Risk Myelodysplastic Syndrome Patients Research Articles

Efficacy of Recombinant Erythropoietin + 13-cis Retinoic Acid + Dihydroxylated Vitamin D3 in the Treatment of Anemia of Low-Intermediate Risk Myelodysplastic Syndrome Patients.

Human recombinant erythropoietin (rEPO) improved anemia, in most of casistics, in about 30–35% of myelodysplastic syndrome (MDS) patients without BM blast excess. More recent sudies, employing either higher rEPO doses (70–80.000 U/week) or combinations of rEPO + G-CSF or all trans retinoic acid reported erythroid responses in 40–50% of patients. However, responses were quite less frequent in transfusion-dependent patients. On the basis of a previous our study (D. Ferrero et al.: Leuk Res 1996; 20: 867–876; Blood 1999; 94 suppl.1: 307) reporting more than 50% transfusion reduction in 30% of MDS patients treated with a combination of 13-cis retinoic acid (RA) + dihydroxylated vitamin D3 (D3), we employed in a new protocol the same combination of differentiating agents + rEPO. Thirty-two MDS patients, 19 males and 13 females, with a median age of 74.5 (46–90) entered the sudy. Diagnosis, according to W.H.O. classification was RA in 10, RARS in 3, RCMD in 7, 5q- syndrome in 2, RAEB1 in 10. IPSS score, available in 21, was: low risk in 4, intermediate-1 risk in 14, intermediate-2 risk in 3. Cytogenetic abnormalities were evidenced in 7/21 patients. Twenty-two/32 patients were transfusion- dependent with a median requirement of 2 U/month (1 – 7). All patients received a combination of RA (20 – 40 mg/day) + D3 (1 microgram/day) + human rEPO (either alpha or beta epoetin), starting from 30–40,000 U/week up to 70 – 80,000 U/week (median maximal dose: 70,000 U). Six/10 RAEB1 patients also received intermittent courses of low-dose 6-thioguanine and 2 patients received G-CSF for coexisting severe neutropenia. Erythroid responses were scored as major in the case of 100% reduction in transfusion requirements or greater than 2 g/dl increase in Hb level in untransfused patients, minor in the case of at least 50% reduction in transfusion requirements or 1–2 g/dl increase in Hb level without transfusions. Erytroid responses (13 major, 7 minor) were detected in 20/32 (62.5%) patients, without significant differences between patients without blast excess (14/22: 63.6% responsive) and RAEB1 patients (6/10: 60% responsive). Responses were observed in 13/22 (59%) transfusion-dependent and in 7/10 (70%) untransfused patients. EPO serum level were tested in 19 patients: 15 had values below 200 U/l and 12 of them (80%) responded, 4 had values greater than 200 U/l and no one of them responded. Median response duration was 9 months (2 – 27+) and 35% of responses are projected to be maintained at 15 – 27 months. Median survival was 12.5 months (6.5 – 25+) in RAEB1 patients, unreached (52% projected alive at 4 years) in patients without blast excess. Therapy was well tolerated, with only mild RA- induced mucosal dryness. In conclusion, our combination of rEPO + differentiating agents seems to be more effective than either treatment alone in ameliorating anemia of MDS patients, particularly in transfusion- dependent patients. However, the efficacy is probably low in patients with very high serum EPO levels.

Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documen...

Priming GM-CSF and low dose cytarabine (LODAC) in the treatment of high risk and elderly acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) patients

6612 Background: Priming of leukemic cells with cytokines may enhance the efficacy of cell cycle chemotherapy. We attempted to use GM-CSF to enhance the effects of low dose cytarabine to increase cell recruitment, and optimize cell cycle chemotherapy in patients who could not tolerate conventional induction chemotherapy. Methods: We evaluated the efficacy of GM-CSF priming with low-dose cytarabine and concomitant hydroxyurea in high risk, elderly AML and advanced MDS patients. Patients received induction chemotherapy with GM-CSF 250mcg/m2/d by continuous infusion days 1–7, hydroxyurea 500 mg po qid day 1 and 500mg po tid days 2–15, and cytarabine 20mg/m2/d by continuous infusion days 2–15. Results: Forty-nine patients (26F, 23M) were treated, median age 68.5 years (range 48–85); 78% had no previous treatment, and 22% of patients had a median of 2 prior treatments (range 1–7). All patients were not eligible for standard induction chemotherapy. Following treatment, 44% of the assessable patients had documented aplastic bone marrows. The overall response rate was 49%; 33% with CR and 16% with PR. Median duration of CR was 251 days (range 36–842). The CR for secondary AML was 18%, for de novo AML 38%, and for MDS 67%. None of the patients developed mucositis or alopecia, and no patient had greater than grade I nausea and vomiting. The most common adverse effects were neutropenic fever (68%), atrial fibrillation (7%) and congestive heart failure (5%). Five patients died of treatment related toxicity (sepsis). The median survival for all patients was 150 days, for patients achieving CR was 290 days, and the 1 year survival rate was 24%. Conclusions: GM-CSF priming can enhance the cytoreductive effects of low doses of cytarabine. This combination therapy is well tolerated, and should be explored as an alternative regimen for high risk and elderly AML and advanced MDS patients. No significant financial relationships to disclose.

Biological characteristics of myelodysplastic syndrome patients who demonstrated high versus no intramedullary apoptosis.

Spontaneous intramedullary apoptosis was measured in bone marrow (BM) biopsies of 175 patients with myelodysplastic syndromes (MDS) using in situ end-labeling (ISEL) of fragmented DNA. Two groups of high (n=71) versus low (n =43) levels of apoptosis were identified while 61 patients were ISEL-negative. Semiquantitative assessment of 3 cytokines, the number of macrophages and in vivo labeling indices (LI) were also determined from consecutive sections of the biopsy. Patients with high apoptosis levels tended to have a high LI (p=0.013), more macrophages in their BM biopsies (p=0.006) and higher tumor necrosis factor alpha (TNF-alpha) levels (not significant) compared to patients with no apoptosis. In addition, low risk MDS patients had significantly lower rates of apoptosis (p = 0.047) and lower levels of TNF-alpha (p = 0.055) compared to high-risk MDS patients. We conclude that the genesis of cytopenias in MDS is of multifactorial origin and that cytokine-associated apoptosis clearly identifies a distinct biological subgroup of patients who may benefit selectively by use of anti-cytokine therapies.