SummaryThe efficacy of human recombinant erythropoietin (rEPO) in myelodysplastic syndromes (MDS) has generally been best in untransfused patients with 'refractory anaemia' according to the World Health Organization (WHO). We treated 63 MDS patients [excluding refractory anaemia with excess blasts, type 2 (RAEB2)] with a previously tested combination of 13-cis-retinoic acid and dihydroxylated vitamin D3 ± 6-thioguanine in addition to rEPO. Most patients were categorized as refractory cytopenia with multilineage dysplasia and RAEB1, with intermediate 1 International Prognostic Scoring System (IPSS) score; all had Hb <95 g/l, and 70% required regular erythrocyte transfusions. Treatment was well tolerated, and erythroid response rate according to new International Working Group criteria was 60%: 50% in RAEB1 and 64% in non-RAEB patients (P ¼ 0AE383). Response rate was not affected by transfusion requirement (63%; 58% in untransfused), IPSS and WHO Prognostic Scoring System scores, and weekly rEPO dosage (30-50 000 U vs. 80 000 U). Median response duration was 16 months. Median survival reached 14 months for RAEB1 and 55 months for non-RAEB patients, with a significant difference in the latter between responders and non-responders (median 82 months vs. 44 months; P ¼ 0AE036). Our combined therapy, independent of rEPO dosage, achieved in patients with unfavourable response predictors, a rate of anaemia improvement comparable to the best obtained in lower risk patients by high-dose rEPO.
SummaryWe previously reported a 60% erythroid response rate with recombinant erythropoietin + 13-cis retinoic acid + dihydroxylated vitamin D3 in 63 elderly myelodysplastic patients (median age 75 years) with unfavourable features for response to erythropoietin alone [70% transfusion-dependent, 35% refractory anaemia with ring sideroblasts/refractory anaemia with excess of blasts type 1 (RAEB1), 70% with International Prognostic Scoring System (IPSS) Intermediate-1 or -2]. This report updates that case study at a 7-year follow-up, and compared the impact on overall survival of erythroid response to known prognostic factors. The erythroid response duration (median 17 months; 22 in non-RAEB patients, with 20% patients in response after 6 years of therapy) was longer than in most studies with erythropoietin alone. Overall survival (median 55 months in non-RAEB, 15 in RAEB1 patients) was negatively affected by RAEB1 diagnosis, IPSS and WPSS intermediate scores and transfusion-dependence. In the multivariate analysis, erythroid response maintained an independent positive impact on survival, particularly in non-RAEB patients in the first 3 years from diagnosis (90% survival compared to 50% of non-responders). In conclusion, the long-term follow-up confirmed the achievement, by our combined treatment, of fairly long-lasting erythroid response in the majority of MDS patients with unfavourable prognostic features for response to erythropoietin: this translated in a survival benefit that was independent from other prognostic features.
Background. A leukaemic evolution is evident in less than 50% of myelodysplastic patients. They can often die of age-related problems which are independent of myelodysplastic syndrome (MDS) itself, and the best therapy is difficult to define for this group of old patients, in which aggressive strategies are at high risk and supportive care can constitute the most useful option. A systematic analysis of causes of death is so far lacking. Aim of the work. To analyse the prognosis of a large group of myelodysplastic syndromes with particular reference to the causes of death. Patients and methods. From January 1999 to June 2005, data from 783 new cases of MDS were prospectively recorded into the Piedmont MDS register through our web site. Thirty two and 68 cases were excluded because RAEB-t and CMMoL respectively. The remaining 680 patients, who are the object of the present analysis, can be subdivided according to the WHO classification as follows: 99 RAEB-II; 160 RAEB-I; 104 RCMD; 317 MDS other than RAEB and RCMD. Data regarding co-morbidity and IPSS score are available for 457 and 404 patients respectively. At the moment of the analysis, 157 deaths were recorded and causes of death were registered for 153 patients. Results. Median age was 73 (range 27–95), with 151 patients (22%) older than 80. One or more co-morbidities were present at diagnosis in 399/457 (87%). The prognostic role of both IPSS scoring system and WHO classification were confirmed. The causes of death were subdivided as follows: complications due to cytopenia and/or leukaemic transformation in 57 patients (37%); infections in 20 patients (13%); other age or co-morbidity related causes in the remaining 76 patients (50%). No significant differences of causes of death were seen according to sex, while deaths from unrelated causes increased with increasing age from 29% under 60 years up to of 61% over 80 years (test for linear trend: p=0.02). Deaths due to cytopenia, and/or leukaemic transformations, and/or infections were more frequent in patients with no co-morbidities (75%), while no differences were seen according to the number of co-morbidities: 44%, 39% and 55% for patients with respectively one, two and three associated diseases. A significant relationship was evident between diagnostic subgroups and deaths from unrelated causes: 21% for RAEB-II; 51% for RAEB-I; 53% for RCMD; 76% for MDS other than RAEB and RCMD (p<0.01). A similar relationship was evident between IPSS score and causes from unrelated causes: 27% for score int-2/high and 60% for score low/int-1 (p=0.01). Conclusions. The prognostic analysis of this group of MDS patients with attention to the causes of dearth suggest that the majority of patients die of unrelated causes. Age and co-morbidities should play a major role in defining the treatment strategy of this group of patients. Anti-leukaemic treatments should therefore be limited to a small group of patients with diagnosis of RAEB and high IPSS score. An improvement in supportive treatment should be useful for the majority of patients.
