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Table of Contents
CASE REPORT
Year : 2021  |  Volume : 9  |  Issue : 1  |  Page : 39-41

High-dose methotrexate: Treatment experience in patient with B-cell philadelphia-positive acute lymphoblastic leukemia


Department of Pharmacology and Pharmacy Practice, Maliba Pharmacy College, Uka Tarsadia University, Surat, Gujarat, India

Date of Submission04-May-2021
Date of Decision11-Jun-2021
Date of Acceptance19-Jun-2021
Date of Web Publication17-Aug-2021

Correspondence Address:
Dr. Avinash Khadela
Maliba Pharmacy College, Uka Tarsadia University, Gopal Vidyanagar, Bardoli Mahuva Road, Surat - 394 350, Gujarat
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jihs.jihs_13_21

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  Abstract 


High-dose methotrexate (HDMTX) is gaining importance in the management of acute lymphoblastic leukemia (ALL). Its efficacy and toxicity depends on dose strength, route of administration, and infusion time. HDMTX toxicities can be controlled by continuous monitoring of urine pH and adequate supportive care (hyper-hydration, alkalinizing agents, and leucovorin rescue). A patient suffering from B cell Ph + ALL was kept on Berlin-Frankfurt-Münster-90 protocol and administered methotrexate 8 g/cycle by intravenous infusion with normal saline over 6 h. He developed leucopenia and severe anemia after receiving the first cycle of chemotherapy, which was treated with subcutaneous filgrastim 300 mcg OD for 5 days and 1 pint red blood cell. After the third cycle, patient developed mucositis and treated with leucovorin and local anesthetics; and continued the chemotherapy. In conclusion, the patient was continuously monitored for urine pH and tolerated the HDMTX well when provided adequate supportive care.

Keywords: Acute lymphoblastic leukemia, high-dose methotrexate, leucovorin


How to cite this article:
Khadela A, Vyas B, Joshi S. High-dose methotrexate: Treatment experience in patient with B-cell philadelphia-positive acute lymphoblastic leukemia. J Integr Health Sci 2021;9:39-41

How to cite this URL:
Khadela A, Vyas B, Joshi S. High-dose methotrexate: Treatment experience in patient with B-cell philadelphia-positive acute lymphoblastic leukemia. J Integr Health Sci [serial online] 2021 [cited 2021 Dec 6];9:39-41. Available from: https://www.jihs.in/text.asp?2021/9/1/39/323949




  Introduction Top


Methotrexate (MTX) is a folate antagonist widely used for the treatment of various malignancies such as acute lymphoblastic leukemia (ALL), osteosarcoma, primary central nervous system (CNS) lymphomas, nonhodgkin lymphomas, and leptomeningeal cancer.[1] The doses may vary from 20 mg/m2 to 33,000 mg/m2 depending on various malignant conditions.[2] Based on dosage strength, MTX therapy is divided into two different regimens; low-dose MTX and high-dose methotrexate (HDMTX). Anything >500 mg/m2 is considered HDMTX regimen, which has been used for adult and childhood leukemia for the past few years.[3] HDMTX regimen is administered through intravenous infusion to the patients suffering from ALL after assessing the blood parameters, renal, and liver function tests. It has numerous benefits such as potential to overcome resistance against MTX, higher efficacy and selectivity toward malignant cells, and provides CNS prophylaxis.[4] Although HDMTX is a promising anti-cancer agent, it can cause significant toxicity such as acute kidney failure (AKF), acute kidney injury (AKI), mucositis, and severe bone marrow suppression.[1],[5],[6] These toxicities can be minimized by concomitant administration of urinary alkalinizing agents, leucovorin with or without thymidine-glucarpidase rescue, and granulocyte colony-stimulating agents granulocyte colony-stimulating factor (G-CSF).[7],[8]

In this case, the patient developed severe bone marrow suppression and mucositis, which was well managed by the administration of filgrastim and leucovorin. Otherwise, the patient had tolerated the treatment well and recovered. This case report provides an overview of HDMTX utilization in the patients suffering from ALL, possible adverse events followed by HDMTX administration and necessary supportive care required to encounter the toxicities associated with HDMTX.


