Efficacy of hypomethylating agents in therapy-related myelodysplastic syndromes

We retrospectively assessed morphologic and cytogenetic responses to 5-azacytidine and decitabine in a cohort of 42 adult therapy-related myelodysplastic syndromes (tMDS) patients treated at Memorial Sloan-Kettering Cancer Center and in 2 industry-sponsored decitabine trials (D0007 and DACO-020). The overall response rate (complete remission+marrow CR+hematologic improvement) was 38%, including 6 patients with complete remission (14%), 6 with marrow CR with or without hematologic improvement (14%), and 4 with hematologic improvement alone (10%). We conclude that DNA methyltransferase inhibitors showed activity in tMDS that is roughly comparable to that seen in de novo MDS.     

A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes

We reviewed 53 publications reporting 751 patients with hematologic malignancies treated with low doses (5 to 20 mg/m2/d) of cytosine arabinoside (LoDAC). Of 507 patients evaluable for response, complete remission (CR) rates varied from 32% for patients with primary acute non-lymphoblastic leukemia (1 degree ANLL) to 16% for patients with hematologic malignancies secondary to previous chemotherapy or following a myelodysplastic syndrome (MDS) (2 degrees ANLL), and 16% for MDS. Median duration of CR was 9.5 months for 1 degree ANLL, and 10.5 months for both 2 degrees ANLL and MDS. Based on limited available survival data, overall median survival for these groups was 9 months, 3 months, and 15 months, respectively. Only three CRs were reported of 31 evaluable patients treated for a variety of other hematologic malignancies. CR rates for patients with 1 degree ANLL greater than or equal to 50 years old was 56%, compared with 29% less than 50 years old (P = .10). While prior chemotherapy was more common in 1 degree ANLL patients less than 50 years of age (86% v 21%; P less than .001), it did not influence response rates in those greater than 50 years of age, suggesting other biases. Hematologic toxicity was mentioned in only 33 of 53 publications, affecting 254 of 289 patients (88%), with at least 15% treatment-related deaths. LoDAC hypothetically acts as a differentiating agent; however, correlative laboratory studies were rarely performed. Cytogenetic data were available for only 15%, and in vitro studies for 10% of all patients with marked discrepancies in the interpretation of results. LoDAC is clearly cytotoxic for both malignant and normal hematopoietic cells. While large numbers of patients have been reported, the lack of well-designed clinical trials prohibits definitive conclusions as to its role as a differentiating agent. Future LoDAC studies should determine optimal dose and schedule, with clinical laboratory correlates to assess differentiation. Trials in ANLL comparing LoDAC with conventional chemotherapy, and in MDS with supportive care alone, may help identify the role of LoDAC. Until appropriate indications can be identified, LoDAC should not be routinely used in clinical practice.     

Survival from acute non-lymphocytic leukaemia (ANLL) and chronic myeloid leukaemia (CML) in European children since 1978: a population-based study

We used data supplied by population-based cancer registries, collected and quality controlled using a common protocol, to analyse survival from acute non-lymphocytic leukaemia (ANLL) and chronic myeloid leukaemia (CML) among children in 17 European countries. Variations in survival in relation to age, country, histologic subtype and period of diagnosis (1978--1992) were examined. These are rare malignancies and survival can be studied reliably only by examination of data from a very large population (in this case EUROCARE). 5 years after diagnosis, overall survival was 44% (95% CI 33--55) for CML and 37% (95% CI 32--43) for ANLL. For both types of leukaemia, survival was slightly better for girls and worse in children under 5 years of age. Consistent with clinical literature, the ANLL subtypes with poorer prognosis were monocytic, megakaryocytic and erythroleukaemia. For ANLL, 5-year survival was better in Finland, the UK, The Netherlands and Germany (> or =40%); for CML, 5-year survival was highest in Italy, although the 95% CI were wide. The risk of death from ANLL and CML fell by 7% per year and 5% per year, respectively, after adjustment for age, gender and country. Since these rare childhood malignancies were virtually untreatable until 1970, these are very welcome trends.     

5'-Azacitidine for therapy-related myelodysplastic syndromes after non-Hodgkin lymphoma treatment

Therapy-related myelodysplastic syndromes are possible complications in patients treated for previous hematologic malignancies. Therapeutic strategies in these type of disorders are still not well defined: azacitidine has been recently approved for the treatment of higher risk myelodysplastic syndromes, but few data are published relating possible efficacy in therapy-related dysplastic disorders. We reported here 4 patients treated with azacitidine for therapy related dysplasia after chemotherapy for non-Hodgkin lymphoma.     

