Therapy-Related Myelodysplastic Syndrome Following Treatment for Childhood Acute Lymphoblastic Leukemia: Outcome of Patients Registered in the EWOG-MDS 98/06 Studies,

Therapy-related myelodysplastic syndrome (tMDS) following treatment of childhood acute lymphoblastic leukemia (ALL) is one of the most frequently observed secondary malignancies in survivors of childhood cancer. Allogeneic stem cell transplantation (SCT) is the only curative treatment. This analysis was performed to asses the outcome of patients with tMDS following treatment for childhood ALL reported to the EWOG-MDS study group.

Forty-three patients (19 male/24 female) were diagnosed with tMDS between August 1989 and August 2009. The median age at diagnosis was 8.9 yrs (3.4–20.5). The median interval from diagnosis of ALL to the diagnosis of tMDS was 3.3 yrs (1.7–7.0). Five patients did not receive SCT and died due to progressive disease at a median of 5.6 mo after diagnosis. Thirty-eight patients were transplanted. One patient was excluded from the analysis due to insufficient data. In the 37 patients karyotype analysis revealed the following results: normal karyotype (5), abnormalities of chromosome 7 +/− additional aberrations (10), random aberrations (9), structurally complex karyotype (9), failed analysis (4). The highest WHO type was refractory cytopenia (RC) in 4 patients, whereas 33 patients had advanced AML like therapy prior to SCT was employed in 11 patients. Donors were matched siblings (13), matched unrelated volunteers (15), or mismatched or insufficiently typed family or unrelated donors (9). Conditioning consisted of busulfan, cyclophosphamide and melphalan (Bu/Cy/Mel) (23), an alternative busulfan based regimen (6), a radiation based regimen (5) or others (3).

After a median follow up of 4.1 (0.5 – 9.4) years, 14 patients are alive in first complete remission (CR). Seventeen patients developed relapse after a median time of 266 days (28 days – 3.4 years). Of these, three patients are alive in CR after a second allograft. Six patients died of transplant-related complications after first (4) or second (2) SCT. In summary, SCT for tMDS following ALL resulted in a probability of event-free and overall survival at 5 years of 0.34 and 0.42, respectively. In univariate analysis, the presence of a structurally complex karyotype, SCT from a mismatched donor and a preparative regimen other than Bu/Cy/Mel were factors predicting a decreased probability of event-free survival. The use of intensive chemotherapy prior to SCT resulted in a trend towards better survival due to a reduction in relapse incidence. In multivariate COX-analysis, a conditioning regimen other than BuCyMel remained the only variable associated with a high risk of treatment failure.

Allogeneic SCT with a preparative regimen consisting of Bu/Cy/Mel is feasible and effective in patients developing tMDS following treatment for childhood ALL. Relapse is the main cause of treatment failure and intensive chemotherapy prior SCT may possibly contribute to an improved outcome.

Hasle:Pfizer: Research Funding.