Cladribine combined with cytarabine in treatment of high-risk/refractory acute myelocytic leukemia and invasive NK/T cell lymphoma

Abstract

Objective To explore the efficacy and safety of cladribine combined with cytarabine in treatment of children with high-risk/refractory acute myelocytic leukemia (AML) and invasive natural killer /T cell lymphoma (NKTCL). Methods From December 2015 to July 2017, 2 cases of children with high risk/refractory AML and 1 case of child with invasive NKTCL in Children′s Hospital, Capital Institute of Pediatrics were selected as the research subjects. For 2 cases of children with high-risk/refractory AML, they were treated by cladribine + cytarabine + mitoxantrone + recombinant human granulocyte colony-stimulating factor (CLAG-M) scheme: intravenous infusion of cladribine 5 mg/(m2·d), d 2-6; intravenous infusion of cytarabine 2 g/(m2·d), d 2-6; intravenous infusion of mitoxantrone 10 mg/(m2·d), d 2-4; subcutaneous injection of recombinant human granulocyte colony-stimulating factor 3-5 μg/(kg·d), d 1-6. For the child with invasive NKTCL, he was treated by cladribine + cytarabine scheme: intravenous infusion of cladribine 5 mg/(m2·d), d 1-5 and intravenous infusion of cytarabine 500 mg/(m2·d), d 1-5. Clinical case data of those 3 children were retrospectively analyzed and their clinical manifestations, diagnoses, treatments and prognoses were summarized. This study met the requirements of the World Medical Association Declaration of Helsinki revised in 2013. The guardians of those 3 children signed informed consent form for clinical treatment before treatment. Results ①The patient 1 was a female, 16 years old, and was clinically diagnosed as high-risk/refractory AML M5. She received CLAG-M scheme as the induction therapy. And after the first course of treatment, she achieved complete remission, there was no leukemia cell in the bone marrow cells morphological examination, and the minimal residual disease (MRD) of bone marrow was 1.37% detected by flow cytometry, the quantitative detection of MLL-AF9 fusion gene was 0. However, patient 1 died of intracranial bleeding due to bone marrow suppression (thrombocytopenia) during subsequent consolidation therapy. ②The patient 2 was a female, 6 years old, and was clinically diagnosed as high-risk/refractory AML M2. After 1 course of CLAG-M scheme induced treatment, she achieved complete remission. And none leukemia cell was found in bone marrow cells morphological examination. The result of flow cytometry showed that bone marrow MRD was 0.81%. Bone marrow MRD was less than 0.001% after receiving the second course of CLAG-M treatment. Since then, haploid allogeneic hematopoietic stem cell transplantation has been carried out in patient 2. Up to now, the event free survival time of patient 2 has reached 2 years after transplantation. ③The patient 3 was a male, 4 years old, hospitalized in our hospital due to skin damage for more than 5 and was clinically diagnosed as invasive NKTCL. After 1 course of treatment with cladribine + cytarabine, no new rash appeared within 7 days. After 20 days, the bleeding and ulceration of the skin were significantly reduced, about 80% of the damaged skin of the nose, trunk and limbs scabbed, and the damaged skin of the nose wing was about 50% less. After 40 days, 50% to 60% of the damaged skin of the trunk and limbs healed, reaching partial remission. In the end, the patient 3 received sibling hematopoietic stem cell transplantation with tumor. One month after transplantation, the bone marrow cells morphological examination showed that he had achieved complete remission, and the bone marrow MRD was less than 0.001%. Two months after transplantation, the invasive NKTCL of the patient 3 recurred, and the donor lymphocyte infusion was performed once, and the tumor burden did not increase again. So far, the tumor-bearing survival time of patient 3 has reached 1 year after transplantation. ③Ⅳ degree of bone marrow suppression and different levels of infection were observed in all those 3 children during treatment, but the symptoms were controlled after symptomatic and anti-infection treatments. Conclusions The CLAG-M scheme, cladribine + cytarabine scheme are effective in treating some children with high-risk/refractory AML and invasive NKTCL, and they are effective bridges for such patients before hematopoietic stem cell transplantation. Prevention and treatment of infection is the key to the success of these two schemes in treatment of children with high-risk/refractory AML and invasive NKTCL. Because this study is only a retrospective case study, the efficacy of cladribine combined with cytarabine in treatment of children with high-risk/refractory AML and invasive NKTCL remains to be confirmed by large-sample, multicenter and randomized controlled trials. Key words: Cladribine; Cytarabine; Leukemia, myeloid, acute; High risk/refractory; Invasive natural killer/T cell lymphoma; Hematopoietic stem cell transplantation; Infection; Child