Abstract: PURPOSE: To evaluate the cost-effectiveness of 12-month adjuvant trastuzumab therapy in women with high-risk human epidermal growth factor receptor 2 (HER2) -positive early breast cancer. METHODS: A Markov model tracked quarterly patients' transitions between five health states: disease free, local relapse, disease free after local relapse, metastatic disease, and death. Patients were allowed to incur symptomatic or asymptomatic transient cardiac dysfunction during trastuzumab administration. Probabilities were derived mainly from the combined report of the National Surgical Adjuvant Breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 trials (95% node positive) and a meta-analysis by the Early Breast Cancer Trialists' Collaborative Group. Costs were estimated from the perspective of the Italian and US health care systems. The analysis was run during a 15-year time horizon. A 3% yearly discount rate was applied to both costs and life-years. Second-order Monte-Carlo and probabilistic sensitivity analyses were performed. RESULTS: Adjuvant trastuzumab increases life expectancy by 1.54 (1.18 discounted) quality-adjusted life-years (QALYs). At a cost of 675 euros and 767 dollars per weekly dose in the Italian and US setting, respectively, trastuzumab achieves its clinical benefit at a cost of 14,861 euros (95% CI, 3,917 euros to 44,028 euros) and 18,970 dollars (95% CI, 6,014 dollars to 45,621 dollars) per QALY saved. The incremental cost effectiveness was higher than 50,000 euros/QALY (or 60,000 dollars/QALY) at time horizons shorter than 7.8 years and for patients older than 76 years or with a 10-year risk of relapse lower than 15%. The results confirmed the cost effectiveness when simulating a Herceptin Adjuvant Trial (HERA) -like scenario at multiway sensitivity analysis. CONCLUSION: In a long-term horizon, adjuvant trastuzumab is a cost-effective therapy for patients with HER2-positive, high-risk, early breast cancer.
Abstract: The European Myelofibrosis Network (EUMNET), a European research network on myelofibrosis with myeloid metaplasia (MMM), has developed a definition of response for the disease by using clinicohematologic, histologic, and cytogenetic criteria. A core set of 5 clinicohematologic criteria was selected out of 9 candidates on the basis of their sensitivity to change measured in 196 patients treated either during clinical trials or routine clinical practice. A consensus panel of 16 international experts was convened and asked to score the level of response in 104 patient profiles as major, moderate, minor, or no response according to changes of the clinicohematologic criteria. Using the experts' consensus as the gold standard, the performance of 100 possible definitions of response was evaluated. Criteria for major or moderate clinicohematologic response were determined to be changes in hemoglobin (Hb) and spleen size and the presence of constitutional symptoms, while changes in platelet count and white blood cell (WBC) count served as complementary criteria and were of value for defining minor responses. A histologic response was defined by changes in bone marrow fibrosis and cellularity grades. The combined use of these response definitions should help standardize the design and reporting of future clinical studies in MMM.
Abstract: BACKGROUND AND OBJECTIVES: The Italian Society of Hematology (SIE) and the two affiliated Societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of essential thrombocythemia (ET) using evidence-based knowledge and consensus formation techniques. DESIGN AND METHODS: Key questions on the optimal management of ET patients were formulated by an Advisory Council (AC) and approved by an Expert Panel (EP) composed of 7 senior hematologists. The AC systematically reviewed the published literature from 1980 to August 2002, and articles were graded according to their internal validity and quality. Using the Delphi technique, the EP was asked to answer the key questions according to the available evidence. From September 2002 to March 2003, four Consensus Conferences were held in accordance with the Nominal Group Technique with the goal of solving residual disagreement on recommendations. RESULTS: The EP provided recommendations on when to start platelet-lowering therapy, the most appropriate platelet-lowering agent, the use of anti-platelet therapy, and the management of women in childbearing age and of pregnant women. INTERPRETATION AND CONCLUSIONS: By using evidence and consensus, recommendations for the treatment of key problems in ET have been issued. Statements are graded according to the strength of the supporting evidence and uncertainty is explicitly declared.
