Preference for involvement in treatment decisions and request for prognostic information in newly diagnosed patients with higher-risk myelodysplastic syndromes.

BACKGROUND: The main objective of this study was to assess preferences for involvement in treatment decisions and requests for prognostic information in newly diagnosed higher-risk myelodysplastic syndrome (MDS) patients. PATIENT AND METHODS: This was a prospective cohort observational study that consecutively enrolled MDS patients with an international prognostic scoring system (IPSS) risk category of intermediate-2 or high risk (summarized as 'higher risk'). The control preference scale was used to assess patient preferences for involvement in treatment decisions, and whether a request by patients for prognostic information during consultation was made, was also recorded. All of the patients were surveyed at the time of diagnosis before receiving treatment. Univariate and multivariate analyses were carried out to assess how sociodemographic, clinical and laboratory data related to decision-making preferences and requests for prognostic information. Relationship with the health-related quality of life (HRQOL) profile was also examined. RESULTS: A total of 280 patients were enrolled, 74% with intermediate-2 and 26% with high-risk IPSS. The mean age of patients was 70-year old (range: 32-89 years). One hundred thirty-two patients (47%) favored a passive role in treatment decision-making, whereas only 14% favored an active role. The remaining 39% of patients favored a shared decision-making approach. Patients with lower hemoglobin levels were more likely to prefer a passive role (P=0.037). HRQOL was generally better in patients preferring an active role versus those preferring a passive one. Overall, 61% (N=171) of patients requested prognostic information on survival during consultation. The likelihood of not requesting prognostic information was higher for older patients (P = 0.003) and for those with lower education (P=0.010). CONCLUSION: Decision-making preferences vary among patients with newly diagnosed higher-risk MDS. Current findings suggest that patients with worse underlying health conditions are more likely to prefer less involvement in treatment decisions.

Combination treatment of flag with non-pegylated liposomal doxorubicin (MYOCET(TM)) in elderly patients with acute myeloid leukemia: a single center experience.

The incidence of acute myeloid leukemia (AML) increases with age, but results of intensive chemotherapy in elderly patients are disappointing. Non-pegylated liposomal formulations of doxorubicin (Myocet™) have been developed with the aim of reducing systemic and cardiac toxicity especially in the elderly. We evaluated the efficacy and toxicity profiles of fludarabine, cytarabine and granulocyte colony-stimulating factor (FLAG) regimen given in association with Myocet™ in 35 patients with AML, median age 69 years (range 61-83 years). Nineteen (54.3%) had newly-diagnosed AML, twelve (34.3%) patients had secondary AML (ten with Myelodisplastic Syndrome, two with Primary Myelofibrosis) and 4 (11.4%) patients had had a late relapse (>12 months) of AML. Complete remission (CR) and partial remission (PR) were obtained in twenty-two (63%) and 3 (8.5%) patients, respectively. Seven (20%) patients showed a resistant disease. There were 3 early deaths (8.5%). Six patients (17%) experienced severe cardiovascular toxicity. The median overall survival (OS) was 12 months (range 1-52 months) with a median disease-free survival (DFS) of 20 months (range 1-48 months). One-year and two-year DFS were 78.9% and 26.7%, respectively. This study demonstrates that in elderly patients with AML, FLAG-Myocet combination shows promising efficacy response with acceptable toxicity, enabling most patients to receive further treatments, including transplantation procedures.

Hepatitis C virus infection and monoclonal gammopathies not associated with cryoglobulinemia.

A pathogenetic role of HCV has been recently postulated in some lymphoproliferative disorders and in particular in essential mixed cryoglobulinemia. To assess the relevance of HCV infection in multiple myeloma, Waldenström's macroglobulinemia and monoclonal gammopathy of undetermined significance in the absence of cryoglobulinemia (cryo-ve MG), 102 patients were evaluated for antiHCV, HCVRNA and HCV genotypes. A control group of 466 patients referring for acute trauma to the Orthopedic Division of our hospital was also studied. The overall prevalence of HCV was 15.6% in MG patients and 5.4% in the control group (P= < 0.001). Since only patients with MG older than 50 years had HCV infection, we compared the prevalence rate of infection in patients aged 50 and older: in cryo-ve MG HCV prevalence was 17.9%, while in patients with an acute trauma it was 10%; the difference was not statistically significant. In addition, occurrence of cryo-ve MG was investigated in 614 antiHCV+ patients with chronic liver disease and was found in 1.9%. Comparing all the 28 cryo-ve MG patients HCV+ with an appropriately matched control group of HCV+ patients without MG, no difference in severity of liver disease and genotype distribution was detected. These findings show that: (1) among cryo-ve MG, HCV infection is frequent as shown in the appropriately matched control population; (2) prevalence of cryo-ve MG in antiHCV patients with chronic liver disease is similar to the rate found in the general population; and (3) HCV infection and disease do not differ in patients with and without cryo-ve MG.

