Skip to main content

Advertisement

SpringerLink
Log in

Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia

  • Original Article
  • Published:
Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Aminopterin offers advantages over the related antifolate, methotrexate, including greater potency, complete bioavailability, and more consistent accumulation and metabolism by patients’ blasts. This current trial was done to document the toxicity of the aminopterin within a multiagent therapeutic regimen for children with newly diagnosed ALL.

Experimental Design

Patients at high risk of relapse were non-randomly assigned to therapy including oral aminopterin 4 mg/m2, in two doses 12 h apart, in place of methotrexate 100 mg/m2 in four divided doses.

Results

Thirty-two patients, 22 with pre-B ALL and ten with T-lineage ALL, have been treated with aminopterin, with median follow up of 40 months. Hematologic, mucosal and hepatic toxicity has been tolerable and reversible. There have been no toxic deaths among patients in remission. During weekly AMT therapy, higher mean neutrophil counts were observed among patients who were wild type for polymorphisms in methylene tetrahydrofolate reductase and methionine synthase reductase.

Conclusions

Aminopterin can be safely incorporated in multiagent therapy for patients with ALL, in place of systemic methotrexate, without causing excessive toxicity. These results support a larger trial comparing the efficacy and toxicity of aminopterin and methotrexate in therapy for patients with ALL.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Asselin BL, Shuster J, Amylon MD, Halperin R, Lipshultz S, Camitta B (2001) Improved event-free survival (EFS) with high dose methotrexate (HDM) in T-cell lymphoblastic leukemia (T-ALL) and Advanced lymphoblastic lymphoma (T-NHL): a Pediatric Oncology Group (POG) Study [Abstract 1464]. Proceedings of the American Society of Clinical Oncology 20

  2. Bettachi CJ, Kamen BA, Cush JJ (1999) Post-methotrexate (MTX) CNS toxicity: symptom reduction with dextromethorphan. Arthritis Rheum 42:S236

    Google Scholar 

  3. Bleyer AW (1977) Clinical pharmacology of intrathecal methotrexate. II. An improved dosage regimen derived from age-related pharmacokinetics. Cancer Treat Rep 61:1419–1425

    PubMed  CAS  Google Scholar 

  4. Capizzi RL (1981) Asparaginase-methotrexate in combination chemotherapy: schedule-dependent differential effects on normal versus neoplastic cells. Cancer Treat Rep 65(Suppl 4):115–121

    PubMed  CAS  Google Scholar 

  5. Cole PD, Drachtman RA, Smith AK, Cate S, Larson RA, Hawkins DS, Holcenberg J, Kelly K, Kamen BA (2005) Phase II trial of oral aminopterin for adults and children with refractory acute leukemia. Clin Cancer Res 11:8089–8096

    Article  PubMed  CAS  Google Scholar 

  6. Cole PD, Zebala JA, Alcaraz MJ, Smith AK, Tan J, Kamen BA (2006) Pharmacodynamic properties of methotrexate and aminotrexate during weekly therapy. Cancer Chemother Pharmacol 57: 826–834, Epub 2005 Sep 17

    Article  PubMed  CAS  Google Scholar 

  7. Costea I, Moghrabi A, Laverdiere C, Graziani A, Krajinovic M (2006) Folate cycle gene variants and chemotherapy toxicity in pediatric patients with acute lymphoblastic leukemia. Haematologica 91:1113–1116

    PubMed  CAS  Google Scholar 

  8. Dacie JV, Dresner E, Mollin DL, White JC (1950) Aminopterin in the treatment of acute leukemia. Br Med J 1:1447–1457

    PubMed  CAS  Google Scholar 

  9. Dameshek W, Freedman MH, Steinberg L (1950) Folic acid antagonists in the treatment of acute and subacute leukemia. Blood 5:898–915

    PubMed  CAS  Google Scholar 

  10. Dervieux T, Furst D, Orentas Lein D, Capps R, Smith K, Caldwell J, Kremer J (2005) Pharmacogenetic and metabolite measurements are associated with clinical status in rheumatoid arthritis patients treated with methotrexate: results of a multicentred cross sectional observational study. Ann Rheum Dis: ard.2004.033399

