Treatment Results of Intensive Chemotherapy for Higher-Risk Myelodysplastic Syndrome (HR-MDS) and Acute Myeloid Leukemia Related to MDS (MDS-AML)

Since MDS is more prevalent in the elderly, use of intensive chemotherapy is considered to be difficult. However, granulocyte colony-stimulating factor (G-CSF) and macrophage colony-stimulating factor (M-CSF), use of clean room and development of promising antifungal agents have resulted in dramatically enhanced safety of post-chemotherapy control of elderly patients. Thus, we attempted to use intensive chemotherapy in HR-MDS and MDS-AML patients.

To evaluate, in HR-MDS and MDS-AML patients, the efficacy and safety of remission induction therapy and post-remission therapy that are standard treatment for de-novo AML in our department.This study enrolled 213 consecutive patients initially treated at our department between 2000 and 2010 who suffered MDS-related disease and whose survival was expected to be less than several months with supportive therapy alone. Almost all of the patients had ≥20% myeloblasts. The age of the patients ranged from 16 to 93 years (median: 70 years). They comprised 2 with good prognosis, 107 with intermediate prognosis and 104 with poor prognosis based on chromosomal findings.

Remission induction therapy consisted of behenoyl-ara-C (BHAC) 350 mg/m² (300 mg/m² for patients aged ≥70 years) over 10 days and idarubicin (IDA) 12 mg/m² (10 mg/m² for patients aged ≥70 years) over 4 days. Additional etoposide 100 mg/m² over 4 days was given if bone-marrow examination on Day 15 revealed residual myeloblasts of ≥5%. The efficacy of the therapy was evaluated after the first course. Patients showing maintained remission received 8 courses of post-remission therapy over 11 months. This post-remission therapy included high-dose cytarabine (2 g/m², or 1g/m² for patients aged ≥60 years) (HDAC) × 10 and mitoxantrone (MIT) 7mg/m² × 3 given initially after remission. Maintenance/intensification therapy mainly consisted of BHAC 350 mg/m² × 4 plus aclarubicin (ACR) 20 mg/body × 6 or IDA 10 mg × 1 alternately every 5 weeks. Outpatient maintenance therapy consisted of M-CSF over 7 days after the end of chemotherapy, followed by administration of G-CSF until neutrophil recovery. Patients were admitted to a clean room if WBC became <1000/mm³. As post-remission therapy, 90 patients received HDAC-MIT, while 50 did not. A total of 28 patients received bone-marrow transplantation during chemotherapy.

CR and PR were achieved in 146/213 (68%) and 43/213 (20%) patients, while 14/213 (7%) showed no response (NR) and 10/213 (5%) died during chemotherapy (CD). CR rate was comparable between patients aged ≥70 years (76/110, 69%) and those aged <70 years (70/103, 68%). Chemotherapy death (CD) occurred in 9/110 (8%) patients aged ≥70 years compared to 1/103 (1%) patients aged <70 years. In terms of prognosis by chromosomal type, CR was achieved in 2/2 (100%), 79/107 (74%) and 65/104 (63%) patients with good, intermediate and poor prognosis, respectively. NR was shown in 3/107 (3%) patients with good prognosis compared to 11/1074 (11%) patients with poor prognosis. The overall survival (OS) in the whole patients ranged 1 to 122 months (median: 11 months), and the event free survival (EFS) in patients achieving CR ranged 1 to 109 months (median: 8 months). Six patients received no treatment after remission because of refusal of post-remission therapy or poor P. S. Among patients receiving post-remission therapy, EFS and OS in 75 patients with intermediate prognosis were 12 and 15 months, respectively, while those in 65 patients with poor prognosis were 6 and 10 months, respectively. EFS in those with and without HDAC-MIT were 8 and 7 months, respectively, showing no difference. OS in 28 patients receiving bone-marrow transplantation ranged 6 to 122 months (median: 17 months). A total of 22 patients (16 with chemotherapy alone and 6 with chemotherapy and bone-marrow transplantation) survived for more than 5 years. There was only one chemotherapy death during post-remission therapy.

The results of this single-center clinical study indicate that major improvement of supportive therapy may allow introduction of remission safely and at a high probability in elderly patients with HR-MDS or MDS-AML. There remains a challenge since the median OS in patients with remission was still as short as around 1 year. One of the future challenges is how to use intensive chemotherapy in combination with distinctive new antileukemics such as lenalidomide.

No relevant conflicts of interest to declare.