Addition of cyclosporin-A to chemotherapy in secondary (post-MDS) AML in the elderly. A multicenter randomized trial of the Leukemia Working Group of the Hellenic Society of Hematology.

In elderly patients with secondary leukemia, poor therapeutic response and low overall survival have been attributed mainly to age and to the primary resistance of leukemic cells to chemotherapy. Modulation of resistance has been attempted in different studies, but the results have been contradictory. We conducted an open, randomized multicenter clinical trial involving patients more than 60 years old with secondary leukemia preceded by a myelodysplastic syndrome. The induction chemotherapy regimen included idarubicin, cytarabine, and etoposide (group A); randomization involved simultaneous administration of cyclosporin-A per os (group B). Fifty-five patients were evaluated, 26 in group A and 29 in group B. Overall complete remission was achieved in 40% of the patients, 27% vs 52% in groups A and B, respectively (p=0.01). Leukemia-free survival was more favorable in patients who received cyclosporin-A, 12 vs 7 months for groups B and A, respectively (p=0.03). In a follow up period of 30 months, 7 out of 55 patients (13%) were alive, 4 of whom were in complete remission. Five out of the 7 alive patients were randomized in group B and had received cyclosporin-A. Treatment failure was higher in group A [19 of 26 patients (73%)] than in group B with CsA [14 of 29 patients (48%)] (p<0.0001). Treatment-related toxicity/mortality was 13%. Modulation of drug resistance by CsA in elderly people suffering from secondary acute leukemia may improve the outcome of chemotherapy without increasing drug toxicity and treatment-related mortality.

Treatment of early clinically staged Hodgkin's disease with a combination of ABVD chemotherapy plus limited field radiotherapy.

The current management of early stage Hodgkin's disease (HD) is usually based on clinical staging, combined modality therapy and the use of less toxic chemotherapy regimens. This approach entails high cure rates, while ensures less long term toxicity with avoidance of laparotomy. The aim of this study was to assess the efficacy of a brief course of Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) chemotherapy followed by limited field radiotherapy (RT) in favorable clinical stage (CS) I and IIA HD. Forty patients, aged 17-68 (median 34) years, with favorable CS I and IIA HD, without bulky mediastinal disease, have been treated with 4-6 (median 4) cycles of ABVD plus limited field RT. Twenty seven (67%) patients received 4 cycles of chemotherapy, while 13 received 5-6 cycles. Thirty five (87%) patients received limited field RT with dose 24-36 Gy and five (13%) received extended field with 36-46 Gy. All patients responded completely to chemotherapy. One patient experienced a relapse two months after the end of therapy. All patients are alive; 39 in continuous complete remission. With a median follow-up period of 44 months (range 18-101) the actuarial overall and progress free survival was 100 and 97% at 5 years. We did not observe any case of secondary leukemia or solid tumor. Pulmonary toxicity was mild in cases of mediastinal irradiation. Considering the short follow-up time and the small number of patients, the combination of a brief course of ABVD plus regional RT is a very efficacious treatment of favorable CS I and IIA HD with mild toxicity. However, long term survival data are needed, which could give confident answers regarding the risk of late therapy related complications, particularly second malignancies.

Immunohistochemical detection of p53, mdm2, waf1/p21, and Ki67 proteins in bone marrow biopsies in myelodysplastic syndroms, acute myelogenous leukaemias and chronic myeloproliferative disorders.

The aim oof this study was to investigate the immunohistochemical expression of p53, mdm2, and waf1/p21 proteins in myelodysplastic syndromes (MDS), acute myelogenous leukaemias (AML), and chronic myeloproliferative disorders (CMPD). Paraffin-sections of bone marrow biopsies from 30 cases of MDS (6 cases of RAEB and RAEB-T) 22 AML (4 cases occurring in the setting of MDS), 16 chronic myeloproliferative disorders (CMPD), and 10 cases without alterations were investigated by immunohistochemistry for p53, waf1/p21, mdm2 and Ki67 proteins. P53 was detected in immature myeloid cells in 6/30 MDS (20%) and in 6/22 AML (27%) while it was not expressed in CMPD. Of the 6 p53 positive AML, 3 occurred as evolution of MDS and 3 were de novo acute leukaemias. Waf1/p21 was detected in 5/22 (23%) AML in immature myeloid cells. Waf1/p21 was also expressed in 18/30 (60%) MDS and 10/16 (63%) CMPD in variable proportion (5-25%) of the mature myeloid cells and megakaryocytes. Waf1/p21 was not detected in immature myeloid cells in MDS and CMPD. Mdm2 protein was expressed in 3/30 (10%) MDS in the immature myeloid cells and in 1/22 AML in blastic cells. The combined immunophenotypes of immature myeloid cells of MDS were: p53+/mdm2+/waf1-: 3, p53+/mdm2-/waf1-: 3, while the immunohistochemical patterns of AML were: p53+/mdm2-/waf1-: 4, p53+/mdm2+/waf1+: 1, p53+/mdm2-/waf1+: 1, p53-/mdm2-/waf1+: 3. Ki67/MIB1 staining was found in at least 30% of immature myeloid cells in MDS and AML and in at least 20% of these cells in CMPD. In conclusion, our results indicate that p53 protein is overexpressed in the myeloid lineage in a proportion of AML and MDS, while is not detected in CMPD and normal bone marrow, p53 expression was much more frequent in AML occurring as an evolution of MDS than in de novo AML. The combined immunophenotypes of p53 positive AML and MDS suggest that p53 overexpression may be due to mutation, in some AML and MDS cases with the p53+/mdm2-/waf1- phenotype. However, it would be also possible that p53 protein accumulation is not related to p53 mutation but to inhibition of p53/mdm2 binding due to mdm2 defects and/or other events related to cell stress signals. On the other hand, waf1/p21 protein overexpression without p53 expression in some AML could be p53-independent and may represent an attempt to control the high proliferation rate which was evidenced by Ki67/MIB1 immunostaining. However, the possibility of p21 to arrest cell-cycle, in these cases of AML, seems to be overridden, suggesting that cell-cycle deregulation may be involved in a proportion of AML.