Abstract: An ideal palliative therapy for bone metastases would successfully reduce skeletal complications in several thousands of breast cancer patients. Second- and third-generation bisphosphonates are effective in reducing the overall skeletal complication rate and the time to first skeletal complication. Nevertheless, not enough evidence supports their benefit on quality of life. Furthermore, bisphosphonates are expensive (up to 775 US dollars per month, 2002 value) and cost-effectiveness evaluations have been limited to pamidronate (pamidronic acid). In economic evaluations of pamidronate, resulting incremental dollar per quality-adjusted life year gained ranged from cost savings to 108,000 US dollars per quality-adjusted life year. The data were quite sensitive to quality-of-life estimates and country-specific cost values. Because of the wide range of the cost-effectiveness ratio, it is uncertain whether the universal prescription of bisphosphonates in this setting represents an efficient use of healthcare resources. Probably, country- and drug-specific policies might increase the efficiency of this treatment. Further outcomes research is required to assess these agents more fully.
Abstract: BACKGROUND AND OBJECTIVES: Novel therapeutic agents and strategies have been introduced into the management of myelodysplastic syndromes (MDS) in the last years. This has led to more treatment options and a better chance of long-term survival for MDS patients, but also to uncertainty regarding the optimal use and possible side effects of these treatments. The Italian Society of Hematology commissioned a project to develop guidelines for the therapy of MDS using evidence-based knowledge and consensus-formation techniques. DESIGN AND METHODS: An Advisory Council (AC) shaped the project around a series of key clinical questions, performed a systematic search for evidence and graded the available evidence according to the Scottish Intercollegiate Guidelines Network (SIGN). A list of clinical questions was mailed to each of 10 senior hematologists composing the Expert Panel (EP): the panelists were asked to rank the most relevant questions, and to formulate answers to the questions according to the tables of evidence. A scenario phase followed, so as to reach a consensus on the three top ranked questions. The EP was asked to score patient profiles as appropriate or not appropriate for the therapeutic strategy under scrutiny, according to the RAND technique. Finally, from September 2001 to January 2002, four Consensus Conferences conducted according to the Nominal Group Technique were held in Milan, Italy. The overall goal of the conferences was to take a final decision upon the appropriateness of the uncertain scenarios and of the uncertain responses to the clinical questions. RESULTS: Evidence was judged sufficient for providing recommendations on the use of allogeneic stem cell transplantation, leukemia-like chemotherapy, autologous stem cell transplantation, low-dose chemotherapy, danazol, immunosuppressive therapy, hypomethylating agents and hematopoietic growth factors. Specific recommendations for supportive therapy, including iron chelation, were issued. Allogeneic stem cell transplantation was unanimously considered as the only curative treatment for MDS patients, and recommendations on its use were agreed based on patient's age, risk, clinical features and donor availability. AML-like chemotherapy was also considered a valuable therapeutic option for subsets of MDS patients. Autologous stem cell transplantation was recommended for patients who lack an HLA identical donor and have achieved complete remission with AML-like chemotherapy. Decitabine, recombinant human erythropoietin and immunosuppressive therapy were judged valuable therapeutic options for subsets of MDS patients whereas low-dose cytarabine was not.Specific therapeutic strategies for those subjects younger than 18 years or older than 75 years and the strategy of watchful waiting were decided by patient-oriented questions. INTERPRETATION AND CONCLUSIONS: Using evidence and consensus, recommendations for the treatment of MDS were issued. Statements were graded according to the strength of the supporting evidence and uncertainty was explicitly declared.