Accuracy of physician assessment of treatment preferences and health status in elderly patients with higher-risk myelodysplastic syndromes.

Higher-risk myelodysplastic syndromes (MDS) are rarely curable and have a poor prognosis. We investigated the accuracy of physicians' perception of patients' health status and the patients' preferences for involvement in treatment decisions. We examined 280 newly diagnosed higher-risk elderly MDS patients paired with their physicians. Survey tools included the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and the Control Preference Scale. Overall concordance was 49% for physician perception of patient preferences for involvement in treatment decisions. In 36.4% of comparisons there were minor differences and in 14.6% there were major differences. In 44.7% of the patients preferring a passive role, physicians perceived them as preferring an active or collaborative role. Absence of the patient's request for prognostic information (P=0.001) and judging the patient as having a poor health status (P=0.036) were factors independently associated with the physicians' attitude toward a lower degree of patient involvement in clinical decisions. Agreement on health status was found in 27.5% of cases. Physicians most frequently tended to overestimate health status of patients who reported low-level health status. The value of decision aid-tools in the challenging setting of higher-risk MDS should be investigated to further promote patient-centered care.

Lenalidomide, melphalan, prednisone and thalidomide (RMPT) for relapsed/refractory multiple myeloma.

This multicenter, open-label, non-comparative phase II trial evaluated the safety and efficacy of salvage therapy with lenalidomide, melphalan, prednisone and thalidomide (RMPT) in patients with relapsed/refractory multiple myeloma (MM). Oral lenalidomide (10 mg/day) was administered on days 1-21, and oral melphalan (0.18 mg/kg) and oral prednisone (2 mg/kg) on days 1-4 of each 28-day cycle. Thalidomide was administered at 50 mg/day or 100 mg/day on days 1-28; six cycles were administered in total. Maintenance included lenalidomide 10 mg/day on days 1-21, until unacceptable adverse events or disease progression. Aspirin (100 mg/day) was given as thromboprophylaxis. A total of 44 patients with relapsed/refractory MM were enrolled and 75% achieved at least a partial response (PR), including 32% very good PR (VGPR) and 2% complete response (CR). The 1-year progression-free survival (PFS) was 51% and the 1-year overall survival (OS) from study entry was 72%. Grade 4 hematologic adverse events included neutropenia (18%), thrombocytopenia (7%) and anemia (2%). Grade 3 non-hematologic adverse events were infections (14%), neurological toxicity (4.5%) and fatigue (7%). No grade 3/4 thromboembolic events or peripheral neuropathy were reported. In conclusion, RMPT is an active salvage therapy with good efficacy and manageable side effects. This study represents the basis for larger phase III randomized trials.

Role of external radiation therapy in urinary cancers.

Invasive urinary tumors are relatively rare and their treatment may cause important changes in urinary, sexual, and social functions. A systematic review of external radiation therapy studies in urinary cancers has been carried out. This synthesis of the literature is based on data from meta-analysis, randomized and prospective trials, and retrospective studies. There are few controlled clinical trials using adjuvant or radical radiotherapy +/- chemotherapy in kidney, ureter, and urethra cancers; there are several reports of muscle-invasive bladder cancer using multimodality treatment: intravesical surgery and neo-adjuvant chemotherapy to radiotherapy or concomitant radiochemotherapy with organ preservation. The conclusions reached for renal cancer are controversial; urethra and ureter cancers data are few and inconclusive; sufficient data now exist in literature to demonstrate that conservative management with organ preservation, for muscle-invasive bladder cancer, is a valid alternative to radical cystectomy, viewed as the gold standard.

All-trans retinoic acid in combination with alpha-interferon and dexamethasone for advanced multiple myeloma.

The in vitro inhibitory effect of all-trans retinoic acid (ATRA) on myeloma cell growth may be synergistically potentiated by the activity of dexamethasone (DEX) and alpha-interferon (IFN). We treated 10 patients with advanced, refractory multiple myeloma (MM) using a combination of ATRA (100 mg p.o., once a day for two weeks every month), DEX (40 mg i.v., for 4 days every 4 weeks) and IFN (3 MU s.c., three times a week). Eight patients completed at least three months of treatment and were evaluable for response. Two of them showed a partial response which persists after 15 to 17 months. Three patients experienced a stable plateau phase of 4 to +11 months, with a significant improvement in the performance status and bone pain. Progressive disease was seen in the remaining three patients. We conclude that the association of ATRA, DEX and IFN warrants further consideration in MM patients.

CD117 (c-kit) is a restricted antigen of acute myeloid leukemia and characterizes early differentiative levels of M5 FAB subtype.

