Mandal Piali, Samaddar Sukla, Chandra Jagdish, Parakh Nupur, Goel Manish
Division of Hematoncology, Department of Pediatrics, Kalawati Saran Children's Hospital and Lady Hardinge Medical College, New Delhi, India.
Department of Community Medicine, Lady Hardinge Medical College, New Delhi, India.
Indian J Hematol Blood Transfus. 2020 Jul;36(3):498-504. doi: 10.1007/s12288-019-01245-z. Epub 2020 Jan 2.
Methotrexate (MTX) forms the backbone of maintenance cycles in childhood acute lymphoblastic leukemia (ALL) chemotherapy, including interim maintenance. There is sufficient published data describing toxicities of high dose MTX (HD-MTX), but toxicities with escalating doses of MTX (Capizzi regimen) is not well documented. Capizzi regimen is thought to be relatively safe; we contend that even low escalating doses of MTX have significant toxicities. Our study intends to characterise such events with Capizzi MTX in comparison to that seen with HD-MTX. The retrospective study was conducted at a tertiary care centre of North India. We looked for the presence of six main toxicities: febrile neutropenia, thrombocytopenia, mucositis, hepatic toxicity, renal toxicity and skin toxicity from the clinical records of children with newly diagnosed acute lymphoblastic leukemia and lymphoma (intermediate and high risk disease), treated at our centre from November 2013 to July 2018. Intermediate risk ALL (IR-ALL) received Capizzi MTX, whereas high risk ALL (HR-ALL/T-NHL), received HD-MTX. Both these regimens do not use L-asparaginase. A total of 237 cycles of Capizzi escalating MTX and 151 cycles of HD-MTX (B cell: 3 gm/m and T cell ALL/T-NHL: 5 gm/m) during interim maintenance were studied in 93 children. Fifty-four (54) children were of IR (all B cell ALL) and 39 of HR-ALL (21 B-ALL, 18 T-ALL/T-NHL). The combined incidence of toxicities, were similar between the two groups: 68/237 cycles (28.7%) of Capizzi MTX and 45/151 cycles (29.8%) of HD-MTX ( = 0.815). However, mucositis was more commonly witnessed in the later group at 22/151 cycle (14.6%) versus 13/237 cycles (5.5%) in Capizzi MTX ( = 0.002). Nephrotoxicity and skin toxicity was seen only in the HD-MTX group. There was no difference in the severity of toxicity, graded using NCI CTCAE v 5.0, between the two groups. There was no mortality directly attributable to methotrexate toxicity (Grade V toxicity). Serum MTX levels were available in 69/151 (45.7%) cycles of HD-MTX and showed no association with toxicity in this group. Also, there was no difference in the incidence of combined toxicities between groups with (19/69 cycles) or without (26/82 cycles) available serum MTX levels in the HR group ( = 0.577). Male gender, lower baseline ANC and lower BMI had significant association with toxicity. Methotrexate related toxicity is common with both Capizzi and HD-MTX schedule in childhood ALL with a correlation of lower BMI, baseline ANC and male gender. However, it is possible to administer Capizzi as well as HD-MTX in lower middle income countries, with manageable toxicity. Further studies will be required to substantiate our findings and determine the predictors of such events.
甲氨蝶呤（MTX）是儿童急性淋巴细胞白血病（ALL）化疗维持周期的核心药物，包括间歇维持治疗。已有足够的公开数据描述高剂量甲氨蝶呤（HD-MTX）的毒性，但甲氨蝶呤剂量递增方案（卡皮齐方案）的毒性尚未得到充分记录。卡皮齐方案被认为相对安全；我们认为，即使是低剂量递增的甲氨蝶呤也有显著毒性。我们的研究旨在比较卡皮齐甲氨蝶呤与HD-MTX的毒性事件特征。这项回顾性研究在印度北部的一家三级医疗中心进行。我们从2013年11月至2018年7月在我们中心接受治疗的新诊断急性淋巴细胞白血病和淋巴瘤（中高危疾病）患儿的临床记录中，寻找六种主要毒性的存在情况：发热性中性粒细胞减少、血小板减少、粘膜炎、肝毒性、肾毒性和皮肤毒性。中危ALL（IR-ALL）接受卡皮齐甲氨蝶呤治疗，而高危ALL（HR-ALL/T-NHL）接受HD-MTX治疗。这两种方案均不使用L-天冬酰胺酶。在93名儿童的间歇维持治疗期间，共研究了237个周期的卡皮齐递增甲氨蝶呤和151个周期的HD-MTX（B细胞：3 g/m²，T细胞ALL/T-NHL：5 g/m²）。54名（54）儿童为IR（均为B细胞ALL），39名儿童为HR-ALL（21名B-ALL，18名T-ALL/T-NHL）。两组的毒性综合发生率相似：卡皮齐甲氨蝶呤组为68/237个周期（28.7%），HD-MTX组为45/151个周期（29.8%）（P = 0.815）。然而，粘膜炎在HD-MTX组中更常见，为22/151个周期（1
