title: Time sequential chemotherapy for primary refractory or relapsed adult acute myeloid leukemia: results of the phase II Gemia protocol.
abstract: OBJECTIVE
  High-dose cytarabine (HDAra-C), mitoxantrone and etoposide are the mainstay of several active regimens against relapsed or refractory acute myelogenous leukemia (AML). We designed a phase II study to assess the efficacy and side effects of a time sequential application of mitoxantrone plus intermediate-dose Ara-C followed by HDAra-C plus etoposide (GEMIA) in adult patients with refractory or relapsed AML.
  
  
  METHODS
  Patients with refractory or relapsed AML were eligible for GEMIA salvage therapy, which comprised mitoxantrone 12 mg/m2/day on days 1-3, Ara-C 500 mg/m2/day as a 24-hour continuous infusion on days 1-3, followed by HDAra-C 2 g/m2/12-hourly on days 6-8 and etoposide 100 mg/m2/12-hourly on days 6-8. Granulocyte colony-stimulating factor was started on day 14. In patients above the age of 55 the dose of Ara-C in the first sequence (days 1-3) was reduced to 250 mg/m2.
  
  
  RESULTS
  Twenty patients were included, of whom 12 achieved complete remission after GEMIA (60%, 95% CI 40-80%), one was refractory and five died early from infection. Two additional patients achieved partial remission after GEMIA and complete remission after consolidation chemotherapy, for a final CR rate of 70% (95% CI 48-88%). Neutrophils recovered at a median of 27 days (range, 22-43) and platelets 46 days (range, 25-59) after the start of treatment. The median duration of remission was 133 days (range, 36-417+) whereas overall survival time lasted for a median of 153 days (range, 13-554+). Treatment-associated toxicity was comprised predominantly of infection, mucositis and diarrhea that reached World Health Organization grades III-V in 40%, 40% and 30% of patients, respectively. Despite the intention to rapidly proceed to a hematopoietic stem cell transplant in patients in remission, only five patients reached the transplant.
  
  
  CONCLUSIONS
  The GEMIA time sequential chemotherapy regimen appears effective in obtaining remissions in refractory and relapsed adult AML. The high toxicity seen, however, suggests that its design is amenable to further improvements, especially in more elderly patients. Since remissions are short-lived, more innovative post-remission strategies are needed.
authors: Servei d'Hematologia Clínica, Hospital de la Santa Creu i Sant Pau, Av. Sant Antoni M Claret, 167, 08025 Barcelona, Spain. 5059@hsp. santpau.es.
authors: R
authors: R
authors: Martino
authors: R
authors: R
authors: Guardia
authors: A
authors: A
authors: Altés
authors: A
authors: A
authors: Sureda
authors: S
authors: S
authors: Brunet
authors: J
authors: J
authors: Sierra
mesh_terms: D000208:Acute Disease; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects; D003131:Combined Modality Therapy; D003561:Cytarabine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007239:Infections / Q000209:etiology; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects; D009503:Neutropenia / Q000139:chemically induced; D012074:Remission Induction; D016879:Salvage Therapy; D016896:Treatment Outcome
chemical_list: D003561:Cytarabine; D005047:Etoposide; D008942:Mitoxantrone