Reduced vs. standard dose native E. coli-asparaginase therapy in childhood acute lymphoblastic leukemia: long-term results of the randomized trial Moscow–Berlin 2002

Abstract

PurposeFavorable outcomes were achieved for children with acute lymphoblastic leukemia (ALL) with the first Russian multicenter trial Moscow–Berlin (ALL-MB) 91. One major component of this regimen included a total of 18 doses of weekly intramuscular (IM) native Escherichia coli-derived asparaginase (E. coli-ASP) at 10000 U/m2 during three consolidation courses. ASP was initially available from Latvia, but had to be purchased from abroad at substantial costs after the collapse of Soviet Union. Therefore, the subsequent trial ALL-MB 2002 aimed at limiting costs to a reasonable extent and also at reducing toxicity by lowering the dose for standard risk (SR−) patients to 5000 U/m2 without jeopardizing efficacy.MethodsBetween April 2002 and November 2006, 774 SR patients were registered in 34 centers across Russia and Belarus, 688 of whom were randomized. In arm ASP-5000 (n = 334), patients received 5000 U/m2 and in arm ASP-10000 (n = 354) 10 000 U/m2 IM.ResultsProbabilities of disease-free survival, overall survival and cumulative incidence of relapse at 10 years were comparable: 79 ± 2%, 86 ± 2% and 17.4 ± 2.1% (ASP-5000) vs. 75 ± 2% and 82 ± 2%, and 17.9 ± 2.0% (ASP-10000), while death in complete remission was significantly lower in arm ASP-5000 (2.7% vs. 6.5%; p = 0.029).ConclusionOur findings suggest that weekly 5000 U/m2E. coli-ASP IM during consolidation therapy are equally effective, more cost-efficient and less toxic than 10000 U/m2 for SR patients with childhood ALL.Electronic supplementary materialThe online version of this article (10.1007/s00432-019-02854-x) contains supplementary material, which is available to authorized users.

Adequate asparaginase is important to prevent central nervous system and testicular relapse of pediatric Philadelphia chromosome‐negative B‐cell acute lymphoblastic leukemia

“…23 Several types of evidence indicate that the therapeutic index of Asp is related to the duration of Asp activity above the lowest effective activity, but not the maximum activity. [22][23][24] Comparatively, for regular L-Asp, the number of doses, instead of a single dosage, was found to correlate with better efficacy and better treatment outcome. In SCMC-ALL-2005, E coli Asp was scheduled to be administered at 6000 U/m 2 every other day for eight doses; this dosing schedule was proven to be effective for most patients.…”

“…Increasing Asp activity by shortening the administration interval or by increasing the single dose to 3500 U/m 2 did not further increase the degree of ASN depletion in the CSF 23 . Several types of evidence indicate that the therapeutic index of Asp is related to the duration of Asp activity above the lowest effective activity, but not the maximum activity 22‐24 . Comparatively, for regular L‐Asp, the number of doses, instead of a single dosage, was found to correlate with better efficacy and better treatment outcome.…”

Low-intensity therapy cures over 40 % of children with rapid Flow-MRD responding ALL: the ALL-MB 2008 trial results

“…In the first study ALL MB 1991, which was carried out in a few better equipped clinics, it could be shown that the results were actually satisfactory and that acute side effects and the need for supportive therapy were significantly lower compared to a slightly modified BFM ALL 90 protocol [36]. The consecutive ALL-MB 2002 study showed that DEXA had a superior effect compared to methylprednisolone, especially in extracompartments [37], and that a single weekly administration of ASP at a dose of 5 kU/m 2 in SR patients was not inferior to 10 kU/m 2 [38]. Since the expected goal of reducing acute side effects with an acceptable rate of recurrences had already been achieved in the first studies, one of the guiding principles of the following MB studies was the possibility of further therapy de-escalation.…”

“…The cooperative Moscow-Berlin ALL studies initially were aimed at achieving favorable results with comparatively moderate treatment intensity, which could be carried out under Russian conditions [36]. Since the expected goal of reducing acute side effects and the need for supportive therapy were achieved in the first study ALL-MB 91, one of the guiding principles of the following MB studies was the possibility of further therapy de-escalation [37,38]. In study ALL-MB-2008, MFC was used for the MRD measurement in parallel to treatment [39,40], initially without drawing any consequences from these results with regard to patient stratification.…”

Efficacy and Toxicity of Different Forms of Asparaginases Against Acute Lymphoblastic Leukemia: A Review

“…Pneumonia was seen in about 50% of patients and hypersensitivity reaction was reported in 4.5% (n=31) patients in E. coli asparaginase 10000 arm. In E. coli 5000 arm 1.8% (n=13) patients showed hypersensitive reaction [24]. Later, 15 out of 16 deaths were for patients over 40 years.…”