Supportive Care in Cancer

, Volume 28, Issue 2, pp 731–738 | Cite as

Profile of anemia in acute lymphoblastic leukemia patients on maintenance therapy and the effect of micronutrient supplementation

  • Jogamaya Pattnaik
  • Smita KayalEmail author
  • Biswajit Dubashi
  • Debdatta Basu
  • K. V. Vinod
  • H. Nandeesha
  • Ponraj Madasamy
  • Ranjith C. S. Kumar
  • Unni S. Pillai
  • Naresh Jadhav
Original Article



Anemia is a common finding and important cause of morbidity in patients with acute lymphoblastic leukemia (ALL) at diagnosis or during the course of its protracted treatment. We studied profile of anemia in ALL patients on maintenance therapy and evaluated specific micronutrients as cause of this anemia.

Patients and methods

ALL patients who were on maintenance therapy and had grade ≥ 2 anemia were recruited for the study. Serum iron studies, folate, and vitamin B12 were done to identify micronutrient deficiency and to initiate supplementation with specific components if found to be deficient. Toxicities, improvement of anemia, micronutrient levels, and disease outcome were studied after 3 months.


From March 2015 to September 2016, 105 ALL patients were found to be on maintenance fulfilling the inclusion criteria. Overall, the proportion of anemia was 80%(N = 84). Majority had normocytic normochromic anemia (71%). Macrocytic anemia was seen in 18% and microcytic hypochromic in 9.5%. In patients with anemia of grade ≥ 2 (N = 84), 38 patients (45%) had biochemical deficiency of serum folate, and 7 (8%) had vitamin B12 deficiency. No biochemical evidence of iron deficiency was found. Supplementation of deficient micronutrients improved anemia: mean hemoglobin significantly increased from 8.06 ± 1.63 to 10.78 ± 1.53 (p < 0.001) at 3 months; and reduced treatment toxicities, mean number of febrile neutropenia episodes (p = 0.007), and treatment interruptions of > 2 weeks (p = 0.002) were lowered. Patients with anemia had significantly more relapses (N = 14,64%) compared to patients without anemia (N = 8,36%), (p = 0.040).


Timely identification and correction of micronutrient deficiencies causing anemia in ALL patients on maintenance can enhance treatment outcomes.


Anemia Micronutrient Iron Folate Vitamin B12 ALL 



Authors thank all the staffs of department of Medical Oncology and laboratory team of departments of Biochemistry and Hemato-pathology for completion of this work.


This work was supported by “intramural funds” from Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)[JIP/Res/Intra-DM/M.Ch/first/01/2014 dated 18/12/2014 and JIP/Res/Intra-DM/M.Ch/s/02/2014 dated 19/12/2015].

Compliance with ethical standards

Informed consent was obtained from all enrolled patients or parents/LAR (legally authorized representative) of patients less than 18 years, and study was approved by the Institute Ethics Committee. The study was conducted in accordance with the Declaration of Helsinki and Indian Council of Medical Research (ICMR) guidelines.

Conflict of interest

The authors declare that they have no conflicts of interest.

Supplementary material

520_2019_4862_MOESM1_ESM.docx (14 kb)
ESM 1 (DOCX 14 kb)
520_2019_4862_MOESM2_ESM.pdf (122 kb)
ESM 2 (PDF 121 kb)