Abstract: The purpose of this work was to develop a definition of myelofibrosis with myeloid metaplasia (MMM) using diagnostic criteria that would remain valid within the set of patients with chronic myeloproliferative disorders or myelodysplastic syndromes. A list of 12 names for the disease and 37 diagnostic criteria were proposed to a Consensus Panel of 12 Italian experts who ranked them in order so as to identify a core set of criteria. The Panel was then asked to score the diagnosis of 46 patient profiles as appropriate or not appropriate for MMM. Using the experts' consensus as the gold standard, the performance of 90 possible definitions of the disease obtained through the core set was evaluated. 'Myelofibrosis with myeloid metaplasia' ranked as the preferred name of the disease. Necessary criteria consisted of 'diffuse bone marrow fibrosis' and 'absence of Philadelphia chromosome or BCR-ABL rearrangement in peripheral blood cells'. The six optional criteria in the core set consisted of: splenomegaly of any grade; anisopoikilocytosis with tear-drop erythrocytes; the presence of circulating immature myeloid cells; the presence of circulating erythroblasts: the presence of clusters of megakaryoblasts and anomalous megakaryocytes in bone marrow sections; myeloid metaplasia. The definition of the disease with the highest final score was as follows: necessary criteria plus any other two criteria when splenomegaly is present or any four when splenomegaly is absent. The use of this definition will help to standardize the conduct and reporting of clinical studies and should help practitioners in clinical practice.
Abstract: BACKGROUND AND OBJECTIVE: Either low molecular weight heparin (LMWH) or unfractionated heparin (UH) may be used for the prophylaxis of post-operative venous thromboembolic disease (VTD) in elective hip replacement. This study was aimed at assessing the cost-effectiveness of LMWH over UH from the society perspective, which considers all the outcomes occurring in the life-long time horizon. DESIGN AND METHODS: A decision tree modeled the clinical outcomes and resources used in consequence of restricted (2 weeks) and extended (4 weeks) prophylaxis of VTD with LMWH or UH. RESULTS: In the studied population, that of 67 year-old patients, restricted prophylaxis with LMWH saved 25 quality-adjusted days and $75 over UH. Extended prophylaxis provided a small additional benefit with additional cost savings. The incremental outcomes of the model proved independent of most parameters. INTERPRETATION AND CONCLUSIONS: We conclude that LMWH has considerable advantages over UH in the prophylaxis of VTD following elective hip replacement, and should be recommended in clinical practice.
Abstract: Recombinant human erythropoietin (rHuEPO) has been advocated for the treatment of anaemia in patients submitted to cancer chemotherapy. We used decision analysis to compare the cost-effectiveness of rHuEPO supplemented with red blood cell (RBC) transfusions with conventional treatment with RBC transfusions alone. At baseline, we analysed the use of rHuEPO as secondary prophylaxis according to effectiveness estimates from a community-based oncology study. In order to reduce the probability of transfusions from 21.9% to 10.4%, and the number of RBC units per patient per month from 0.55 to 0.29, 150 units kg(-1) s.c. rHuEPO three times per week for 4 months resulted in an incremental cost of $189,652 per quality-adjusted life year (QALY). In patients treated with cisplatin-containing chemotherapy, rHuEPO added $190,142 per QALY. In a hypothetical scenario of a transfusion pattern that maintained the same haemoglobin level of rHuEPO-responsive patients, the marginal cost of rHuEPO was always greater than $100,000 per QALY. Results were stable with regard to variations in the probability of blood-borne infections, quality of life of responding patients and cancer-related mortality. The additional cost could be lowered to less than $100,000 per QALY by saving 4.5 RBC units over 4 months for any patient treated. In conclusion, according to current use, rHuEPO is not cost-effective in the treatment of chemotherapy-induced anaemia. More tailored utilization of the drug and better consideration of predictive response indicators may lead to an effective, blood-sparing alternative.
Abstract: PURPOSE: To evaluate the cost-effectiveness of interferon alfa (IFN alpha) treatment of patients with chronic myelogenous leukemia relative to conventional chemotherapy. MATERIALS AND METHODS: A decision-analysis model that involved a multistate Markov process was designed to estimate the expected cost and quality-adjusted life expectancies for two cohorts of patients to be administered conventional chemotherapy or IFN alpha. Two IFN alpha strategies were modeled: prolonged treatment for patients who achieved a hematologic response (scenario A) or only for patients who achieved a cytogenetic remission in a 2-year period (scenario B). Data on response and transition probabilities between health states were obtained from the literature by a MEDLINE search and pooled with a meta-analytic method. Costs were based on local charges. Expected survival was adjusted for quality of life on the basis of an expert panel judgment. RESULTS: Baseline analysis showed IFN alpha treatment to increase the quality-adjusted life expectancy by 15.5 and 12.5 months relative to conventional chemotherapy, in scenarios A and B, respectively. Marginal cost-effectiveness was $89,500 and $63,500 per quality-adjusted life-year (QALY) gained. Sensitivity analysis confirmed IFN alpha as the most effective approach. Cost-effectiveness results were sensitive to the cost of IFN alpha therapy and to the assumptions about the rate of cytogenetic remission. Reducing the drug dose, as suggested by a recent report, would decrease the marginal cost-effectiveness to less than $20,000. CONCLUSION: IFN alpha is substantially superior to conventional chemotherapy in terms of quality-adjusted survival, but, at the current doses, marginal cost-effectiveness ranges from $50,000 to $100,000 per QALY gained under most of our assumptions.
