A Retrospective Study of Clofarabine Based Therapy in Patients With Relapsed or Refractory Acute Leukemia

Öz

Overall response rates of clofarabine-based rescue regimens in relapsed or refractory acute leukemia range from 17-48%. In our study, response rates, infection-related complications and side effects were evaluated after salvage therapy with clofarabine-based regimens in patients diagnosed with relapsed and/or refractory acute leukemia. Twelve patients who received clofarabine-based rescue therapy in our clinic between January 2015 and December 2020 were evaluated retrospectively. Fifty-eight percent of the patients were male and the mean age was 36.6±16.4 years. Seventy-five percent of the patients had a diagnosis of acute lymphoblastic leukemia, 25% had a diagnosis of acute myeloid leukemia. A median of 3 cycles of chemotherapy was given before clofarabine. Sixty-six percent of the patients were followed as refractory to the last treatment, and 33% as early relapse. Patients received intravenous treatment between 1st and 5th days at a dose of clofarabine 22,5 mg/m2+cytarabine 1000 mg/m2. During the treatment, all patients were complicated with febrile neutropenia, 58% of them developed sepsis. Serious (grade 3-4) non-hematological side effects were hepatotoxicity in 33%, diarrhea in 25%, nausea and vomiting in 16%, and mucositis in 16%. Neurotoxicity related to clofarabine was not observed. One of the patients achieved complete response (8%), 33% of the patients were unresponsive. The mortality rate within the first 30 days was 50% (n = 6). Early death (<2 weeks) occurred in one of the severe patient. For patients with refractory or early relapse acute leukemia, the main goal is to progress to allogeneic bone marrow transplantation after salvage therapy. Although complete remission can be achieved with bone marrow transplantation, 4-year survival does not exceed 25-30%. Therefore, a powerful and effective salvage treatment regimen is still needed in patients with relapsed or refractory acute leukemia.

Anahtar Kelimeler

• CLOFARABINE
• RELAPSED OR REFRACTORY ACUTE LEUKEMIA
• SIDE EFFECT

Klofarabin Bazlı Tedavi Alan Relaps veya Refrakter Akut Lösemi Tanılı Hastaların Retrospektif Değerlendirilmesi

Öz

Relaps veya refrakter akut lösemide klofarabin bazlı kurtarma tedavilerinin genel yanıt oranları %17-48 arasında değişmektedir. Çalışmamızda relaps veya refrakter akut lösemi tanılı hastalarda klofarabin bazlı kurtarma tedavisi sonrası yanıt oranları, enfeksiyon ile ilişkili komplikasyonları ve yan etkileri değerlendirildi. Ocak 2015 ile Aralık 2020 tarihleri arasında kliniğimizde klofarabin bazlı kurtarma tedavisi alan 12 hasta retrospektif olarak değerlendirildi. Hastaların %58 (n=7)’i erkek olup ortalama yaş 36,6±16,4 olarak saptandı. Hastaların %75 (n=9)’i akut lenfoblastik lösemi, %25 (n=3)’i akut myeloid lösemi tanısı ile takip edilmekteydi. Klofarabin öncesi almış oldukları kemoterapi rejim sayısı medyan 3 idi. Hastaların %66 (n=8)’sı son aldığı tedaviye refrakter, %33 (n=4)’ü erken nüks ile başvurdu. Hastalar klofarabin 22,5 mg/m2 + sitozin arabinozid 1000 mg/m2 dozunda intravenöz 1-5. gün olacak şekilde tedavi aldılar. Tedavi esnasında tüm hastalar febril nötropeni ile komplike oldu, hastaların %58 (n=7)’inde sepsis gelişti. Ciddi (grade 3-4) non- hematolojik yan etkiler arasında hepatotoksisite %33, diyare %25, bulantı-kusma %16, mukozit %16 civarındaydı. Klofarabine bağlı nörotoksisite izlenmedi. Hastaların birinde tam yanıt (%8) elde edildi. Hastaların %33 (n=4)’ü tedaviye yanıtsızdı. İlk 30 gün içindeki mortalite oranı %50 (n=6) idi. Mortal seyreden hastaların bir tanesinde erken ölüm (<2 hafta) oldu. Refrakter veya erken nüks akut lösemi hastaları için esas amaç kurtarma tedavisi sonrası allojenik kemik iliği nakline ilerlemektir. Her ne kadar kemik iliği nakli ile kür sağlanabilse de 4 yıllık sağ kalım %25-30’u geçmemektedir. Dolayısıyla relaps veya refrakter akut lösemi hastalarında günümüzde halen güçlü ve etkili bir kurtarma tedavi rejimine ihtiyaç duyulmaktadır.