  1. 1.
    Steele M, Narendran A (2012) Mechanisms of defective erythropoiesis and anemia in pediatric acute lymphoblastic leukemia (ALL). Ann Hematol 91(10):1513–1518CrossRefGoogle Scholar
  2. 2.
    Bhakhri BK, Vaidya PC, Trehan A, Marwaha RK, Garewal G (2012) Iron deficiency anemia in children presenting with lymphoreticular malignancies and the effect of induction therapy. Pediatr Hematol Oncol 29(2):148–153CrossRefGoogle Scholar
  3. 3.
    Kelemen LE (2006) The role of folate receptor α in cancer development, progression and treatment: cause, consequence or innocent bystander? Int J Cancer 119(2):243–250CrossRefGoogle Scholar
  4. 4.
    Schmutte C, Jones PA (1998) Involvement of DNA methylation in human carcinogenesis. Biol Chem 379(4–5):377–388PubMedGoogle Scholar
  5. 5.
    Blount BC, Mack MM, Wehr CM, MacGregor J, Hiatt RA, Wang G, Wickramasinghe SN, Everson RB, Ames BN (1997) Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. Proc Natl Acad Sci U S A 94(7):3290–3295CrossRefGoogle Scholar
  6. 6.
    Skibola CF, Smith MT, Kane E, Roman E, Rollinson S, Cartwright RA, Morgan G (1999) Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. Proc Natl Acad Sci U S A 96(22):12810–12815CrossRefGoogle Scholar
  7. 7.
    Lucock M, Yates Z, Glanville T et al (2003) A critical role for B-vitamin nutrition in human developmental and evolutionary biology. Nutr Res 23(11):1463–1475CrossRefGoogle Scholar
  8. 8.
    Thompson JR, Gerald PF, Willoughby ML et al (2001) Maternal folate supplementation in pregnancy and protection against acute lymphoblastic leukaemia in childhood: a case-control study. Lancet Lond Engl 358(9297):1935–1940CrossRefGoogle Scholar
  9. 9.
    Wien TN, Pike E, Wisløff T, Staff A, Smeland S, Klemp M (2012) Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open 2(1):e000653CrossRefGoogle Scholar
  10. 10.
    Robien K (2005) Folate during antifolate chemotherapy: what we know... and do not know. Nutr Clin Pract Off Publ Am Soc Parenter Enter Nutr 20(4):411–422CrossRefGoogle Scholar
  11. 11.
    Liu Y, Wang B, Liu X et al (2011) Clinical variations of serum levels of ferritin, folic acid and vitamin B12 in acute leukemia patients. J Med Coll PLA 26(5):264–270CrossRefGoogle Scholar
  12. 12.
    Honein MA, Paulozzi LJ, Mathews TJ, Erickson JD, Wong LY (2001) Impact of folic acid fortification of the US food supply on the occurrence of neural tube defects. JAMA 285(23):2981–2986CrossRefGoogle Scholar
  13. 13.
    De Wals P, Tairou F, Van Allen MI et al (2007) Reduction in neural-tube defects after folic acid fortification in Canada. N Engl J Med 357(2):135–142CrossRefGoogle Scholar
  14. 14.
    Greer JP, Foerster J, Rodgers GM et al (2008) Wintrobes clinical hematology. Vol 1, 12th edn. Lippincott Williams and Wilkins, PhiladelphiaGoogle Scholar
  15. 15.
    Thorpe SJ, Heath A, Blackmore S, Lee A, Hamilton M, O’broin S, Nelson BC, Pfeiffer C (2007) International standard for serum vitamin B(12) and serum folate: international collaborative study to evaluate a batch of lyophilised serum for B(12) and folate content. Clin Chem Lab Med 45(3):380–386CrossRefGoogle Scholar
  16. 16.
    Ihara H, Hirota K, Watanabe T et al (2015) Recommended use of cut-off folate concentrations in serum and erythrocyte (red blood cell) as expressed by folic acid equivalent for the diagnosis of deficiency in deliberating the creation of dietary reference intakes. Aust J Nutr Food Sci 3(1):1055Google Scholar
  17. 17.
    WHO | WHO Anthro (version 3.2.2, January 2011) and macros. WHO. [cited 2017 January 15] Available from:
  18. 18.
    WHO | Application tools. WHO. [cited 2017 January 15] Available from:
  19. 19.
    750210webbook - guidelines_for_Iron_supplementation.pdf [Internet]. [cited 2017 January 15]. Available from:
  20. 20.
    Kuzminski AM, Del Giacco EJ, Allen RH et al (1998) Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 92(4):1191–1198CrossRefGoogle Scholar
  21. 21.
    Knight K, Wade S, Balducci L (2004) Prevalence and outcomes of anemia in cancer: a systematic review of the literature. Am J Med 116(Suppl 7A):11S–26SCrossRefGoogle Scholar
  22. 22.
    Tandon S, Moulik NR, Kumar A, Mahdi AA, Kumar A (2015) Effect of pre-treatment nutritional status, folate and vitamin B12 levels on induction chemotherapy in children with acute lymphoblastic leukemia. Indian Pediatr 52(5):385–389CrossRefGoogle Scholar
