A New Asparaginase for Acute Lymphoblastic Leukemia

Home , Asparaginase, Pegaspargase

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

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,

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.

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

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].

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 by COG for newly diagnosed T-ALL. Might a single CALASP dose be considered in the context of this type of therapy? Protocols for

relapsed ALL in both the USA and UK also use multiple pegaspargase doses during

induction, and might be another area where CALASP integration could be explored.

In conclusion, calaspargase pegol-mknl is now FDA-approved for use in children

and young adults up to 21 years of age with acute lymphoblastic leukemia. Any new

drug developed and approved for a pediatric cancer (without an adult indication at this

time) is a welcome rarity. Yet how calaspargase fits into the landscape of the

complicated, multi-agent chemotherapy protocols used in pediatric ALL remains to be

determined, and will require further study before its role is truly defined.

FIGURE – Timeline of Asparaginase Development

REFERENCES

[1] Li RJ, Jin R, Liu C, Cao X, Manning ML, Di XM, et al. FDA Approval Summary:

Calaspargase Pegol-mknl For Treatment of Acute Lymphoblastic Leukemia in

Children and Young Adults. Clin Cancer Res, Epub ahead of print 2019 August

23.

[2] Egler RA, Ahuja SP, Matloub Y. L-asparaginase in the treatment of patients with

acute lymphoblastic leukemia. J Pharmacol Pharmacother 2016; 7: 62-71.

[3] Angiolillo AL, Schore RJ, Devidas M, Borowitz MJ, Carroll AJ, Gastier-Foster JM,

et al. Pharmacokinetic and pharmacodynamic properties of calaspargase pegol

Escherichia coli L-asparaginase in the treatment of patients with acute

lymphoblastic leukemia: results from Children's Oncology Group Study

AALL07P4. J Clin Oncol 2014; 32: 3874-82

[4] Silverman LB, Stevenson KE, O'Brien JE, Asselin BL, Barr RD, Clavell L, et al.

Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for

children with newly diagnosed acute lymphoblastic leukemia (1985-2000).

Leukemia 2010; 24: 320-34

[5] Rodriguez V, Kairalla J, Salzer WL, Raetz EA, Loh ML, Carroll AJ, et al. A Pilot

Study of Intensified PEG-Asparaginase in High-risk Acute Lymphoblastic

Leukemia: Children's Oncology Group Study AALL08P1. J Pediatr Hematol

Oncol 2016; 38: 409-17.

History of asparaginase 1950 Guinea pig serum inhibits lymphosarcoma in mice

1960

Asparaginase produced from E. coli 1970

E. coli asparaginase approved by FDA 1980

1990

Pegaspargase approved by FDA

2000

Erwinia E. coli 2010 asparaginase asparaginase approved by withdrawn FDA

Calaspargase approved by 2020 FDA

© 2019 American Association for Cancer Research 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.

Space for Calaspargase? A New Asparaginase for Acute Lymphoblastic Leukemia.

Glen Lew

Clin Cancer Res Published OnlineFirst October 22, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-19-2975

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