  11. Drachtman RA, Cole PD, Golden CB, James SJ, Melnyk S, Aisner J, Kamen BA (2002) Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol 19:319–327

    Article  PubMed  CAS  Google Scholar 

  12. Farber S, Diamond L, Mercer RD, Sylvester RF Jr, Wolff JA (1948) Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid (aminopterin). N Eng J Med 238:787

    Article  CAS  Google Scholar 

  13. Farrow AC, Buchanan GR, Zwiener RJ, Bowman WP, Winick NJ (1997) Serum aminotransferase elevation during and following treatment of childhood acute lymphoblastic leukemia. J Clin Oncol 15:1560–1506

    PubMed  CAS  Google Scholar 

  14. George S, Cichowicz DJ, Shane B (1987) Mammalian folylpoly-gamma-glutamate synthetase. 3. Specificity for folate analogues. Biochemistry 26:522–529

    Article  PubMed  CAS  Google Scholar 

  15. Goldberg JM, Silverman LB, Levy DE, Dalton VK, Gelber RD, Lehmann L, Cohen HJ, Sallan SE, Asselin BL (2003) Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol 21:3616–3622

    Article  PubMed  Google Scholar 

  16. Goldin A, Venditti JM, Humphreys SR, Dennis D, Mantel N (1955) A quantitative comparison of the antileukemic effectiveness of two folic acid antagonists in mice. J Natl Cancer Inst 15:1657–1664

    PubMed  CAS  Google Scholar 

  17. Graham M, Winick N, Camitta B, Kamen BA (1992) Equivalence of methotrexate concentration in erythrocytes between IV and oral dosing regimens. Cancer Res Therapy Control 3:53–55

    Google Scholar 

  18. Haghbin M, Zuelzer WW (1965) A long-term study of cerebrospinal leukemia. J Pediatr 67:23–28

    Article  PubMed  CAS  Google Scholar 

  19. Hendel J, Nyfors A (1984) Pharmacokinetics of methotrexate in erythrocytes in psoriasis. Eur J Clin Pharmacol 27:607–610

    Article  PubMed  CAS  Google Scholar 

  20. Jacques PF, Bostom AG, Williams RR, Ellison RC, Eckfeldt JH, Rosenberg IH, Selhub J, Rozen R (1996) Relation between folate status, a common mutation in methylenetetrahydrofolate reductase, and plasma homocysteine concentrations. Circulation 93:7–9

    PubMed  CAS  Google Scholar 

  21. Jacques PF, Selhub J, Bostom AG, Wilson PW, Rosenberg IH (1999) The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Eng J Med 340:1449–1454

    Article  CAS  Google Scholar 

  22. Jaffe N, Takaue Y, Anzai T, Robertson R (1985) Transient neurologic disturbances induced by high-dose methotrexate treatment. Cancer 56:1356–1360

    Article  PubMed  CAS  Google Scholar 

  23. Kearney PJ, Light PA, Preece A, Mott MG (1979) Unpredictable serum levels after oral methotrexate in children with acute lymphoblastic leukaemia. Cancer Chemother Pharmacol 3:117–120

    Article  PubMed  CAS  Google Scholar 

  24. Kluijtmans LAJ, Young IS, Boreham CA, Murray L, McMaster D, McNulty H, Strain JJ, McPartlin J, Scott JM, Whitehead AS (2003) Genetic and nutritional factors contributing to hyperhomocysteinemia in young adults. Blood 101:2483–2488

    Article  PubMed  CAS  Google Scholar 

  25. Krajinovic M, Lemieux-Blanchard E, Chiasson S, Primeau M, Costea I, Moghrabi A (2004) Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia. Pharmacogenomics J 4:66–72