Low-dose cytarabine for acute myeloid leukaemia and myelodysplastic syndromes: in vivo and in vitro cytotoxicity

14 patients with acute myeloid leukaemia (AML) and 7 with myelodysplastic syndrome (MDS) were treated with cytarabine in low dosage. In AML a complete remission rate of 43% was found and in all patients profound cytopenia was noticed without any sign of maturation induction. In MDS no effect of low-dose cytarabine could be detected. We also studied the effect of low-dose cytarabine in vitro in freshly isolated leukaemic cells of 10 patients with AML. Maturation induction was measured by a comprehensive panel of quantitative and qualitative markers of maturation. No differentiation inducing effect of low-dose cytarabine could be found. We conclude on the basis of our own results and after reviewing the literature that low-dose cytarabine exerts its effect by cytotoxicity instead of maturation induction.     

Cytogenetic studies on acute myelomonocytic leukaemia (M4) with eosinophilia

Cytological and cytogenetic studies on 17 acute myelomonocytic leukemia with bone marrow eosinophilia (M4EO) are reported. Cytological criteria include an unusual high proportion of eosinophilic cells containing abnormal granules. Abnormal karyotypes have been found in 12 patients but chromosome 16 abnormalities were present in only 9. In two of them only one such mitosis was detected whereas in 7 others inv(16)(p13q22) and/or del (16)(q22) clones were present. However in 16 cases normal karyotypes were also present. Other abnormal clones coexisted in three patients, suggesting that chromosome 16 abnormalities are not linked to a primary leukemogenic event. M4EO was found to be associated with a favourable prognosis.     

Low-dose cytosine arabinoside (Ara-C) therapy in the myelodysplastic syndromes and acute leukemia

Twenty-two patients with either a myelodysplastic syndrome or acute nonlymphocytic leukemia were treated with 10-21 days of subcutaneous cytosine arabinoside (Ara-C) (5-10 mg/m2 every 12 hours). There were two complete remissions and ten partial responses. Clinically significant improvements in peripheral blood counts persisted for periods of 8 weeks to greater than 21 weeks. Responses were seen even in patients who had previously proven refractory to conventional induction regimens or high-dose Ara-C. The toxicity, however, was considerable. Nearly all patients developed significant thrombocytopenia. Platelet and red cell transfusion support was required in many cases. The response to low-dose Ara-C therapy seen in patients with the leukemic and myelodysplastic disorders may be mediated by the induction of cell differentiation or a direct cytotoxic effect on a sensitive population of cells. Low-dose Ara-C may provide an alternative therapy in the selected patient with acute nonlymphocytic leukemia or a myelodysplastic syndrome.     

Cytogenetic aspects of adult primary myelodysplastic syndromes: clinical implications

Myelodysplastic syndrome (MDS) is a heterogeneous disease from the clinical, biological and morphological point of view. The pathogenesis of MDS is not well established and it appears to occur complex changes in the stem cell biology. Clonal chromosomal aberrations are found in 30-50% of primary MDS and no specific cytogenetic abnormality has as yet been defined. The chromosomal abnormalities are predominantly characterized by partial/total chromosomal losses or chromosomal gains. These chromosomal abnormalities include mainly -5/del(5q), -7/del(7q), del(11q), del(12p), del(20q), -Y, and +8. The role of cytogenetic analysis in the diagnosis, prognosis, taking treatment decisions and follow up of patients with MDS has been clearly defined. Despite its difficulties in obtaining for analysis high quality metaphases conventional cytogenetics continues to be the basic technique for cytogenetic evaluation of a MDS patient. Other molecular cytogenetic methods have been shown to be complementary, without replacing the information obtained with this technique. Further investigations with both conventional and molecular cytogenetics in relation to clinical features as well as other molecular methods will undoubtedly contribute to improve understanding of the underlying genetic events responsible for the development and evolution of MDS leading to more accurate classification and management of MDS patients.     

Survivin expression in acute leukemias and myelodysplastic syndromes

We analyzed by immunocytochemistry the expression of survivin in bone marrow cells from 36 acute myeloid leukemia (AML) cases, from 98 patients with myelodysplastic syndrome (MDS), and from 41 non hemopathic subjects. Our aim was to evaluate whether abnormalites in survivin expression were associated with peculiar laboratory and clinical findings, altered apoptosis levels or altered proliferative rate. In normal samples survivin was never detectable. It was detected in almost all AML and MDS cases. In AML and in MDS with more than 5% bone marrow blasts survivin levels higher than in RA and RARS were observed (P = 0.04). In MDS a tendential inverse correlation between survivin and TUNEL positivity was identified (P = 0.08), whereas survivin expression was independent of the proliferative rate. Survivin levels did not predict disease progression in MDS; among AML patients treated with intensive polichemotherapy, survivin expression was significantly higher in resistant cases (P = 0.01). Our findings confirm the high incidence of survivin expression in AML. Its abnormal expression also in MDS may play a role in promoting aberrantly increased cell viability and contribute to the altered homeostatic balance between cell growth and cell death.     

