Treatment-related Acute Myeloid Leukemia Following Capecitabine Chemotherapy: A case report
Niloufar Saber-Moghaddam1, Sajad Ataei Azimi2, Alireza Bari2, Omid Arasteh1
1Department of Clinical Pharmacy, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
2Hematology-Oncology department, School of medicine, Mashhad University of Medical Sciences, Mashhad, Iran
*Omid Arasteh ,Department of Clinical Pharmacy, Faculty of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Figure 1: Cytogenetic analysis of A. V.’s bone marrow sample
1: 5-Fluorouracil. 2: esophageal squamous cell carcinoma. 3: Radiation therapy. 4: Cytarabine. 5: All-trans retinoic acid
Our Case had a history of exposure to Capecitabine (cumulative dose of 336000 mg) and developed AML 42 months after the exposure. Capecitabine is a prodrug and metabolized to its active metabolite, 5-fluoroxyuridine monophosphate (5-FUMP) inside the body, so despite there being no report of developing t-AML with that, it would not be out of mind. The latency period of developing t-AML was nearly similar between our case and other case reports. It seems that a higher cumulative dose of 5-FU is associated with the more rapid development of t-AML. However, more studies are needed to confirm this result.
Genetic basis of t-AML:
It seems that mutation is the main mechanism of developing AML following the administration of cytotoxic agents. Cytogenetic abnormalities such as -5 and -7/del(5q and 7q), translocation of (11q23), complex karyotypes, or +8 trisomy have been frequently seen in t-AML patients(17). Other cytogenetic abnormalities such as trisomy in one or more pairs of other chromosomes are also reported in t-AML patients(20). Baeu et al reported abnormalities in chromosomes 5 and 7 as the most common cytogenetic abnormalities in alkylating agents and/or radiotherapy recipients (9). The result of del. (5q and 7q) is haploinsufficiency in genes that are responsible for cell growth and proliferation(21).
An interruption in the expression of cell cycle control genes is also seen in t-AML patients, which can justify the occurrence of MDS/AML (22). Furthermore, some studies mentioned that CYP polymorphisms can play a role in the development of t-AML (23-26). Studies also mentioned that Germ-line mutations in the NF-1 and p53 tumor-suppressor genes are repeatedly seen in patients who develop t-AML following MDS (27, 28). Other probable causes of developing t-AML include induction of genome instability or a fusion oncogene, hyper-proliferation of mutant cells, and inflammation(24, 29, 30).
The cytogenetic analysis showed no abnormal translocations, but hyperploidism (trisomy in pairs 7,8, and 21) was seen in our patient.
Clinical presentation and prognosis of t-AML:
Alkylating agents, topoisomerase II inhibitors, and some other drugs like Bimolane are well-known for the development of t-AML(7). Anti-metabolites are less often suspected for the development of t-AML. however, the rate of developing t-AML in anti-metabolite recipients is higher compared to the general population(7, 13).
The time period between receiving chemo/radiotherapy for the primary disease and developing AML varies from months to years and depends on many factors such as chemotherapeutic agent class, cumulative dose of chemotherapeutic drugs or radiation, and dose intensity in each chemotherapy cycle (8, 31, 32).
The clinical presentation is the same in all types of AML(24). In patients who received alkylating agents, t-AML occurs following the presentation of MDS with symptoms of fatigue, fever and cytopenia (9). In topoisomerase II inhibitors recipients, MDS phase does not exists and patients present with overt AML (11). In all case reports of developing t-AML following the administration of 5-FU, patients presented with common symptoms of overt AML including general weakness, fatigue, fever and weight loss in addition to cytopenia and presenting blasts in peripheral blood smear and bone marrow sample (16-19, 33) . our patient’s primary symptom was general weakness and anorexia. Physical examination was negative for fever, lymphadenopathy, organomegaly or skin lesions. The patient's baseline laboratory data showed a leukocytosis with 93% blast and 3% lymphocytes, thrombocytopenia and increase in inflammatory markers.
Patients who develop t-AML have a poor prognosis compared to other patients with AML (20, 34, 35). Samra et al mentioned that overall survival and relapse-free survival is significantly worse in t-AML patients compared to other AML patients. Furthermore, the mortality rate in remission was higher in t-AML patients compared to AML patients (51% vs 16% ) (36). It seems like the reason for poor outcomes in this population is the higher incidence of unfavorable karyotypes and cytogenetic abnormalities, respecting that patients with favorable karyotype and good performance status have treatment outcomes same as patients with de novo AML (37-40). However, a recent retrospective study on 742 AML patients showed that t-AML patients had older age but similar mutation profile compared to other AML patients(36).
A brief review of genetic and clinical features of t-AML subtypes and comparison to our case is reviewed in Table 2.
Table 2: A comparison of characteristics between different types of t-AML
1: Topoisomerase. 2: 5-Fluorouracil. 3: Treatment-related AML. 4: Deletion. 5: Myelodysplastic syndrome
Treatment of t-AML:
The treatment of t-AML is the same as the de novo form, including the standard dose of an Anthracycline (D1-D3) plus Cytarabine (Ara-C) (D1-D7) for induction of remission, following a consolidation regimen with a high dose of Cytarabine (HiDAC). In reported cases, 3 studies used Idarubicin plus Ara-C, one study used Mitoxantrone and one study used Danorubicin plus Ara-C for the induction of remission. Except for the Danorubicin recipient, other patients reached complete remission(CR) and also received consolidation treatment with HiDAC (16-19). Although it seems like the achievement of CR is expected in 5-FU recipients who developed t-AML, a review article has reported that remission was achieved in only a small number of t-the AML patients while using the conventional 7+3 regimen (24). Our patient also received a standard 7+3 regimen with Danorubicin plus Ara-C but developed febrile neutropenia during the recovery time, and finally expired because of sepsis and cardiac arrest.
Despite the conflicting treatment outcomes with standard treatments of AML in t-AML patients, there is no other proven choice for the treatment of this population. CPX351 is an investigational formulation that contains liposomal Daunorubicin plus Cytarabine which is under evaluation for the treatment of t-AML patients. Clinical studies have shown that CPX351 is effective and can have beneficial effects on patients’ performance status before allogeneic bone marrow transplantation (41-43).
Allogenic Hematopoietic Stem Cell Transplantation (HSCT) is another treatment for all-cause AML. Compare to de novo AML, patients with t-AML Samra et al also mentioned that both induction of remission with chemotherapy and HSCT had a higher rate of remission and survival in de novo AML patients compared to t-AML patients (36).
Table 3: A review of t-AML case reports.
SA and AB collected and interpreted the patient data regarding the hematological disease.
NS and OA analyzed the patient’s data and were the major contributors to writing the manuscript.
All authors read and approved the final manuscript.
Ethics approval and consent to participate
Before writing the article, consent was obtained from the patient to use his medical information without mentioning his name or providing identifying information
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