    Article  PubMed  CAS  Google Scholar 

  26. Krug LM, Ng KK, Kris MG, Miller VA, Tong W, Heelan RT, Leon L, Leung D, Kelly J, Grant SC, Sirotnak FM (2000) Phase I and pharmacokinetic study of 10-propargyl-10-deazaaminopterin, a new antifolate. Clin Cancer Res 6:3493–3498

    PubMed  CAS  Google Scholar 

  27. Kuehl M, Brixner DI, Broom AD, Avery TL, Blakley RL (1988) Cytotoxicity, uptake, polyglutamate formation, and antileukemic effects of 8-deaza analogues of methotrexate and aminopterin in mice. Cancer Res 48:1481–1488

    PubMed  CAS  Google Scholar 

  28. Mahoney DH Jr, Shuster JJ, Nitschke R, Lauer SJ, Steuber CP, Winick N, Camitta B (1998) Acute neurotoxicity in children with B-precursor acute lymphoid leukemia: an association with intermediate-dose intravenous methotrexate and intrathecal triple therapy—a Pediatric Oncology Group study. J Clin Oncol 16:1712–1722

    PubMed  CAS  Google Scholar 

  29. Mahoney DH Jr, Shuster J, Nitschke R, Lauer SJ, Winick N, Steuber CP, Camitta B (1998) Intermediate-dose intravenous methotrexate with intravenous mercaptopurine is superior to repetitive low-dose oral methotrexate with intravenous mercaptopurine for children with lower-risk B-lineage acute lymphoblastic leukemia: a Pediatric Oncology Group phase III trial. J Clin Oncol 16:246–254

    PubMed  CAS  Google Scholar 

  30. Mantadakis E, Smith AK, Hynan L, Winick NJ, Kamen BA (2002) Methotrexate polyglutamation may lack prognostic significance in children with BCP-ALL treated with intensive oral methotrexate. J Pediatr Hematol Oncol 24:636–642

    Article  PubMed  Google Scholar 

  31. Mattano LA Jr, Sather HN, Trigg ME, Nachman JB (2000) Osteonecrosis as a complication of treating acute lymphoblastic leukemia in children: a report from the Children’s Cancer Group. J Clin Oncol 18:3262–3272

    PubMed  Google Scholar 

  32. Meyer LM, Fink H, Sawitsky A, Rowen M, Ritz ND (1949) Aminopterin (a folic acid antagonist) in the treatment of leukemia. Am J Clin Pathol 19:119–126

    PubMed  CAS  Google Scholar 

  33. Mills SD, Stickney JM, Hadedorn AB (1950) Observations on acute leukemia in children treated with 4-aminopteroylglutamic acid. Pediatrics 5:52–56

    PubMed  CAS  Google Scholar 

  34. Moran RG, Colman PD, Rosowsky A, Forsch RA, Chan KK (1985) Structural features of 4-amino antifolates required for substrate activity with mammalian folylpolyglutamate synthetase. Mol Pharmacol 27:156–166

    PubMed  CAS  Google Scholar 

  35. Nachman J (2005) Clinical characteristics, biologic features and outcome for young adult patients with acute lymphoblastic leukaemia. Br J Haematol 130:166–173

    Article  PubMed  Google Scholar 

  36. Nachman JB, Sather HN, Sensel MG, Trigg ME, Cherlow JM, Lukens JN, Wolff L, Uckun FM, Gaynon PS (1998) Augmented post-induction therapy for children with high-risk acute lymphoblastic leukemia and a slow response to initial therapy. N Eng J Med 338:1663–1671

    Article  CAS  Google Scholar 

  37. O’Connor O (2006) Pralatrexate: an emerging new agent with activity in T-cell lymphomas. Curr Opin Oncol 18:591–597

    Article  PubMed  CAS  Google Scholar 

  38. Piper JR, Montgomery JA (1974) A convenient synthesis of aminopterin and homologues via 6-(bromethyl)-2,4-disminopteridine hydrobromide. J Heterocycl Chem 11:279–280

