158/1078-0432.CCR-19-2975 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 2100 IU/m2 group (excess number of patients showing slow early response or minimal residual disease positivity) that crossed predefined monitoring boundaries. There are other concerns arising from the AALL07P4 results besides the pharmacokinetic data. It was hypothesized that the more stable SC linker used in CALASP might reduce the incidence of hypersensitivity compared to pegaspargase. However, the incidence of hypersensitivity to CALASP remained above 20% and did not differ from that of pegaspargase. Also, although there were no differences in severe toxicities, the incidences of hyperglycemia and hyperbilirubinemia were higher in patients receiving CALASP. So, after the FDA’s approval of CALASP, the real question is how and when should it be used? In the context of DFCI-based therapy, the answer may be relatively simple – 11-001 showed CALASP can replace pegaspargase, with administration every three weeks during Intensification instead of every two weeks for pegaspargase. From a practical standpoint, CALASP might be a better fit than pegaspargase in the context of DFCI therapy given the other chemotherapy drugs during Intensification are already given in cycles every three weeks. However, the number of centers using DFCI-based therapy represents a small minority of North American institutions compared to those using COG-based protocols. AALL07P4 did not give a clear answer on how CALASP could be incorporated onto the chemotherapy platform for ALL used by COG. And although more prolonged asparagine depletion within the context of COG therapy might improve outcomes in theory, this strategy was attempted but not successful in COG AALL08P1, in which pegaspargase was given every two weeks mimicking DFCI therapy [5]. 5 Downloaded from clincancerres.aacrjournals.org on October 1, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on October 22, 2019; DOI: 10.1158/1078-0432.CCR-19-2975 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. So, where else might CALASP, with its prolongation of activity over pegaspargase be a consideration? Protocols that use multiple doses of pegaspargase during a month might be the best area to consider. Recent ALL protocols in the United Kingdom have used two pegaspargase doses 14 days apart during Induction, and this platform has also recently been evaluated
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