Side Effects of Vincristine and L-Asparaginase in Patients with Acute Lymphoblastic Leukemia in a Mexican Pediatric Hospital

Mario I. Ortiz, Sandra Rivera-Roldán, Marco A. Escamilla-Acosta, Georgina Romo-Hernández, Héctor A. Ponce-Monter, Rita Escárcega-Ángeles

área Académica de Farmacia, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, Mexico..
área Académica de Medicina, Instituto de Ciencias de la Salud, Universidad Autónoma del Estado de Hidalgo, Pachuca, Mexico;.
Hospital del Ni?o DIF Hidalgo, Pachuca, Mexico.

DOI: 10.4236/pp.2013.43050                

Abstract

Background: The treatment used to combat acute lymphoblastic leukemia (ALL) is multidrug; therefore it is important to use active pharmacovigilance to detect, assess and analyze the likely adverse reactions which may occur during the same period. Objective: To determine the frequency of adverse reactions to chemotherapeutic drugs in children with ALL. Material and Methods: Intensive pharmacovigilance was used to record the reports of adverse reactions to vincristine, L-asparaginase and the vincristine-L-asparaginase combination in children with ALL in a paediatric hospital. For each notification, the adverse reactions were analyzed in order to verify causality. Results: Forty patients were evaluated. Twenty children were female (50.0%) and 20 were male (50%). The children had a mean age, weight and height (±standard deviation: SD) of 8.1 (±3.4) years, 31.4 (±13.9) kg and 1.3 (±0.2) m, respectively. Vincristine was administered to 19 patients, vincristine plus L-asparaginase were given to 19 patients and only 2 patients used L-asparaginase. One-hundred-ninety adverse reactions were detected in the patients, with an average (±SD) of 4.8 (±2.6). Ondansetron was the drug administered for the treating of nausea and vomiting. One hundred eighty-one (95.3%) adverse reactions were identified as “definite”, 5 (2.6%) as “probable” and 4 (2.1%) as “doubtful”. Conclusions: There is a high incidence of adverse reactions by the administration of vincristine and L-asparaginase; the reactions of highest incidence were: nausea, vomiting, neutropenia, diarrhea, constipation, mucositis, headache, and abdominal pain. It is important to promote the detection, collection, reporting, assessment and treatment of ARD’s in children. It is necessary to promote the conduct further studies on pharmacovigilance with this type of treatments and to increase the duration of the studies.

Keywords

Pharmacovigilance; Acute Lymphoblastic Leukemia; Vincristine; L-Asparaginase; Children