Abstract: We report on a patient affected by multicentric Castleman's disease who developed an acute immunohemolytic anemia due to warm antibody. The clinical course was characterized by refractoriness to the steroidal treatment and by a dramatic improvement of the hematological and objective picture following combination chemotherapy (CHOP regimen). The possible existence of a link between the lymphoproliferative syndrome and the immunological derangement is also discussed.
Abstract: In order to study the relationship between erythropoiesis and serum ferritin (SF) during erythropoietin (rHuEPO) therapy in the anaemia of end-stage renal disease (ESRD), 19 patients were followed without iron supplementation and at a fixed dose of the drug (40 U/kg). Twelve patients failed to attain the target haemoglobin (Hb) value, 7 of whom due to the appearance of iron deficiency. Erythropoiesis, as measured by the serum transferrin receptor concentration, increased from 12 to 120% of the basal value. This increment was not constantly associated with a proportional rise of Hb or reticulocyte count. SF decreased exponentially from a median value of 221 micrograms/dl (range 42-470) to a median value of 54 micrograms/dl (range 20-172). Halving of the basal SF value (SF-T50) was reached at the 18th-95th day of therapy (median = 43), representing a iron shift of 3.4-11.6 mg/day (median = 5.4). SF-T50 was not correlated with the Hb increase, but with that of erythropoiesis (r = 0.78; p = 0.003). The minimum SF (MSF) value attained was not correlated with the appearance of iron deficiency. The conclusion is that the rate of SF decrease during rHuEPO in ESRD is a reliable measure of iron mobilisation for erythropoiesis, but not for haematologic response. The MSF value reached during therapy is not representative of available iron for erythropoiesis.
Abstract: Since according to the early studies, the outcome after splenectomy in the individual patient with myelofibrosis with myeloid metaplasia (MMM) is unpredictable, we assessed retrospectively the pre-intervention characteristics that best predicted adverse events, hematological consequences, and survival in 71 splenectomized MMM patients. The findings indicate that the operative risk of splenectomy for both mortality (8.4%) and morbidity (39.3%) was unpredictable. New hemorrhagic or thrombotic complications occurred in 16.9% of surviving patients and were predicted by age < 50 years, a normal to high platelet count (> 200 x 10(9)/l) and huge splenomegaly (> 16 cm from the costal margin). Massive liver enlargement occurred in 24% of patients and has to be expected in patients splenectomized for transfusion-dependent anemia. Anemia improved substantially in 45% and 52% of patients at 3 months and at 1 year, respectively, and was predicted by severe anemia, low platelet count (< 100 x 10(9)/l) or normal to high white blood cell (WBC) count (> 4 x 10(9)/l). Survival from splenectomy was superior in patients < 45 years with WBC < 10 x 10(9)/l count. An unexpectedly high rate of blastic transformation was observed. It accounted for 42.8% of the deaths. The results suggest trials for prophylactic cytoreductive treatment in young patients and when platelet count is normal to increased. Further study is needed for elucidating the possible role played by splenectomy in inducing blastic transformation.
