M alignant disorders are poorly understood at the biological level in general, and myelodysplastic syndromes (MDS), a heterogeneous clonal stem cell disorder, in particular, are further confounded by representing a group of diseases rather than a single entity with clinical and biological heterogeneity within each subtype. The basis for grouping these assorted diseases under one MDS umbrella is the clinical presentation of variable cytopenias despite a generally cellular and dysplastic marrow. Diagnosis is based on bone marrow morphology, percentage of blasts, unexplained cytopenias and cytogenetics. These components have been used to classify the disease (French-American British 1 or FAB and World Health Organization 2 or WHO classifications) and to predict prognosis (International Prognostic Scoring System 3 or IPSS). The typical patient is elderly; thus with the increase in our aging population, the incidence of MDS has now surpassed that of acute myeloid leukemia (AML). Approximately 30% of MDS patients will progress to AML, but the majority die from infection or bleeding due to an increasing profundity of the cytopenias. The paradox of MDS is that despite peripheral cytopenia, the marrow is most often hypercellular. The initial breakthrough in understanding the biological basis of this paradox came with the demonstration that, in MDS, bone marrow cells were not only rapidly proliferating, but also undergoing excessive apoptosis. [4][5][6][7] As a result, the maturing hematopoietic cells are eliminated in the marrow and do not reach the peripheral blood, accounting for the cytopenias in the presence of a cellular marrow composed of mostly apoptotic cells. Furthermore, it was demonstrated that multiple cytokines involved in mediating apoptosis and proliferation are deregulated in MDS marrows. [7][8][9] While the MDS cell itself probably contributes, recent insights suggest that it is the bone marrow microenvironment that is also responsible for potentiating disease pathology and progression through cytokine imbalance. In summary then, MDS appears to be a disease of both the seed and the soil (the cell and its microenvironment) where peripheral cytopenias appear to be the result of an increased proliferation-increased apoptosis in the clonal cells and deregulated proapoptotic and trophic cytokines in the marrow.Approximately half the patients with MDS present with recurring cytogenetic abnormalities most commonly affecting chromosomes 5, 7, 8, and 20. These have been shown to greatly affect prognosis and survival. 3 Despite the presence of these well recognized karyotypic aberrations, genetic mutations that accompany them have not been well understood and, in fact, mutation in a specific biological pathway that is common to multiple MDS subtypes has not been identified. In short, apoptosis has remained the sole unifying biological characteristic of the disease.Recently, however, a possible cohesive genetic explanation for this increased apoptosis has been taking shape. Initial hints began with the study of pat...
3815 Poster Board III-751 Following initial promising clinical results reported at ASH 2008 (Shenoy et al) in RAEB MDS and AML patients treated with the new investigational agent ON 01910.Na, we have initiated a phase 1/2 single arm escalating dose study in advanced MDS patients with a shorter schedule of administration of ON 01910.Na. The first 13 patients enrolled in our ongoing trial (6 high risk, 1 Intermediate-2 and 5 Intermediate-1 according to IPSS classification; 7 females/6 males, age range: 47-83ys), most of them having failed prior MDS therapies were administered ON 01910.Na as a 48 h continuous intravenous infusion weekly for 3 weeks of a 4-week cycle. Ten patients were treated at the 800 mg/m2/day dose level and 3 at the 1500 mg/m2/day dose level for 4 to 27+ weeks (1 to 6 four-week cycles). Most patients had grade 3 or 4 cytopenias at baseline. Overall the therapy was well tolerated and a few patients reported improvements of well being and pain relief. The most frequently reported adverse events were thrombocytopenia, neutropenia, anemia, fatigue and nausea. Serious adverse events were typical of this patient population and none of them was related to ON 01910.Na except for one case of neutropenia. Bone marrow blastic response was evaluated by bone marrow morphology. Five patients had a pretreatment blast count lower than 5% and no worsening of blast count was observed in the 3 patients who had follow-up bone marrow examination. Another six patients had more than 5% pretreatment bone marrow blasts. Among these patients, two had significant decreases in blast counts compared to pre-treatment values, while two showed stabilization and two progressed. Two patients had hematological improvements (neutrophil and erythroid responses). These results are encouraging and the trial is continuing. Patient Bone Marrow Blasts Hematological Improvement Pre-Treatment 4-8 week Follow-up 1 <2% 2% 2 10-13% Death end 1st cycle 3 1-2% Not Done (Platelet =4) 4 20-30% 30% N wk 10-18 5 <5% 3% 6 3% Death end 2nd cycle 7 <5% 1-2% 8 25% 11% 9 10-13% 15%* E wk 1-13 10 35% Discontinued mid 2nd cycle (transplant) 11 9% 5% 12 10% 2% 13 15% 20% * 16 week Follow-up: 25% blasts Disclosures: Wilhelm: Onconova: Employment.
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