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	J. F. Margolin, K. R. Rabi, C. P. Steuber and D. G. Poplack, “Acute Lymphoblastic Leukemia,” In: P. A. Pizzo and D. G. Poplack, Eds., Principles and Practice of Pediatric Oncology, Lippincott Williams & Wilkins, Philadelphia, 2011, pp. 518-565.
[2]	D. W. Parkin and C. A. Stiller, “Childhood Cancer in Developing Countries: Environmental Factors,” In-ternational Journal of Pediatric Hematology/Oncology, Vol. 2, 1995, pp. 411-417.
[3]	M. J. Matasar, E. K. Ritchie, N. Consedine, C. Magai and A. I. Neugut, “Incidence Rates of the Major Leukemia Subtypes among US Hispanics, Blacks, and Non-Hispanic Whites,” Leukemi & Lymphoma, Vol. 47, No. 11, 2006, pp. 2365-2370. doi:10.1080/10428190600799888
[4]	J. M. Mejía-Aranguré, M. Bonilla, R. Lorenzana, S. Juárez-Ocaña, G. de Reyes, M. L. Pérez-Saldivar, G. González-Miranda, R. Bernáldez-Ríos, A. Ortiz-Fernández, M. Ortega-Alvarez, C. Martínez-García Mdel and A. Fajardo-Gutiérrez, “Incidence of Leukemias in Children from El Salvador and Mexico City between 1996 and 2000: Population-Based Data,” BMC Cancer, Vol. 5, 2005, p. 33. doi:10.1186/1471-2407-5-33
[5]	C. H. Pui, D. Campana, D. Pei, W. P. Bowman, J. T. Sandlund, S. C. Kaste, R. C. Ribeiro, J. E. Rubnitz, S. C. Raimondi, M. Onciu, E. Coustan-Smith, L. E. Kun, S. Jeha, C. Cheng, S. C. Howard, V. Simmons, A. Bayles, M. L. Metzger, J. M. Boyett, W. Leung, R. Handgretinger, J. R. Downing, W. E. Evans and M. V. Relling, “Treating Childhood Acute Lymphoblastic Leukemia without Cranial Irradiation,” The New England Journal of Medicine, Vol. 360, No. 26, 2009, pp. 2730-2741. doi:10.1056/NEJMoa0900386
[6]	C. H. Pui, L. L. Robison and A. T. Look, “Acute Lymphoblastic Leukaemia,” Lancet, Vol. 371, No. 9617, 2008, pp. 1030-1043. doi:10.1016/S0140-6736(08)60457-2
[7]	WHO, “Looking at the Pharmacovigilance: Ensuring the Safe Use of Medicines. WHO Policy Perspectives on Medicines,” World Health Organization, Geneva, 2004. http://www.whqlibdoc.who.int/hq/2004/WHO_EDM_2004.8.pdf
[8]	G. Jeetu and G. Anusha, “Pharmacovigilance: A Worldwide Master Key for Drug Safety Monitoring,” Journal of Young Pharmacists: JYP, Vol. 2, No. 3, 2010, pp. 315320. doi:10.4103/0975-1483.66802
[9]	G. J. Ruiz-Argüelles, L. N. Coconi-Linares, J. GarcésEisele and V. Reyes-Núñez, “Methotrexate-Induced Mucositis in Acute Leukemia Patients Is Not Associated with the MTHFR 677T Allele in Mexico,” Hematology, Vol. 12, No. 5, 2007, pp. 387-391. doi:10.1080/10245330701448479
[10]	L. I. Castro-Pastrana and B. C. Carleton, “Improving Pediatric Drug Safety: Need for More Efficient Clinical Translation of Pharmacovigilance Knowledge,” Journal of Population Therapeutics and Clinical Pharmacology, Vol. 18, No. 1, 2011, pp. e76-e88.
[11]	C. A. Naranjo, U. Busto, E. M. Sellers, P. Sandor, I. Ruiz, E. A. Roberts, E. Janecek, C. Domecq and D. J. Greenblatt, “A Method for Estimating the Probability of Adverse Drug Reactions,” Clinical Pharmacology and Therapeutics, Vol. 30, No. 2, 1981, pp. 239-245. doi:10.1038/clpt.1981.154
[12]	D. G. Warr, “Chemotherapyand Cancer-Related Nausea and Vomiting,” Current Oncology, Vol. 15, Supplement 1, 2008, pp. S4-S9. doi:10.3747/co.2008.171
[13]	J. Herrstedt, J. M. Koeller, F. Roila, P. J. Hesketh, D. Warr, C. Rittenberg and M. Dicato, “Acute Emesis: Moderately Emetogenic Chemotherapy,” Support Care Cancer, Vol. 13, No. 2, 2005, pp. 97-103. doi:10.1007/s00520-004-0701-7
[14]	F. Roila, D. Warr, R. A. Clark-Snow, M. Tonato, R. J. Gralla, L. H. Einhorn and J. Herrstedt, “Delayed Emesis: Moderately Emetogenic Chemotherapy,” Support Care Cancer, Vol. 13, No. 2, 2005, pp. 104-108. doi:10.1007/s00520-004-0700-8
[15]	M. S. Aapro, A. Molassiotis and I. Olver, “Anticipatory Nausea and Vomiting,” Support Care Cancer, Vol. 13, No. 2, 2005, pp. 117-121. doi:10.1007/s00520-004-0745-8
[16]	F. Roila, J. Herrstedt, M. Aapro, R. J. Gralla, L. H. Einhorn, E. Ballatori, E. Bria, R. A. Clark-Snow, B. T. Espersen, P. Feyer, S. M. Grunberg, P. J. Hesketh, K. Jordan, M. G. Kris, E. Maranzano, A. Molassiotis, G. Morrow, I. Olver, B. L. Rapoport, C. Rittenberg, M. Saito, M. Tonato and D. Warr, “ESMO/MASCC Guidelines Working Group. Guideline Update for MASCC and ESMO in the Prevention of Chemotherapyand Radiotherapy-Induced Nausea and Vomiting: Results of the Perugia Consensus Conference,” Annals of Oncology, Vol. 21, Supplement 5, 2010, pp. v232-v243. doi:10.1093/annonc/mdq194
[17]	F. Turpin, M. Tubiana-Hulin, L. Meeus, A. Goupil, J. Berlie and B. Clavel, “Complications of Antitumor and Antileukemic Chemotherapy,” La Semaine des Hôpitaux, Vol. 58, No. 36, 1982, pp. 2047-2057.
