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 Table of Contents  
Year : 2020  |  Volume : 11  |  Issue : 2  |  Page : 77-79

Valproic acid for the treatment of refractory pediatric primary bone anaplastic large-cell lymphoma: A case report and literature review

1 Department of Hematology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
2 Department of Hematology, King Abdulaziz University Hospital; King Faisal Special Hospital and Research Center, Jeddah, Saudi Arabia

Date of Submission12-Jan-2020
Date of Acceptance03-Apr-2020
Date of Web Publication28-Jul-2020

Correspondence Address:
Dr. Ali H Algiraigri
Department of Hematology, King Abdulaziz University Hospital, Jeddah 22252
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/joah.joah_3_20

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Primary bony anaplastic large-cell lymphoma is quite rare in children but potentially life-threatening lymphoma. Such disease is challenging and often carries a poor prognosis. Here, we report a patient who presented with an aggressive bony lymphoma and failed to respond to conventional chemotherapy; however, he had a robust response to valproic acid, which changed his status from hopeless palliative case to a success story and allowed him to complete his intended chemotherapy protocol.

Keywords: Bony anaplastic large-cell lymphoma, lymphoma, valproic acid

How to cite this article:
Al-Bloushy RI, Sait SH, Algiraigri AH. Valproic acid for the treatment of refractory pediatric primary bone anaplastic large-cell lymphoma: A case report and literature review. J Appl Hematol 2020;11:77-9

How to cite this URL:
Al-Bloushy RI, Sait SH, Algiraigri AH. Valproic acid for the treatment of refractory pediatric primary bone anaplastic large-cell lymphoma: A case report and literature review. J Appl Hematol [serial online] 2020 [cited 2023 Feb 4];11:77-9. Available from: https://www.jahjournal.org/text.asp?2020/11/2/77/290961

  Introduction Top

Non-Hodgkin lymphoma (NHL) is a malignant neoplasm of the lymphoid tissues. NHL is the fifth most common malignant disease in children under the age of 15 years and representing about 7% of pediatric malignancies in the developed world.[1] Most pediatric NHL cases are of high grade and have an aggressive clinical behavior and can be of four main subtypes: Burkitt lymphoma, diffuse large-cell lymphoma, lymphoblastic lymphoma, and anaplastic large-cell lymphoma (ALCL).[2] ALCL is a T-cell lymphoma that typically presents as painless lymphadenopathy with or without skin or subcutaneous involvement. Systemic symptoms such as fever and constitutional symptoms are often reported.[3] However, primary bony ALCL is extremely rare in children and often carries a poor prognosis.[3]

  Case Report Top

We present a case of biopsy-proven primary bony ALCL (anaplastic lymphoma kinase positive) presenting with systemic symptoms including high-grade fever, bedridden due to severe bony aches, and generalized edema in an 8-year-old boy. Spine magnetic resonance imaging showed extensive vertebral involvement of the whole spine as well as both iliac bones. Gallium scan showed uptake at above-mentioned sites as well as some ribs. Surprisingly, there were no significant lymph nodes enlargement nor hepatosplenomegaly. As such, a decision was made to go after the bony lesion, which revealed a classical picture of ALCL. He was started on chemotherapy per ALCL 99 which used six cycles of intensive chemotherapy after cytoreductive prophase. Such protocol contains the following chemotherapeutic agents: dexamethasone, cyclophosphamide, ifosfamide, etoposide, doxorubicin, high-dose methotrexate (3 g/m2 arm), cytarabine, and prednisolone.[4]

Despite such intense chemotherapy protocol, his systemic symptoms did not respond to cytoreductive prophase phase or to the first cycles of the protocol. His course was complicated with posterior reversible encephalopathy syndrome, presenting as a seizure. Soon after starting him on valproic acid (VA) 15 mg/kg/day as an anti-seizure medication, his lymphoma symptoms started to be improved and disappeared completely with 1 week. We thought to stop VA to prove its association, but we hesitated to do so due to his critical condition and the encouraging preclinical data about VA as histone deacetylase (HDAC) inhibitor. He then continued VA as well as his chemotherapy protocol (ALCL 99). The planned duration of VA is to be continued for at least 2 years. End-of-therapy restaging showed a complete resolution of disease. He is currently 1 year of therapy, doing well, and completely mobilized with no restriction.

  Discussion Top

The current best treatment modality for ALCL is combination chemotherapy. There is a very limited role for surgical as well as radiotherapy in such a diagnosis. There is no consensus about a common treatment regimen, and chemotherapy approaches differ across the Atlantic.[4],[5] For instance, in North America, prolonged yet outpatient therapies with vincristine, doxorubicin, and steroids are used.[5] In contrast, a short yet more intense inpatient chemotherapy has been utilized in Europe.[4] Prognosis of ALCL is quite reasonable with 5-year event-free survival approaching 70% using either above-mentioned treatment approaches.[4],[5] However, our patient exhibited an aggressive and refractory course to one of the standard of care approaches (ALCL 99) until he got exposed to VA which changed his disease status from refractory to very responsive case.