BACKGROUND AND OBJECTIVE: The CD117 molecule is an antigen more frequently found on early normal and leukemic hematopoietic cells, but its correlation with the FAB subtypes and with other lineage and stage associated antigens is still not well established. In this study we investigated the surface expression of CD117 antigen in 135 patients with acute leukemia in relationship to de novo or secondary origin of AML, subtypes of FAB classification, expression of other antigens such as CD34, HLA-DR, CD15, CD14, CD45RA, CD45RO, CD11b, CD11c, CD4, CD7, mixed antigen co-expression (LyAg + AML and MyAg + ALL) and features of leukemic mass. DESIGN AND METHODS: The CD117 antigen expression (clone 95C3) was determined by flow cytometry in a series of 135 patients with acute leukemia at diagnosis consecutively observed during the years 1995-1997: 82 AML (including 51 cases of de novo AML, 22 cases of AML following myelodysplastic syndromes (MDS), 9 cases of myeloid blastic crisis of chronic myeloid leukemia (BC-CML) and 53 ALL. All cases were stratified in CD117+ and CD117- groups and the differences were analyzed by using appropriate statistical analyses. RESULTS: CD117 antigen was found over 10% in 74% of AML without significant differences of positivity between AML after MDS or BC-CML and de novo AML. We did not note a significant correlation between FAB classification and CD117 which was expressed in 100% of M1 and M7 cases, in 80% of M0 cases, in 75% of M2 cases, in 70% of M3 cases and in 82% of M4 cases. Instead, in M5 subtype CD117 was strictly restricted to earlier stages: ten of the eleven M5b (91%) cases completely lacked CD117 antigen expression, whereas 100% of M5a cases were positive. The results of Pearson's coefficient showed: 1) a significant inverse relationship between CD117 and CD15, CD4 and CD14 (only in M5 subtypes) and CD11b, CD11c and CD45RO (in all cases); 2) a significant direct correlation between CD117 and CD34 and CD45RA (in all cases); and 3) an independent expression between CD117 and CD15 associated with a low correlation between CD117 and HLA-DR antigen (only in non-monocytic cases). In ALL, whether of B or T lineages, surface expression of CD117 was never observed. INTERPRETATION AND CONCLUSIONS: We conclude that the CD117 antigen shows a high specificity for AML, independently upon FAB classification, and represents a reliable marker in characterizing the differentiative degree of the monocytic blasts.

Adding growth factors or interleukin-3 to erythropoietin has limited effects on anemia of transfusion-dependent patients with myelodysplastic syndromes unresponsive to erythropoietin alone.

BACKGROUND AND OBJECTIVES: Recombinant erythropoietin (r-EPO) induces erythroid responses in patients affected by myelodysplastic syndromes (MDS). However, the response rate declines to 10-15% in MDS with substantial transfusion needs. Both in vitro and in vivo studies have suggested that the addition of growth factors (G-CSF, GM-CSF) or interleukin-3 (IL-3) may potentiate the effect of r-EPO on dysplastic erythropoiesis. The aim of this study was to evaluate the effects of the combination of r-EPO with G-CSF, GM-CSF or IL-3 on the anemia of heavily transfusion-dependent MDS patients, previously unresponsive to r-EPO alone. PATIENTS AND METHODS: Sixty patients with transfusion-dependent MDS, already treated without significant erythroid response with r-EPO alone, were scheduled to receive, for at least 8 weeks, r-EPO subcutaneously at the dose of 300 U/kg t.i.w. in combination with G-CSF (300 microcg s.c. t.i.w., 27 patients), or GM-CSF (300 microcg s.c. t.i.w., 23 patients), or IL-3 (5 microcg/kg s.c. t.i.w., 10 patients), after a two-week pre-phase during which G-CSF, GM-CSF and IL-3 were administered daily at the same dose, as single drugs. RESULTS: Ten patients were not evaluable for erythroid response because of relevant side effects related to GM-CSF or IL-3 administration. Overall, among 50 patients who completed the study, there were 3 erythroid responses (as determined by complete abolition of red-cell transfusions): 1 (4%) in the G-CSF + r-EPO and 2 (10.5%) in the GM-CSF + r-EPO treated groups. No patient responded to the combination of r-EPO + IL-3. All responders had inappropriate serum levels of endogenous EPO and a relatively short disease duration. Both responders to GM-CSF + r-EPO developed acute myeloid leukemia 2-9 months after the start of the combined therapy. A third elderly patient, treated with the same association, developed marrow hypoplasia. A significant increase in leukocyte count occurred in 96% of patients who received r-EPO + G-CSF, 78.9% of those treated with r-EPO + GM-CSF and 66% of subjects receiving r-EPO + IL-3. A significant increase in platelet count was observed in a single patient receiving r-EPO and GM-CSF, while a slight decrease in platelet count with respect to baseline levels occurred in about 20% of patients. INTERPRETATION AND CONCLUSIONS: Our results suggest that the combination of r-EPO with G-CSF, GM-CSF or IL-3, at least at the doses and schedules employed in the present study, has limited efficacy on the anemia of heavily transfusion-dependent MDS patients previously unresponsive to r-EPO alone. However, in this setting of patients, the combination of G-CSF or GM-CSF + r-EPO may occasionally be effective in subjects with low circulating levels of serum EPO and short disease duration.