    Article  CAS  Google Scholar 

  39. Quinn CT, Kamen BA (1996) A biochemical perspective of methotrexate neurotoxicity with insight on nonfolate rescue modalities. J Invest Med 44:522–530

    CAS  Google Scholar 

  40. Ratliff AF, Wilson J, Hum M, Marling-Cason M, Rose K, Winick N, Kamen BA (1998) Phase I and pharmacokinetic trial of aminopterin in patients with refractory malignancies. J Clin Oncol 16:1458–1464

    PubMed  CAS  Google Scholar 

  41. Reddick WE, Glass JO, Helton KJ, Langston JW, Xiong X, Wu S, Pui C-H (2005) Prevalence of leukoencephalopathy in children treated for acute lymphoblastic leukemia with high-dose methotrexate. Am J Neuroradiol 26:1263–1269

    PubMed  Google Scholar 

  42. Renard D, Westhovens R, Vandenbussche E, Vandenberghe R (2004) Reversible posterior leucoencephalopathy during oral treatment with methotrexate. J Neurol 251:226–228

    Article  PubMed  Google Scholar 

  43. Rieselbach RE, Morse EE, Rall DP, Frei E, Freireich EJ (1963) Intrathecal aminopterin therapy of meninigeal leukemia. Arch Intern Med 111:620–630

    PubMed  CAS  Google Scholar 

  44. Robien K, Boynton A, Ulrich CM (2005) Pharmacogenetics of folate-related drug targets in cancer treatment. Pharmacogenomics 6:673–689

    Article  PubMed  CAS  Google Scholar 

  45. Rocha JC, Cheng C, Liu W, Kishi S, Das S, Cook EH, Sandlund JT, Rubnitz J, Ribeiro R, Campana D, Pui CH, Evans WE, Relling MV (2005) Pharmacogenetics of outcome in children with acute lymphoblastic leukemia. Blood 105:4752–4758

    Article  PubMed  CAS  Google Scholar 

  46. Rubnitz JE, Lensing S, Zhou Y, Sandlund JT, Razzouk BI, Ribeiro RC, Pui CH (2004) Death during induction therapy and first remission of acute leukemia in childhood: the St. Jude experience. Cancer 101:1677–1684

    Article  PubMed  Google Scholar 

  47. Schoenbach EB, Colsky J, Greenspan EM (1952) Observations on the effects of the folic acid antagonists, aminopterin and amethopterin, in patients with advanced neoplasms. Cancer 5:1201–1220

    Article  PubMed  CAS  Google Scholar 

  48. Schroder H (1990) In vivo methotrexate kinetics and metabolism in human hematopoietic cells. Clinical significance of methotrexate concentrations in erythrocytes. Dan Med Bull 37:22–40

    PubMed  CAS  Google Scholar 

  49. Sirotnak FM, DeGraw JI, Colwell WT, Piper JR (1998) A new analogue of 10-deazaaminopterin with markedly enhanced curative effects against human tumor xenografts in mice. Cancer Chemother Pharmacol 42:313–318

    Article  PubMed  CAS  Google Scholar 

  50. Sirotnak FM, DeGraw JI, Schmid FA, Goutas LJ, Moccio DM (1984) New folate analogs of the 10-deaza-aminopterin series. Further evidence for markedly increased antitumor efficacy compared with methotrexate in ascitic and solid murine tumor models. Cancer Chemother Pharmacol 12:26–30

    PubMed  CAS  Google Scholar 

  51. Sirotnak FM, Donsbach RC (1972) Comparitive studies on the transport of aminopterin, methotrexate, and methasquin by the L1210 leukemia cell. Cancer Res 32:2120–2126

    PubMed  CAS  Google Scholar 

  52. Sirotnak FM, Donsbach RC (1975) A basis for the difference in toxicity of methotrexate, aminopterin and methasquin in mice. Biochem Pharmacol 24:156–158

    Article  PubMed  CAS  Google Scholar 

  53. Smith A, Hum M, Winick NJ, Kamen BA (1996) A case for the use of aminopterin in treatment of patients with leukemia based on metabolic studies of blasts in vitro. Clin Cancer Res 2:69–73