Abstract: Serum erythropoietin levels (s-Epo) were measured by radioimmunoassay in 61 consecutive anaemic patients (Hb < 12 g/dl) with myelofibrosis with myeloid metaplasia (MMM). S-Epo was inversely correlated with Hb (r = -0.48, P < 0.0001). When observed s-Epo values were compared with predicted levels based on the relationship between s-Epo and Hb in control subjects, all but eight patients (87%) had s-Epo levels appropriate for the degree of anaemia. The observed/predicted (O/P) s-Epo ratio was significantly lower in patients with signs of active disease, and a significant inverse correlation was found between the O/P ratio and erythrokinetic measurement of the extent of erythropoiesis (r = 0.31; P = 0.02). Circulating Epo levels were appropriate for the variations in Hb during the postsplenectomy period in three patients. In conclusion, this study does not support the idea that therapy with erythropoietin should be extensively used in anaemic patients with MMM, but rather that it should be considered only in selected cases.
Abstract: Two children affected by severe aplastic anaemia (SAA) underwent allogeneic bone marrow transplantation (BMT) using partially matched family donors. In both cases there was a successful engraftment of donor haemopoietic stem cells. However, after an initial erythropoietic recovery, 5 months following BMT both children became severely anaemic. Although multiple factors were responsible for anaemia, in both cases there was a markedly impaired erythropoietin response to anaemia, as indicated by the inappropriately low levels of serum erythropoietin (EPO). Treatment with recombinant human erythropoietin (rHuEPO) induced a sustained erythropoietic response with complete correction of anaemia. This pilot study suggests that rHuEPO can be effective in correcting long-lasting anaemia after marrow transplantation, characterized by inadequate erythropoietin production.
Abstract: We have used recombinant human erythropoietin (rHuEPO) in a phase I/II clinical trial to evaluate its ability to reverse refractory anemia in hematologic disorders. rHuEPO was administered subcutaneously 5 days per week at escalating doses (50 to 150 U/kg per day). The aim of treatment was a hemoglobin (Hb) level greater than or equal to 10 g/dL without blood transfusion. Of 25 patients treated, 17 were evaluable, most of them with a regular need for transfusion. Eight of these had lymphoproliferative disorders (three cases of malignant lymphoma and five of monoclonal gammopathy) and were exposed to cytotoxic therapy. The other nine patients had hematopoietic stem cell disorders (four cases of myelodysplastic syndrome, three of idiopathic myelofibrosis, and two of chronic myelogenous leukemia). All patients with lymphoproliferative disorder had serum EPO levels inappropriately low for the degree of anemia, while patients with stem cell disorder showed variable values. Erythroid marrow activity was inadequate in all cases. Seven of eight patients with lymphoproliferative disorder responded to treatment maintaining Hb above 10 g/dL without transfusion. The median dose of rHuEPO required for correction of anemia was 75 U/kg. In four cases response was maintained with 50 U/kg, three times per week. There was no complete response among patients with hematopoietic stem cell disorder, although transfusion requirement was eliminated or reduced in four cases. Four patients developed functional iron deficiency during rHuEPO treatment and required iron supplementation to obtain response. Aggravation of splenomegaly was observed in two cases of myeloproliferative disorder. We conclude that: (1) subcutaneous administration of rHuEPO can be effective and safe in patients with lymphoproliferative disorder exposed to chemotherapy and showing inappropriate EPO response to anemia; (2) this is less likely in hematopoietic stem cell disorders, although favorable responses may be observed in occasional patients; and (3) functional iron deficiency as a cause of nonresponse to rHuEPO is frequent also in nonrenal anemia.
Abstract: Among 761 consecutive patients with chronic myeloproliferative disorders (CMD), it was found that 18 (nine men and nine women) did not fulfill at presentation the established diagnostic criteria for the typical forms. In seven patients, the diagnosis of CMD was made on the basis of an intense and persistent thrombocytosis that complicated splenectomy. The other 11 patients had various combinations of the following signs suggesting CMD: splenomegaly, bone marrow myeloid hyperplasia and/or slight myelofibrosis, mild thrombocytosis and/or leukocytosis, and rare immature myeloid cells in the peripheral blood. All patients were younger than 46 years of age (median age, 31.5 years; range, 20 to 45 years). A major thrombotic event was the most frequent presenting feature (eight of 18 cases), and thrombotic complications supervened in seven of the eight splenectomized patients (six in the portal system), raising the overall rate of patients with thrombotic events in their history to 11 of 18. At a median follow-up of 50 months (range, 24 to 241 months), three patients had died of thrombotic complications (two after splenectomy). The 15 surviving patients had stable disease, and 12 of them were not receiving cytoreductive therapy. Spontaneous growth of circulating burst-forming units erythroid was demonstrated in one patient, and erythroid responsiveness to erythropoietin appeared higher than in the normal controls in four. Spontaneous in vitro platelet aggregation in whole blood and/or platelet-rich plasma was seen in five of seven patients. It was concluded that a difficult to identify, slowly progressive form of CMD occurs in young people, that it carries a high risk of thrombosis, and that splenectomy is a high risk procedure in these cases.