Hidden chromosomal aberrations are rare in primary myelodysplastic syndromes with evolution to acute myeloid leukaemia and normal cytogenetics

In myelodysplastic syndromes (MDS) a normal karyotype by cytogenetic analysis (CA) corresponds to a low cytogenetic risk for acute myeloid leukaemia (AML) evolution, a subset of patients however develops AML. We evaluated the use of interphase fluorescence in situ hybridisation (I-FISH) in 31 patients with evolution from primary MDS to AML and a normal CA at all stages of disease. Monosomy 7 was found in 4/31 cases, one patient had a terminal deletion 5q, each after AML evolution. The low frequency and unclear prognostic value of I-FISH anomalies in MDS related AML suggests that these alterations play a minor role for AML evolution.     

Farnesyltransferase inhibitors in acute myeloid leukemia and myelodysplastic syndromes

Farnesyltransferase inhibitors were initially developed as Ras inhibitors as they inhibit the prenylation necessary for Ras activation. It is clear now that their mechanism of action is more complex and probably involves other proteins unrelated to Ras. At least 3 drugs within this family have been investigated in acute myeloid leukemia, myelodysplastic syndromes, and other leukemias. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), and BMS-214662. The first 2 are administered orally, whereas BMS-214662 is given intravenously. These drugs are at different stages of development, and design of treatment schedules and methodology of the available studies are very different. Although most of the information is still preliminary, these agents have demonstrated clear evidence of clinical activity in these diseases and very favorable toxicity profiles. Several studies are still ongoing to better define the efficacy of these agents in the treatment of leukemias, as well as to determine the best schedules, the role of combination with other agents, and the role of these agents in different settings, such as the management of minimal residual disease. It is very possible that these agents will soon find their way to the ranks of established agents for the management of myeloid malignancies     

Pregnancy in patients with myelodysplastic syndromes (MDS)

We report 6 pregnancies in 5 females with low-risk myelodysplastic syndromes (MDS) (median age at diagnosis 28 years, range 26-29) observed in the last 15 years. In 2 cases pregnancy was concomitant to the diagnosis of MDS, in the remaining 4 cases the intervals from diagnosis were 2, 3, 4 and 9 years, respectively. One patient had a foetal growth retardation corrected with steroid treatment while the remaining 5 pregnancies were uneventful. After a median time from delivery of 104 months (range 18-187) none of the patients developed acute myeloid leukemia (AML) and all are alive in stable disease. In conclusion, selected females with low-risk MDS could not be discouraged to have full term pregnancies.     

Cytogenetic and clonal culture evaluation after response to low dose Ara-C in myelodysplastic syndromes

Cytogenetic and bone marrow culture studies were performed sequentially in 13 patients with myelodysplastic syndromes (MDS) who responded to low dose cytosine arabinoside (Ara-C) treatment (complete in nine and partial in four patients). Of nine patients with initial clonal karyotypic abnormalities, six recovered a normal karyotype after attaining a response to treatment, but the other three patients retained partial or total karyotypic abnormalities. A new clonal karyotypic abnormality appeared after treatment in one patient. Eight patients showed normal colony growth of both granulocyte-macrophage colony-forming units and erythroid burst-forming units after treatment, but five were still defective. There was a clear difference in the duration of response to treatment between these two groups. Consolidation treatment was not effective in patients with persistent karyotypic abnormalities or defective colony formation. Although the number of patients studied is small, these results suggest that hemopoiesis in patients with MDS following a response to treatment with low dose Ara-C is heterogeneous. Consolidation chemotherapy is recommended to ensure and prolong the response in patients showing normalization of both cytogenetic and bone marrow culture results.     

Chromosome characteristics of therapy-related acute non-lymphocytic leukemia and preleukemia: possible implications for pathogenesis of the disease

Most cases of therapy-related acute nonlymphocytic leukemia or preleukemia show chromosome aberrations, primarily loss of whole chromosomes No. 5 and/or No. 7 or the long arms of these two chromosomes. Other abnormalities involve chromosome No. 21, often rearranged at band 21q22, and chromosome No. 17, in some cases rearranged at band 17p13. Important cellular genes have recently been localized to these regions, including the gene for one hematopoietic growth factor and the gene for the receptor for another hematopoietic growth factor. It is suggested that the total loss or change of structure or expression of some of these genes resulting from the various chromosome aberrations may be of pathogenetic significance in therapy-related acute nonlymphocytic leukemia.     

Mutation of the human FMS gene (M-CSF receptor) in myelodysplastic syndromes and acute myeloid leukemia

We studied 41 patients with myelodysplastic syndromes or acute myeloid leukemia to assess the presence of point mutations in the human FMS gene (M-CSF receptor). Using the polymerase chain reaction and hybridization of oligonucleotide probes to the amplified sequences, we have detected mutations in eight of 41 patients, at codons 301 and 969. In vitro work has highlighted mutations at these codons as being oncogenic. We now report the detection of potentially activating mutations of the human FMS gene in vivo. The consequence of these mutations in the multistep pathogenesis of myeloid malignancy and their relevance to prognosis remains to be determined.