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Published in: Supportive Care in Cancer 2/2020

01-02-2020 | Acute Lymphoblastic Leukemia | Original Article

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

Authors: Jogamaya Pattnaik, Smita Kayal, Biswajit Dubashi, Debdatta Basu, K. V. Vinod, H. Nandeesha, Ponraj Madasamy, Ranjith C. S. Kumar, Unni S. Pillai, Naresh Jadhav

Published in: Supportive Care in Cancer | Issue 2/2020

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Abstract

Background

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.

Results

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).

Conclusion

Timely identification and correction of micronutrient deficiencies causing anemia in ALL patients on maintenance can enhance treatment outcomes.
Appendix
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Literature
1.
go back to reference Steele M, Narendran A (2012) Mechanisms of defective erythropoiesis and anemia in pediatric acute lymphoblastic leukemia (ALL). Ann Hematol 91(10):1513–1518CrossRef Steele M, Narendran A (2012) Mechanisms of defective erythropoiesis and anemia in pediatric acute lymphoblastic leukemia (ALL). Ann Hematol 91(10):1513–1518CrossRef
2.
go back to reference 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):148–153CrossRef 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):148–153CrossRef
3.
go back to reference 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):243–250CrossRef 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):243–250CrossRef
4.
go back to reference Schmutte C, Jones PA (1998) Involvement of DNA methylation in human carcinogenesis. Biol Chem 379(4–5):377–388PubMed Schmutte C, Jones PA (1998) Involvement of DNA methylation in human carcinogenesis. Biol Chem 379(4–5):377–388PubMed
5.
go back to reference 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):3290–3295CrossRef 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):3290–3295CrossRef
6.
go back to reference 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):12810–12815CrossRef 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):12810–12815CrossRef
7.
go back to reference 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):1463–1475CrossRef 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):1463–1475CrossRef
8.
go back to reference 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):1935–1940CrossRef 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):1935–1940CrossRef
9.
go back to reference 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):e000653CrossRef 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):e000653CrossRef
10.
go back to reference 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):411–422CrossRef 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):411–422CrossRef
11.
go back to reference 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):264–270CrossRef 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):264–270CrossRef
12.
go back to reference 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):2981–2986CrossRef 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):2981–2986CrossRef
13.
go back to reference 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):135–142CrossRef 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):135–142CrossRef
14.
go back to reference Greer JP, Foerster J, Rodgers GM et al (2008) Wintrobes clinical hematology. Vol 1, 12th edn. Lippincott Williams and Wilkins, Philadelphia Greer JP, Foerster J, Rodgers GM et al (2008) Wintrobes clinical hematology. Vol 1, 12th edn. Lippincott Williams and Wilkins, Philadelphia
15.
go back to reference 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):380–386CrossRef 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):380–386CrossRef
16.
go back to reference 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):1055 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):1055
20.
go back to reference Kuzminski AM, Del Giacco EJ, Allen RH et al (1998) Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 92(4):1191–1198CrossRef Kuzminski AM, Del Giacco EJ, Allen RH et al (1998) Effective treatment of cobalamin deficiency with oral cobalamin. Blood. 92(4):1191–1198CrossRef
21.
go back to reference 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–26SCrossRef 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–26SCrossRef
22.
go back to reference 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):385–389CrossRef 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):385–389CrossRef
23.
go back to reference 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):235–238CrossRef 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):235–238CrossRef
24.
go back to reference Carmel R, Eisenberg L (1977) Serum vitamin B12 and transcobalamin abnormalities in patients with cancer. Cancer. 40(3):1348–1353CrossRef Carmel R, Eisenberg L (1977) Serum vitamin B12 and transcobalamin abnormalities in patients with cancer. Cancer. 40(3):1348–1353CrossRef
25.
go back to reference Chiche L, Jean R, Romain F et al (2008) Clinical implications of high cobalamin blood levels for internal medicine. Rev Med Interne 29(3):187–194CrossRef Chiche L, Jean R, Romain F et al (2008) Clinical implications of high cobalamin blood levels for internal medicine. Rev Med Interne 29(3):187–194CrossRef
26.
go back to reference 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):e45979 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):e45979
27.
go back to reference 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):371–383CrossRef 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):371–383CrossRef
28.
go back to reference 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):1515–1524CrossRef 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):1515–1524CrossRef
29.
go back to reference 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):833–841CrossRef 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):833–841CrossRef
30.
go back to reference 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):36–43PubMed 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):36–43PubMed
31.
go back to reference 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):1556–1561CrossRef 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):1556–1561CrossRef
32.
go back to reference 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):2636–2644CrossRef 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):2636–2644CrossRef
33.
go back to reference 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):3235–3239PubMed 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):3235–3239PubMed
34.
go back to reference 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):241–247CrossRef 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):241–247CrossRef
35.
go back to reference 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):91–96CrossRef 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):91–96CrossRef
36.
go back to reference Eng J, Fish JD (2011) Insidious iron burden in pediatric patients with acute lymphoblastic leukemia. Pediatr Blood Cancer 56(3):368–371CrossRef Eng J, Fish JD (2011) Insidious iron burden in pediatric patients with acute lymphoblastic leukemia. Pediatr Blood Cancer 56(3):368–371CrossRef
Metadata
Title
Profile of anemia in acute lymphoblastic leukemia patients on maintenance therapy and the effect of micronutrient supplementation
Authors
Jogamaya Pattnaik
Smita Kayal
Biswajit Dubashi
Debdatta Basu
K. V. Vinod
H. Nandeesha
Ponraj Madasamy
Ranjith C. S. Kumar
Unni S. Pillai
Naresh Jadhav
Publication date
01-02-2020
Publisher
Springer Berlin Heidelberg
Published in
Supportive Care in Cancer / Issue 2/2020
Print ISSN: 0941-4355
Electronic ISSN: 1433-7339
DOI
https://doi.org/10.1007/s00520-019-04862-6

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