[18]	S. L. Figliolia, D. T. Oliveira, M. C. Pereira, J. R. Lauris, A. R. Maurício, D. T. Oliveira and M. L. Mello de Andrea, “Oral Mucositis in Acute Lymphoblastic Leukaemia: Analysis of 169 Paediatric Patients,” Oral Diseases, Vol. 14, No. 8, 2008, pp. 761-766. doi:10.1111/j.1601-0825.2008.01468.x
[19]	S. Yilmaz, H. Oren, F. Demircioglu and G. Irken, “Assessment of Febrile Neutropenia Episodes in Children with Acute Leukemia Treated with BFM Protocols,” Pediatric Hematology and Oncology, Vol. 25, No. 3, 2008, pp. 195-204. doi:10.1080/08880010801938231
[20]	M. Diezi, A. Nydegger, E. R. Di Paolo, H. Kuchler and M. Beck-Popovic, “Vincristine and Intestinal Pseudo-Obstruction in Children: Report of 5 Cases, Literature Review, and Suggested Management,” Journal of Pediatric Hematology/Oncology, Vol. 32, No. 4, 2010, pp. e126e130. doi:10.1097/MPH.0b013e3181d7742f
[21]	R. Pieters, S. P. Hunger, J. Boos, C. Rizzari, L. Silverman, A. Baruchel, N. Goekbuget, M. Schrappe and C. H. Pui, “L-Asparaginase Treatment in Acute Lymphoblastic Leukemia: A Focus on Erwinia Asparaginase,” Cancer, Vol. 117, No. 2, 2011, pp. 238-249. doi:10.1002/cncr.25489
[22]	B. Sikorska-Fic, E. Stańczak, M. Matysiak and A. Kamiński, “Acute Pancreatitis during Chemotherapy of Acute Lymphoblastic Leukaemia Complicated with Pseudocyst,” Medycyna Wieku Rozwojowego, Vol. 12, No. 4, 2008, pp. 1051-1055.
[23]	D. Schuler, R. Koós, T. Révész, I. Virág and I. Gálfi, “LAsparaginase Therapy and Its Complications in Acute Lymphoid Leukaemia and Generalized Lymphosarcoma,” Haematologia (Budap), Vol. 10, No. 2, 1976, pp. 205211.
[24]	J. S. Withycombe, J. E. Post-White, J. L. Meza, R. G. Hawks, L. M. Smith, N. Sacks and N. L. Seibel, “Weight Patterns in Children with Higher Risk ALL: A Report from the Children’s Oncology Group (COG) for CCG 1961,” Pediatr Blood & Cancer, Vol. 53, No. 7, 2009, pp. 1249-1254. doi:10.1002/pbc.22237
[25]	T. J. Nevalainen, “Cytotoxicity of Vinblastine and Vincristine to Pancreatic Acinar Cells,” Virchows Archives B: Cell Pathology Including Molecular Pathology, Vol. 18, No. 2, 1975, pp. 119-127.
[26]	Z. Wright, J. Steiner, J. Suchodolski, K. Rogers, C. Barton and M. Brown, “A Pilot Study Evaluating Changes in Pancreatic Lipase Immunoreactivity Concentrations in Canines Treated with L-Asparaginase (ASNase), Vincristine, or Both for Lymphoma,” Canadian Journal of Veterinary Research, Vol. 73, No. 2, 2009, pp. 103-110.
[27]	S. Sleijfer, P. H. Willemse, E. G. de Vries, W. T. van der Graaf, H. Schraffordt Koops and N. H. Mulder, “Treatment of Advanced Seminoma with Cyclophosphamide, Vincristine and Carboplatin on an Outpatient Basis,” British Journal of Cancer, Vol. 74, No. 6, 1996, pp. 947950. doi:10.1038/bjc.1996.462
[28]	World Health Organization, “Information Exchange System,” Alert No. 115, 2007. http://www.who.int/patientsafety/highlights/PS_alert_1b15_ vincristine.pdf
[29]	A. S. Jaggi and N. Singh, “Mechanisms in Cancer-Chemotherapeutic Drugs-Induced Peripheral Neuropathy,” Toxicology, Vol. 291, No. 1-3, 2012, pp. 1-9. doi:10.1016/j.tox.2011.10.019
[30]	A. Egbelakin, M. J. Ferguson, E. A. MacGill, A. S. Lehmann, A. R. Topletz, S. K. Quinney, L. Li, K. C. McCammack, S. D. Hall and J. L. Renbarger, “Increased Risk of Vincristine Neurotoxicity Associated with Low CYP3A5 Expression Genotype in Children with Acute Lymphoblastic Leukemia,” Pediatric Blood & Cancer, Vol. 56, No. 3, 2011, pp. 361-367. doi:10.1002/pbc.22845
[31]	B. M. Frost, G. Lönnerholm, P. Koopmans, J. Abrahamsson, M. Behrendtz, A. Castor, E. Forestier, D. R. Uges and S. S. de Graaf, “Vincristine in Childhood Leukaemia: No Pharmacokinetic Rationale for Dose Reduction in Adolescents,” Acta Paediatrica, Vol. 92, No. 5, 2003, pp. 551-557. doi:10.1111/j.1651-2227.2003.tb02505.x
[32]	A. S. Moore, R. Norris, G. Price, T. Nguyen, M. Ni, R. George, K. van Breda, J. Duley, B. Charles and R. Pinkerton R, “Vincristine Pharmaco-dynamics and Pharmacogenetics in Children with Cancer: A Limited-Sampling, Population Modelling Approach,” Journal of Paediatrics and Child Health, Vol. 47, No. 12, 2011, pp. 875882. doi:10.1111/j.1440-1754.2011.02103.x
[33]	C. H. Fu and K. M. Sakamoto, “PEG-Asparaginase,” Expert Opinion of Pharmacotherapy, Vol. 6, No. 12, 2007, pp. 1977-1984. doi:10.1517/14656566.8.12.1977
[34]	A. Rasheed, A. Iqtidar and S. Khan, “Hematological and Biochemical Changes in Acute Leukemic Patients after Chemotherapy,” Zhongguo Yao Li Xue Bao, Vol. 17, No. 3, 1996, pp. 207-208.