    PubMed  CAS  Google Scholar 

  54. Strauss AJ, Su JT, Dalton VM, Gelber RD, Sallan SE, Silverman LB (2001) Bony morbidity in children treated for acute lymphoblastic leukemia. J Clin Oncol 19:3066–3072

    PubMed  CAS  Google Scholar 

  55. Ulrich CM, Robien K, Sparks R (2002) Pharmacogenetics and folate metabolism—a promising direction. Pharmacogenomics 3:299–313

    Article  PubMed  CAS  Google Scholar 

  56. Vezmar S, Becker A, Bode U, Jaehde U (2003) Biochemical and clinical aspects of methotrexate neurotoxicity. Chemotherapy 49:92–104

    Article  PubMed  CAS  Google Scholar 

  57. Winick NJ, Bowman WP, Kamen BA, Roach ES, Rollins N, Jacaruso D, Buchanan GR (1992) Unexpected acute neurologic toxicity in the treatment of children with acute lymphoblastic leukemia. J Natl Cancer Inst 84:252–256

    Article  PubMed  CAS  Google Scholar 

  58. Winick N, Shuster JJ, Bowman WP, Borowitz M, Farrow A, Jacaruso D, Buchanan GR, Kamen BA (1996) Intensive oral methotrexate protects against lymphoid marrow relapse in childhood B-precursor acute lymphoblastic leukemia. J Clin Oncol 14:2803–2811

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

PDC is a Damon Runyon-Lilly Clinical Investigator, supported in part by the Damon Runyon Cancer Research Foundation (CI-16-03). BAK is an American Cancer Society Professor. This work was supported in part by an FDA Orphan Products Development grant (FD-R-001832-03) and by the Institute for Children with Cancer and Blood Disorders, New Brunswick, NJ.

Author information

Authors and Affiliations

  1. Pediatric Hematology/Oncology, The Cancer Institute of New Jersey, Robert Wood Johnson Medical School/UMDNJ, 195 Little Albany Street, New Brunswick, NJ, 08901, USA

    Peter D. Cole, Richard A. Drachtman, Margaret Masterson, Angela K. Smith, John Glod & Barton A. Kamen

  2. Department of Pharmacology, Robert Wood Johnson Medical School/University of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA

    Peter D. Cole & Barton A. Kamen

  3. Albert Einstein College of Medicine, Montefiore Medical Center, 3415 Bainbridge Avenue, Bronx, NY, 10467, USA

    Peter D. Cole

  4. Syntrix Biosystems, Inc., 215 Clay Street NW, Suite B-5, Auburn, WA, 98001, USA

    John A. Zebala

  5. Research Pharmacy, The Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ, 08901, USA

    Stacey Lisi

  6. Bioarray Solutions, 35 Technology Drive, Suite 100, Warren, NJ, 07059, USA

    Drew-Anne Drapala

Authors
  1. Peter D. Cole
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard A. Drachtman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Margaret Masterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Angela K. Smith
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John Glod
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. John A. Zebala
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Stacey Lisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Drew-Anne Drapala
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Barton A. Kamen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter D. Cole.

Additional information

Disclosure: The following relationships could be construed as resulting in an actual, potential, or apparent conflict of interest with regard to the manuscript submitted for review: Dr. Zebala works for Syntrix Biosystems, Inc., which is commercializing aminopterin under an exclusive license from UMDNJ. If aminopterin were approved and made commercially available, Drs. Cole and Kamen are entitled to a portion of royalties paid to UMDNJ as per the UMDNJ employment agreement.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cole, P.D., Drachtman, R.A., Masterson, M. et al. Phase 2B trial of aminopterin in multiagent therapy for children with newly diagnosed acute lymphoblastic leukemia. Cancer Chemother Pharmacol 62, 65–75 (2008). https://doi.org/10.1007/s00280-007-0576-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00280-007-0576-7

Keywords

Search

Navigation