Chemotherapy-Colchicine Interaction in a Child with Familial Mediterranean Fever and Hodgkin Lymphoma
1 Division of
Hematology/Oncology, Department of Paediatrics, The Hospital for Sick
Children, University of Toronto, Toronto, Ontario, Canada.
2 Division of Rheumatology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
3 Department of Pharmacy, The Hospital for Sick Children, Toronto, Canada.
4 Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada.
5 Research Institute, The Hospital for Sick Children, Toronto, Canada.
6 The Hospital for Sick Children, University of Toronto, Toronto, Canada.
Received: December 6, 2017
Accepted: January 15, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018019 DOI 10.4084/MJHID.2018.019
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Mediterranean fever (FMF) has been associated with hematological
malignancies but has not been reported in association with Hodgkin
lymphoma (HL). We hereby describe the first pediatric patient with FMF
and stage IIA nodular sclerosis HL. She was treated with prednisone,
doxorubicin, vincristine and etoposide (OEPA) being on therapy with
colchicine. However, she suffered more than expected treatment-related
toxicity attributed either to chemotherapy (severe neutropenia) or
colchicine (Abdominal pains and diarrhoea). Colchicine had to be
discontinued. In the absence of colchicine, she tolerated very well the
second cycle of chemotherapy. Currently, she is in remission at 17
months after her HL diagnosis, and her FMF is under control with
colchicine without any signs of toxicity.
Familial Mediterranean fever (FMF) (OMIM 249100) is an autoinflammatory syndrome that can be adequately treated in the majority of cases with colchicine. Clinically, FMF is characterized by recurrent episodes of fever, serositis, arthritis, dermal manifestations and long-term renal complications. The goals of FMF treatment are to prevent acute attacks, decrease the subclinical inflammation between the attacks and to prevent the development of amyloidosis. Colchicine suppresses pyrin oligomerization and interferes with neutrophil migration. It also prevents cytoskeletal changes that lead to pyrin inflammasome assembly. Alternative treatment options, particularly for colchicine-resistant or intolerant patients include interleukin-1 inhibitors such as anakinra and canakinumab. FMF has been reported in association with adult hematological malignancies such as multiple myeloma, acute lymphoblastic and myeloid leukemias and myelodysplastic syndromes.[7-12] However, this entity has not been reported in association with HL in adults or children. We describe the first case of HL in a pediatric patient with FMF, who developed myelotoxicity due to the combination of colchicine with chemotherapy.
|Figure 1. Clinical course and neutrophils count in relationship with drugs administration.|
Her first treatment course was complicated by prolonged myelosuppression including CTCAE grade 4 neutropenia, fever and severe abdominal pain. She needed to be admitted on day 8 for clinical sepsis, requiring three intravenous fluid boluses and antibiotics. Furthermore the second infusion of Vincristine and Doxorubicin was postponed to Day 16. No other signs of colchicine toxicity, such as bloody stool, renal failure or disseminated intravascular coagulation were noted. Blood cultures remained negative. She was discharged home after twelve days but needed readmission on day 22 due to severe abdominal pain and loose stools, treated with intravenous hydration and morphine for nine days. After consultation with the Rheumatology service, colchicine was discontinued from day 27 of cycle 1 onwards, to prevent possible interactions with chemotherapy. Cycle 2 was started 36 days after start of cycle 1. She tolerated this much better, without any complications and count recovery within the expected timeframe. Clinical and radiographic evaluations showed no evidence of disease at the end of therapy. The patient currently remains in remission 17 months after completion of therapy. Subsequently, she developed similar fever attacks and colchicine was resumed at the same dose 3 months after completion of chemotherapy. Her FMF has been well controlled since, without any signs of colchicine toxicity.
Management of FMF with colchicine has benefitted patients by reducing painful attacks and preventing amyloidosis. Therefore, this drug was continued during initiation of anti-cancer treatment. However, our patient did not tolerate the combination with the low-intensity chemotherapy regimen.
Colchicine has a narrow therapeutic index. It is readily absorbed after oral administration, but has a variable bioavailability (ranging from 25% to 88%) and undergoes extensive first-pass metabolism. It has a wide volume of distribution (Vd) and binds to intracellular elements. Colchicine is primarily metabolized by the liver, undergoes significant enterohepatic re-circulation, and is also excreted by the kidneys. CYP3A4 and P-glycoprotein inhibitors can increase serum colchicine concentrations. Etoposide, prednisone, vincristine and doxorubicin are substrates of CYP3A4, and therefore the clearance of these drugs may decrease with concurrent administration of colchicine, and their side effects may increase. Since colchicine is also a substrate of CYP3A4, its clearance may be decreased by these drugs due to competitive inhibition. In addition, the target for both colchicine and vincristine is tubulin beta chain which may add to toxicity when administered together. Thus, our patient may have experienced gastrointestinal adverse effects and prolonged bone marrow suppression, as described in patients with colchicine toxicity, due to CYP3A4-mediated impairment of colchicine or antineoplastic agent metabolism or an additive effect on tubulin inhibition.
Colchicine was discontinued in our patient and the second cycle of chemotherapy was well tolerated, without fever or abdominal pain. She is currently disease-free 17 months after completing therapy.
In summary, to the best of our knowledge, we describe the first case of Hodgkin lymphoma in a patient with familial Mediterranean fever. Colchicine should be given with caution in patients treated with drugs substrate of CYP3A4 and/ or effecting on tubulin polymerization, like vincristine. To this end, a strict collaboration between oncology and rheumatology is warranted when managing these patients.
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