  Case Report Top


A 50-year-old male weighing 71 kg was suffering from Philadelphia chromosome positive ALL (Ph + ALL) for the past 1 year. He also had deep vein thrombosis for the past 7 years and kept on tablet nicoumalone 4 mg. As per the national comprehensive cancer network guidelines and evidence-based medicine approach, the patient was treated with Berlin-Frankfurt-Münster 90 (BFM-90) protocol and tolerated the induction phase without much complication.[9] Consolidation therapy was then started which includes HDMTX (8 g I. V. infusion in 500 ml NS, administered over 6 h) with 6-mercaptopurine (6-MP) in 50 mg dose PO (6 cycles in consolidation phase). Before initiation of HDMTX therapy at each cycle, he was hydrated well with 500 ml normal saline and administered alkalinizing agent (sodium bicarbonate 2 tablets qid PO) before 12 h of HDMTX administration to prevent HDMTX-induced metabolic acidosis and acute kidney failure.[10] Afterward 30 min before initiation of HDMTX therapy, he was administered with antiemetics namely aprepitant (125 mg po stat), palonosetron with dexamethasone (0.25 mg and 12 mg, respectively through 100 ml saline over 30 min) as a prechemotherapy medication, and urine pH of patient was monitored 6 hourly at each cycle. After receiving two cycles, patient's general condition was fair and vitals were normal. The patient advised for complete blood count, liver function test, chest-X ray-PA, serum creatinine and prothrombin time, and international normalized ratio before further chemotherapy. The laboratory data were found to be normal except Hemoglobin (7.3 g%) and total leukocyte count (1400 cells/cumm) which revealed severe anemia and leucopenia, respectively. This could be ascribed to HDMTX therapy as per the WHO and Naranjo's scale of causality assessment. The patient was prescribed with Inj. Filgrastim 300 mcg S. C. OD for leucopenia and 1 pint packed red blood cell to maintain hemoglobin content. Therapy was continued till anemia and leucopenia were subsided. Two days later, the laboratory data were found to be normal and initiated the next cycle of chemotherapy with HDMTX. Renal function test was carried out at regular interval throughout the treatment and no toxicity was reported. After 24 h of HDMTX infusion, the patient started with Inj. Leucovorin 15 mg I. V. 6 hourly for two consecutive days. The patient was stable and discharged with medications cap. Aprepitant 80 mg PO stat, tablet. Sodium bicarbonate 50 mEq PO double strength Q. I. D for 2 days, tablet. Pantoprazole 40 mg PO once a day for 7 days, tablet. 6-MP 50 mg PO once a day for 15 days, tablet leucovorin 15 mg PO thrice a day for 3 days. The patient developed grade III mucositis on 3rd day of discharge and was admitted to the hospital for monitoring HDMTX toxicity.[11] On examination, his vital was found to be stable and advised to take tablet. Leucovorin 15 mg twice daily for 2 days, tablet paracetamol 650 mg (as and when needed), tablet diclofenac 100 mg twice daily for 3 days, xylocaine jelly, and povidone-iodine lotion. The laboratory data were monitored throughout the hospital stay of the patient and found to be unremarkable. The patient was recovered from mucositis, was stable and discharged after 2 days. No further complications were reported throughout the consolidation therapy and the patient tolerated all three phases of the BFM-90 protocol.


  Discussion Top


MTX is a potent cytotoxic drug and can illicit numerous lethal side-effects ranging from severe bone-marrow suppression to acute kidney failure (AKI). The potency of MTX plays a vital role in curing deadly diseases such as hematological malignancies. If the normal dose of MTX imparts a high risk of toxicities, the toxicities of HDMTX may be life-threatening and needs careful medical attention for smooth tolerance of the treatment.[11] In this case, the patient was prescribed with BFM-90 protocol which consists of the four phases induction, consolidation, re-induction, and maintenance. In consolidation phase, the patient had been prescribed with HDMTX and 6 MP for complete elimination of malignant cells.[12] HDMTX can completely destroy the cancerous cells by competing with folic acid and binds to dihydrofolate reductase and disturb the formation of new DNA.