Abstract: The small-dose iron tolerance test (SD-ITT) was performed in 37 healthy subjects (20 females and 17 males). The area under the curve (AUC) of serum iron variations after the test dose (10 mg of iron as iron sulphate) was corrected by the expected plasma iron disappearance rate, the expected subject's plasma volume and the measured spontaneous time-dependent serum iron variations, and was used as a summary measure of the outcome, Q-ITT. Q-ITT correlated strictly with the maximum serum iron increase (SImax). Q-ITT gave positive (greater than zero) values in only 14 out of the 37 subjects (11 females and 3 males). Serum ferritin proved to be the best discriminating parameter between positive and non-positive subjects, and was inversely correlated with Q-ITT in the positive ones. In 2 male subjects, aged 43 and 34 years, SD-ITT proved to be highly sensitive to the progressive decrease of mobilizable body iron content during repeated venesections. In these patients the threshold for a positive test result was obtained at values lower than 1050 and 950 mg of body iron content, respectively. The threshold-dependent sensitivity, simplicity, and repeatability of this method favor its becoming a useful technique for studying the up-regulation of iron absorption in normal subjects and in pathological conditions.
Abstract: In 12 patients having myelofibrosis with myeloid metaplasia (MMM), recombinant- alpha interferon (r-alpha INF) was given for 16 weeks at an initial dose of 3 x 10(6) U/day as a cytoreductive agent. At the end of the 16th wk, Hb showed minor changes; WBC were reduced from 43 x 10(9)/l, range 6.4-69.4, to 16 x 10(9)/l, range 5-39 (p = 0.05); platelets decreased from 845 x 10(9)/l, range 215-1748, to 370 x 10(9)/l, range 96-730 (p = 0.005). 2 cases responded at the starting dose, while the effective dose was 5 x 10(6) U/d in the others. Minor changes in spleen size were noted, while no significant changes in bone marrow fibrosis occurred. After induction therapy, 3 patients were allocated to maintenance therapy (from 10 up to 34 months). To maintain platelet count lower than 500 x 10(9)/l, the required r-alpha-INF dose was constantly 10 MU/wk, while the same result was not achieved in 1 case with hydroxyurea, 1 g/die. The association with hydroxyurea, 500 mg/die, allowed reduction of the r-alpha INF dose to 6 MU/die in 1 other case.
Abstract: The various association of polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes has been called the POEMS syndrome. Herein we report a case in which all the typical clinical and laboratory findings of the POEMS syndrome were present. We emphasize as the most striking features of our case the following: the similarity with scleroderma, the peripheral nerve demyelination without the presence of antibodies against nerve components, the occurrence of an IgA lambda monoclonal gammopathy and Castleman-like features at a single enlarged lymph node. To our knowledge, this is the first such case reported in Italy.
Abstract: In the eighties there has been an enormous increase in our knowledge about erythropoietin, previously defined as "an elusive hormone". In this review we summarize the structural and molecular features, the mechanisms of production and of metabolism, the more important methods of assay, the mechanism of action and the biological effects, the main pathophysiological aspects and the therapeutic usefulness of the hormone.
Abstract: We report a male patient in whom a diagnosis of essential thrombocythaemia was made at the age of 25. The clinical course was characterised by recurrent thrombotic episodes during the first few years of the disease, followed by a relatively benign course. He was treated with 32P, nitrogen mustard and plateletpheresis. A transformation into myelofibrosis with myeloid metaplasia was revealed 20 years after ET diagnosis. The length of the disease and the 32P therapy are discussed as factors favouring this metamorphosis.