Introduction: Elderly patients (pts) with FL do worse than younger ones and the aim of the treatment is usually palliation rather than cure. In order to outline a treatment plan specifically devised for elderly pts with a reduced amount of chemotherapy, we investigated the efficacy and safety of a brief chemo-immunotherapy FND plus Rituximab. Patients and methods: from March 1999 to March 2003, 80 elderly pts (age >60) with advanced stage FL at diagnosis were enrolled. Treatment plan was: 4 courses of FND (Fludarabine 25 mg/m2 days 1–3, Mitoxantrone 10 mg/m2 day 1 and Dexamethasone 20 mg days 1–3) followed by 4 Rituximab infusions at 375 mg/m2/week; pts in partial remission received 2 further FND and 2 Rituximab infusions. PCR molecular monitoring for the presence of IgH/Bcl2 and/or Ig heavy chain gene rearrangement was performed at the beginning of the treatment, after FND, after Rituximab and during follow-up time on bone marrow (BM) samples. Results: median age was 66 (range 60–78); 42 males and 38 females; 16% had stage II, 12% stage III and 72% stage IV disease; 61% had BM involvement; 41% had bulky disease and 24% were at high risk according to IPI score. PCR molecular analysis was performed in 46 pts at diagnosis: 63% were Bcl2 rearranged and 37% were not; IgH rearrangement was detected in 24% of Bcl2 negative pts. Up to date, 70 pts are evaluable. Overall response at the end of treatment was achieved in 63 pts (90%) with 58 pts (83%) in complete remission (CR) and 5 pts (7%) in partial remission (PR). Six pts (9%) did not respond and one patient (1%) died of neutropenic sepsis during a FND course. The addition of Rituximab allowed to increase CR rate from 44% (31 pts) after FND to 83% (58 pts); 73% of responding pts did so with a brief treatment program (4 FND + 4 Rituximab). Patients with adverse prognostic features at diagnosis responded as well as those with more favorable ones with no significant differences in CR rates: BM+ 89%, BM- 79%; low IPI 83%, high IPI 82%; Bulky+ 85%, Bulky- 79%; stage II 90%, III 87%, IV 84%. A thorough molecular analysis is ongoing; to date a molecular marker was detectable in 26 pts. After FND 9/26 pts (35%) did not show anymore BM molecular disease, while PCR negativity was achieved in 23/26 pts (88%) after Rituximab treatment. With a median follow-up of 30 months, 3-yr failure free survival was 50% for the whole series of pts. Failures were observed more frequently in PCR+ pts: all 3 PCR+ pts failed compared to only 7/23 PCR- pts (p=.01). The toxicity was mild with grade 3–4 neutropenia reported in 22% of FND courses, but only 3 pts developed grade 3–4 infections. The whole program was performed in an outpatient setting. Rituximab toxicity was as expected. Conclusions: a brief course of chemo-immunotherapy is able to achieve high clinical and molecular response rates in elderly pts with low toxicity. The sequential use of FND and Rituximab induces a CR rate >80% also in unfavorable subsets of pts. The achievement of PCR negative status correlates with a lower risk of failure.
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