  23. 23.
    Sadananda Adiga MN, Chandy S, Ramaswamy G, Appaji L, Krishnamoorthy L (2008) Homocysteine, vitamin B12 and folate status in pediatric acute lymphoblastic leukemia. Indian J Pediatr 75(3):235–238CrossRefGoogle Scholar
  24. 24.
    Carmel R, Eisenberg L (1977) Serum vitamin B12 and transcobalamin abnormalities in patients with cancer. Cancer. 40(3):1348–1353CrossRefGoogle Scholar
  25. 25.
    Chiche L, Jean R, Romain F et al (2008) Clinical implications of high cobalamin blood levels for internal medicine. Rev Med Interne 29(3):187–194CrossRefGoogle Scholar
  26. 26.
    Arendt JFB, Nexo E (2012) Cobalamin related parameters and disease patterns in patients with increased serum cobalamin levels. Szecsi PB, ed. PLoS ONE 7(9):e45979Google Scholar
  27. 27.
    Mead JAR, Venditti JM, Schrecker AW et al (1963) The effect of reduced derivatives of folic acid on toxicity and antileukemic effect of methotrexate in mice. Biochem Pharmacol 12(4):371–383CrossRefGoogle Scholar
  28. 28.
    van Ede AE, Laan RF, Rood MJ, Huizinga TW, van de Laar M, van Denderen C, Westgeest TA, Romme TC, de Rooij DJ, Jacobs MJ, de Boo TM, van der Wilt G, Severens JL, Hartman M, Krabbe PF, Dijkmans BA, Breedveld FC, van de Putte L (2001) Effect of folic or folinic acid supplementation on the toxicity and efficacy of methotrexate in rheumatoid arthritis: a forty-eight week, multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum 44(7):1515–1524CrossRefGoogle Scholar
  29. 29.
    Morgan SL, Baggott JE, Vaughn WH, Austin JS, Veitch TA, Lee JY, Koopman WJ, Krumdieck CL, Alarcón GS (1994) Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann Intern Med 121(11):833–841CrossRefGoogle Scholar
  30. 30.
    Ortiz Z, Shea B, Suarez-Almazor ME, Moher D, Wells GA, Tugwell P (1998) The efficacy of folic acid and folinic acid in reducing methotrexate gastrointestinal toxicity in rheumatoid arthritis. A metaanalysis of randomized controlled trials. J Rheumatol 25(1):36–43PubMedGoogle Scholar
  31. 31.
    Scagliotti GV, Shin D-M, Kindler HL, Vasconcelles MJ, Keppler U, Manegold C, Burris H, Gatzemeier U, Blatter J, Symanowski JT, Rusthoven JJ (2003) Phase II study of pemetrexed with and without folic acid and vitamin B12 as front-line therapy in malignant pleural mesothelioma. J Clin Oncol Off J Am Soc Clin Oncol 21(8):1556–1561CrossRefGoogle Scholar
  32. 32.
    Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P (2003) Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol Off J Am Soc Clin Oncol 21(14):2636–2644CrossRefGoogle Scholar
  33. 33.
    Worzalla JF, Shih C, Schultz RM (1998) Role of folic acid in modulating the toxicity and efficacy of the multitargeted antifolate, LY231514. Anticancer Res 18(5A):3235–3239PubMedGoogle Scholar
  34. 34.
    Schrøder H, Clausen N, Ostergård E, Pressler T (1986) Folic acid supplements in vitamin tablets: a determinant of hematological drug tolerance in maintenance therapy of childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol 3(3):241–247CrossRefGoogle Scholar
  35. 35.
    Halonen P, Mattila J, Suominen P, Ruuska T, Salo MK, Mäkipernaa A (2003) Iron overload in children who are treated for acute lymphoblastic leukemia estimated by liver siderosis and serum iron parameters. Pediatrics 111(1):91–96CrossRefGoogle Scholar
  36. 36.
    Eng J, Fish JD (2011) Insidious iron burden in pediatric patients with acute lymphoblastic leukemia. Pediatr Blood Cancer 56(3):368–371CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jogamaya Pattnaik
    • 1
  • Smita Kayal
    • 1
    Email author
  • Biswajit Dubashi
    • 1
  • Debdatta Basu
    • 2
  • K. V. Vinod
    • 3
  • H. Nandeesha
    • 4
  • Ponraj Madasamy
    • 1
  • Ranjith C. S. Kumar
    • 1
  • Unni S. Pillai
    • 1
  • Naresh Jadhav
    • 1
  1. 1.Department of Medical Oncology, Regional Cancer CentreJawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)PuducherryIndia
  2. 2.Department of PathologyJawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)PondicherryIndia
  3. 3.Department of Medicine (Haematology)Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)PondicherryIndia
  4. 4.Department of BiochemistryJawaharlal Institute of Postgraduate Medical Education and Research (JIPMER)PondicherryIndia

Personalised recommendations