Abstract: In 78 patients with myelofibrosis with myeloid metaplasia (MMM) the serum procollagen III peptide activity (s-PIIIP) had a higher mean value than in 22 normal adult volunteers (22.5 v. 10 ng/ml). Nevertheless, 21.8% of the patients had s-PIIIP within the 95th percentile of the normal control group (16 ng/ml): with respect to those whose concentrations exceeded this limit, patients with normal s-PIIIP levels were younger (55.8 v. 61.2 years), had a higher Hb value (12.3 v. 10.5 g/l), a lower serum ferritin level (106 v. 464 micrograms/l) and a higher platelet count (390 v. 216 x 10(9)/l). In the overall patient population, s-PIIIP was significantly higher in those with symptoms of active disease (fever, sweating, weight loss) than in subjects with non-active disease (28 v. 16.9 ng/ml). At univariate analysis s-PIIIP correlated (at the 5% level) with increasing WBC, serum ferritin and number of transfusions and with decreasing Hb and platelet count. At multivariate analysis increasing WBC, serum ferritin and age proved to be independently associated with s-PIIIP. No relationship was found between the s-PIIIP level and morphometric grading of bone marrow fibrosis, megakaryocyte number, or lymphoid infiltration. Longitudinal studies showed that s-PIIIP increased with disease progression. The conclusion of the study is that s-PIIIP correlates more with overall disease activity than with the extent of bone marrow fibrosis.
Abstract: In an attempt to reduce myeloproliferation, we administered recombinant alpha-2b interferon (r-alpha INF) to ten patients with myelofibrosis with myeloid metaplasia (MMM) in a hypercellular phase, as part of a phase II trial. Two patients experienced severe side effects and stopped treatment before completion of the first week. In the eight evaluable patients, r-alpha INF was given for 16 weeks at an initial dosage of 3 X 10(6) U/day, with monthly increments in the case of response failure, i.e. a decrease in WBC or platelet count of less than 25% of the initial value. Two cases responded at the starting dosage, while the effective dosage was 5 X 10(6) U/day in the others. At the end of the 16th week, Hb showed minor changes: from an initial value of 12.08 g/dl, range 8.3-17.3, to 11.6 g/dl, range 7.7-18 (P = 0.12); WBC were reduced from 54 X 10(9)/l, range 6.4-69.4, to 17.5 X 10(9)/l, range 5-39 (P = 0.09, 4/8 responses); platelets decreased from 775 X 10(9)/l, range 215-1748, to 403 X 10(9)/l, range 118-730 (P = 0.008, 8/8 responses). Minor changes in spleen size were also noted, while no significant changes in bone marrow fibrosis occurred. Influenza-like symptoms and fatigue were common side effects. In conclusion, r-alpha INF has a role as a non-leukemogenic cytoreductive agent in the therapy of MMM, especially for cases with thrombocytosis.
Abstract: The dependence of survival time on a set of prognostic factors was explored by means of Cox's regression model in 137 cases of myelofibrosis with myeloid metaplasia (MMM). The following parameters recorded at diagnosis proved to be important independent indicators of a poor prognosis: a higher value for age, a lower value for Hb concentration, a higher value for immature myeloid cells in peripheral blood (IMC), a lower value for total erythroid iron turnover (TEIT), and a bone marrow red cell aplasia (RCA). A prognostic classification tree was constructed whose terminal nodes (risk groups), described by simple logical conditions upon important indicators, were characterized by significantly different expected survival. The two extreme risk groups lend themselves to a simple, but complete description. The low-risk group (19.7% of the sample) comprises cases who had the diagnosis of MMM before age 45 and a number of IMC constantly lower than 24%. The actuarial proportion of patients surviving at 15 years was 100%. The high-risk group (29.9% of cases) comprises patients with age greater than 45 and Hb lower than 13 g/dl, associated with RCA, or with a relatively decreased erythropoiesis (TEIT lower than 2 times the normal) or with IMC greater than 24%. Seven out of the 11 who died within this group developed blastic crisis. Median survival time of the group was 69 months.