VA is a well-known antiepileptic agent that has been used for many decades.[6] Although not known as a chemotherapeutic drug, it has antineoplastic properties due to its inhibitory effect on the HDAC, an essential step in tumorigenesis.[7] As mentioned above, our use of VA in this case was primarily as anti-seizure; however, the quick and sustained response of VA in such aggressive refractory lymphoma grabbed our attention to investigate its rule as anticancer drug. A literature review of such a rule revealed promising clinical and preclinical evidence.[8],[9],[10],[11] For instance, a retrospective study on adult T-cell leukemia/lymphoma showed that out of 175, 10 patients presented with a long survival rate, 5 of these patients used VA for neurological disorders. Those who were treated with VA had a higher survival rate.[12]

Although we cannot be certain, the good response that we observed in our case is due to the additive synergistic rather than the sole effect of VA to the chemotherapy backbone of ALCL 99. As such, we continued both chemotherapy as well as VA throughout his treatment course. Such a response is likely through the HDAC inhibition mechanism which triggers lymphoma cell autophagy.

Although the VA is well tolerated by most of the patients, it can cause some adverse events. These adverse events are related to gastrointestinal, neurological, and dermatological systems and others.[6] The most common side effect is gastrointestinal manifestations including nausea, vomiting, and abdominal discomfort.[6] On the other hand, it seems that there is no documented or known major drug-to-drug interaction when using VA with chemotherapeutic agents.[13] Such a feature is very important in choosing antiepileptic medication in an oncological patient who is receiving active chemotherapy.

Although it was used for a different purpose, our observations suggest that VA may be effective for treating ALCL. Prospective studies are needed to confirm its efficacy. Being an HDAC inhibitor and has no major drug interaction with chemotherapeutic agents, VA appeared very attractive option to be used in an oncological patient who is suffering from seizure and needed antiepileptic medication.

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


Conflicts of interest

There are no conflicts of interest.

  References Top

Kaatsch P. Epidemiology of childhood cancer. Cancer Treat Rev 2010;36:277-85.  Back to cited text no. 1
Ries LA, Smith MA, Gurney JG, Linet M, Tamra T, Young JL, et al. Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995; 1999.  Back to cited text no. 2
Sandlund JT, Downing JR, Crist WM. Non-Hodgkin's lymphoma in childhood. N Engl J Med 1996;334:1238-48.  Back to cited text no. 3
Le Deley MC, Rosolen A, Williams DM, Horibe K, Wrobel G, Attarbaschi A, et al. Vinblastine in children and adolescents with high-risk anaplastic large-cell lymphoma: Results of the randomized ALCL99-vinblastine trial. J Clin Oncol 2010;28:3987-93.  Back to cited text no. 4
Laver JH, Kraveka JM, Hutchison RE, Chang M, Kepner J, Schwenn M, et al. Advanced-stage large-cell lymphoma in children and adolescents: Results of a randomized trial incorporating intermediate-dose methotrexate and high-dose cytarabine in the maintenance phase of the APO regimen: A Pediatric Oncology Group phase III trial. J Clin Oncol 2005;23:541-7.  Back to cited text no. 5
Perucca E. Pharmacological and therapeutic properties of valproate: A summary after 35 years of clinical experience. CNS Drugs 2002;16:695-714.  Back to cited text no. 6
Marks P, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: Causes and therapies. Nat Rev Cancer 2001;1:194-202.  Back to cited text no. 7
Garcia-Manero G, Kantarjian HM, Sanchez-Gonzalez B, Yang H, Rosner G, Verstovsek S, et al. Phase ½ study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia. Blood 2006;108:3271-9.  Back to cited text no. 8
Soriano AO, Yang H, Faderl S, Estrov Z, Giles F, Ravandi F, et al. Safety and clinical activity of the combination of 5-azacytidine, valproic acid, and all-trans retinoic acid in acute myeloid leukemia and myelodysplastic syndrome. Blood 2007;110:2302-8.  Back to cited text no. 9
Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, et al. The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia. Cancer 2006;106:112-9.  Back to cited text no. 10
Blum W, Klisovic RB, Hackanson B, Liu Z, Liu S, Devine H, et al. Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia. J Clin Oncol 2007;25:3884-91.  Back to cited text no. 11
Yves P, Stephane M, Rishika B, Christine D, Gérard P. Characteristics of adult T-cell leukemia/lymphoma patients with long survival: Prognostic significance of skin lesions and possible beneficial role of valproic acid. Leuk Res Treatment 2015;2015:476805.  Back to cited text no. 12
Su JM, Li XN, Thompson P, Ou CN, Ingle AM, Russell H, et al. Phase 1 study of valproic acid in pediatric patients with refractory solid or CNS tumors: A children's oncology group report. Clin Cancer Res 2011;17:589-97.  Back to cited text no. 13

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