Anahtar Kelimeler

• KLOFARABİN
• RELAPS VEYA REFRAKTER AKUT LÖSEMİ
• YAN ETKİ

Kaynakça

1. Emadi A. Baer MR. Acute Myeloid leukemia in adults. In: Greer JP, Arber DA, Glader B, List AF, Means RT, Paraskevas F, Rodgers G (eds). Wintrobe’s Clinical Hematology. Wolters Kluwer business 13th edition. Philadelphia: Lippincott Williams&Wilkins; 2014.
2. Löwenberg B, Downing JR, Burnett A. Acute myeloid leukemia. N Engl J Med. 1999;341:1051-62.
3. Creutzig U, Kaspers GJ. Revised recommendations of the International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2004;22:3432-33.
4. Fielding AK, Richards SM, Chopra R, et al. Medical Research Council of the United Kingdom Adult ALL Working Party; Eastern Cooperative Oncology Group. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-50.
5. Dohner H, Estey EH, Amadori S, et al. European LeukemiaNet. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115: 453-74.
6. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28:3730-38.
7. Camera A, Annino L, Chiurazzi F, et al. GIMEMA ALL - Rescue 97: a salvage strategy for primary refractory or relapsed adult acute lymphoblastic leukemia. Haematologica 2004;89:145-153.
8. Estey E, Kornblau S, Pierce S, et al. A stratification system for evaluating and selecting therapies in patients with relapsed or primary refractory acute myelogenous leukemia. Blood 1996;88:756.

9. Giles F, Verstovsek S, Garcia-Manero G, et al. Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse. British journal of haematology. 2006;134:58-60.
10. Montillo M, Mirto S, Petti MC, et al. Fludarabine, cytarabine, and G-CSF (FLAG) for the treatment of poor risk acute myeloid leukemia. Am J Hematol 1998;58:105-109.
11. Schlenk RF, Dohner K, Mack S, et al. Prospective evaluation of allogeneic hematopoietic stem-cell transplantation from matched related and matched unrelated donors in younger adults with high-risk acute myeloid leukemia: German-Austrian trial AMLHD98A. J Clin Oncol. 2010;28:4642-48.
12. Bonate PL, Arthaud L, Cantrell WR Jr, et al. Discovery and development of clofarabine: a nucleoside analogue for treating cancer. Nat Rev Drug Discov. 2006;5(10):855-63.
13. Huguet F, Leguay T, Raffoux E et al. Clofarabine for the treatment of adult acute lymphoid leukemia: the Group for Research on Adult Acute Lymphoblastic Leukemia intergroup. Leuk Lymphoma. 2015;56(4):847-57.
14. Kantarjian HM, Gandhi V, Kozuch P, et al. Phase I clinical and pharmacology study of clofarabine in patients with solid and hematologic cancers. J Clin Oncol. 2003;21(6):1167-73.
15. Jeha S, Gaynon PS, Razzouk BI, et al. Phase II study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clinc Oncol. 2006;24(12):1917-23.
16. Kantarjian H, Gandhi V, Cortes J, et al. Phase 2 clinical and pharmacologic study of clofarabine in patients with refractory or relapsed acute leukemia. Blood. 2003;102(7):2379-86.
17. Faderl S, Ravandi F, Huang X, et al. A randomized study of clofarabine versus clofarabine plus low-dose cytarabine as front-line therapy for patients aged 60 years and older with acute myeloid leukemia and high risk myelodysplastic syndrome. Blood. 2008;112:1638-45.
18. Faderl S, Wetzler M, Rizzieri D, et al. Clofarabine plus cytarabine compared with cytarabine alone in older patients with relapsed or refractory acute myelogenous leukemia: results from the CLASSIC I Trial. J Clin Oncol. 2012:30(20):2492-9.
19. Moujaess E, Kourie HP, Ghosn M. Cancer patients and research during COVID-19 pandemic: A systematic review of current evidence. Crit Rev Oncol Hematol. 2020;150:102972.