It is a great challenge for the medical oncologist to preserve the normal cells from HDMTX toxicities and can only be achieved by continual monitoring and adequate supportive care. The patient would be given vigorous hydration to avoid MTX-induced nephrotoxicity, leucovorin rescue in the patients having normal renal function, and G-CSF namely filgrastim and peg-filgrastim to prevent MTX-induced leukopenia. In addition, appropriate antiemetic agents should be prescribed to avoid chemotherapy-induced nausea and vomiting (CINV). In this case, the patient was prescribed two potential antiemetic drugs such as aprepitant i. e., neurokinin 1 antagonist and palonosetron, i.e., 5-HT3 receptor antagonist. These potential antiemetic drugs prevent CINV that decreases patient's suffering and improve medication adherence. Moreover, vigorous hydration and urinary alkalizing agents would prevent HDMTX-induced AKI and helps to maintain the normal pH. In addition, leucovorin rescue should be provided to maintain the integrity of normal host cells. If prescribed rationally leucovorin prevents HDMTX toxicities such as myelosuppression, mucositis, and stomatitis.[13] G-CSF plays an essential role in the prevention of chemotherapy-induced bone marrow suppression which ultimately the major cause of delayed initiation of subsequent chemotherapy.[14]


  Conclusion Top


To summarize, the patient initially developed severe anemia and leucopenia that was treated with 1 pint red blood cell followed by iron supplement and filgrastim. The patient recovered within 2 days after providing necessary treatment and subsequent chemotherapy resumed. Few days later, he developed grade III mucositis which was treated with high-dose leucovorin and symptomatically with local anesthetic and mild analgesics. The patient recovered and tolerated all the subsequent cycles of chemotherapy without any significant adverse events.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Green MR, Chamberlain MC. Renal dysfunction during and after high-dose methotrexate. Cancer Chemother Pharmacol 2009;63:599-604.  Back to cited text no. 1
    
2.
Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist 2006;11:694-703.  Back to cited text no. 2
    
3.
Walling J. From methotrexate to pemetrexed and beyond. A review of the pharmacodynamic and clinical properties of antifolates. Invest New Drugs 2006;24:37-77.  Back to cited text no. 3
    
4.
Gökbuget N, Hoelzer D. High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia. Ann Hematol 1996;72:194-201.  Back to cited text no. 4
    
5.
Kintzel PE, Campbell AD, Yost KJ, Brinker BT, Arradaza NV, Frobish D, et al. Reduced time for urinary alkalinization before high-dose methotrexate with preadmission oral bicarbonate. J Oncol Pharm Pract 2012;18:239-44.  Back to cited text no. 5
    
6.
Von Hoff DD, Penta JS, Helman LJ, Slavik M. Incidence of drug-related deaths secondary to high-dose methotrexate and citrovorum factor administration. Cancer Treat Rep 1977;61:745-8.  Back to cited text no. 6
    
7.
Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol 1981;19:453-6.  Back to cited text no. 7
    
8.
Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 1977;297:630-4.  Back to cited text no. 8
    
9.
Chang JE, Medlin SC, Kahl BS, Longo WL, Williams EC, Lionberger J, et al. Augmented and standard Berlin-Frankfurt-Munster chemotherapy for treatment of adult acute lymphoblastic leukemia. Leuk Lymphoma 2008;49:2298-307.  Back to cited text no. 9
    
10.
Khadela A, Vyas B, Joshi S. Role of glucarpidase for intoxication of high dose methotrexate toxicity. J Pharm Appl Sci 2019;6:1-10.  Back to cited text no. 10
    
11.
Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and managing toxicities of high-dose methotrexate. Oncologist 2016;21:1471-82.  Back to cited text no. 11
    
12.
Dolai TK, Panigrahi A, De R, Kumar M, Mandal P, Bagchi B, et al. Outcome of ALL-BFM (Berlin-Frankfurt-Münster) 90 Protocol in childhood acute lymphoblastic leukemia in a resource constraint setting. Washington, DC: American Society of Hematology; 2015.  Back to cited text no. 12
    
13.
Ferdousi SA, Akhter A, Nahar K, Islam A. High dose methotrexate and leucovorin rescue therapy in childhood malignancies: Experience in resource-limited country. Bangladesh J Child Health 2017;41:15-23.  Back to cited text no. 13
    
14.
Bendall LJ, Bradstock KF. G-CSF: From granulopoietic stimulant to bone marrow stem cell mobilizing agent. Cytokine Growth Factor Rev 2014;25:355-67.  Back to cited text no. 14
    




 

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