Randomized phase-II trial evaluating induction therapy with idarubicin and etoposide plus sequential or concurrent azacitidine and maintenance therapy with azacitidine.

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18-82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

A unified definition of clinical resistance/intolerance to hydroxyurea in essential thrombocythemia: results of a consensus process by an international working group.

A widely accepted definition of resistance or intolerance to hydroxyurea (HU) in patients with essential thrombocythemia (ET) is lacking. An international working group (WG) was convened to develop a consensus formulation of clinically significant criteria for defining resistance/intolerance to HU in ET. To this aim, an analytic hierarchy process (AHP), a multiple-attribute decision-making technique, was used. The steps consisted of selecting the candidate criteria for defining resistance/intolerance; identifying the motivations that could influence the preference of the WG for any individual criterion; comparing the candidate criteria in a pair-wise manner; and grading them according their ability to fulfill the motivations. Every step in the model was derived by questionnaires or group discussion. The WG proposed that the definition of resistance/intolerance should require the fulfillment of at least one of the following criteria: platelet count greater than 600,000/micro l after 3 months of at least 2 g/day of HU (2.5 g/day in patients with a body weight over 80 kg); platelet count greater than 400,000/micro l and WBC less than 2500/micro l or Hb less than 10 g/dl at any dose of HU; presence of leg ulcers or other unacceptable muco-cutaneous manifestations at any dose of HU; HU-related fever.

Which patients with myelofibrosis should receive ruxolitinib therapy? ELN-SIE evidence-based recommendations.

Ruxolitinib is an oral Janus-activated kinase 1 (JAK1)/JAK2 inhibitor approved for the treatment of patients with myelofibrosis based on the results of two randomized clinical trials. However, discordant indications were provided by regulatory agencies and scientific societies for selecting the most appropriate candidates to this drug. The European LeukemiaNet and the Italian Society of Hematology shared the aim of building evidence-based recommendations for the use of ruxolitinib according to the GRADE methodology. Eighteen patient-intervention-comparator-outcome profiles were listed, each of them comparing ruxolitinib to other therapies with the aim of improving one of the three clinical outcomes: (a) splenomegaly, (b) disease-related symptoms, and (c) survival. Ruxolitinib was strongly recommended for improving symptomatic or severe (>15 cm below the costal margin) splenomegaly in patients with an International Prognostic Scoring System (IPSS)/dynamic IPSS risk intermediate 2 or high. Ruxolitinib was also strongly recommended for improving systemic symptoms in patients with an MPN10 score >44, refractory severe itching, unintended weight loss not attributable to other causes or unexplained fever. Because of weak evidence, the panel does not recommend ruxolitinib therapy for improving survival. Also, the recommendations given above do not necessarily apply to patients who are candidates for allogeneic stem cell transplant.

Pomalidomide in myeloproliferative neoplasm-associated myelofibrosis.

Myeloproliferative neoplasm (MPN)-associated myelofibrosis is a MPN characterized by bone marrow fibrosis, cytopenias, splenomegaly and constitutional symptoms. Pomalidomide, an immune-modifying drug, is reported to improve anaemia and thrombocytopenia in some patients with MPN-associated myelofibrosis. We designed a phase 2 study of pomalidomide in patients with MPN-associated myelofibrosis and anaemia and/or thrombocytopenia and/or neutropenia. Subjects received pomalidomide 2.0 mg/day in cohort 1 (n=38) or 0.5 mg/day in cohort 2 (n=58). Prednisolone was added if there was no response after 3 months in cohort 1 and based on up-front randomization in cohort 2 if there was no response at 3 or 6 months. Response rates were 39% (95% confidence interval (CI), 26-55%) in cohort 1 and 24% (95% CI, 15-37%) in cohort 2. In a multivariable logistic regression model pomalidomide at 2.0 mg/day (odds ratio (OR), 2.62; 95% CI, 1.00-6.87; P=0.05) and mutated TET2 (OR, 5.07; 95% CI, 1.16-22.17; P=0.03) were significantly associated with responses. Median duration of responses was 13.0 months (range 0.9-52.7). There was no significant difference in response rates or duration in subjects receiving or not receiving prednisolone. Clinical trial MPNSG 01-09 is registered at ClinicalTrials.gov (NCT00949364) and clinicaltrialsregister.eu (EudraCT Number: 2009-010738-23).

High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists.

The optimal duration of treatment with vitamin K antagonists (VKA) after venous thromboembolism (VTE) in patients with Philadelphia-negative myeloproliferative neoplasms (MPNs) is uncertain. To tackle this issue, we retrospectively studied 206 patients with MPN-related VTE (deep venous thrombosis of the legs and/or pulmonary embolism). After this index event, we recorded over 695 pt-years 45 recurrences, venous in 36 cases, with an incidence rate (IR) of 6.5 per 100 pt-years (95% confidence interval (CI): 4.9-8.6). One hundred fifty-five patients received VKA; the IR of recurrent thrombosis per 100 pt-years was 4.7 (95% CI: 2.8-7.3) on VKA and 8.9 (95% CI: 5.7-13.2) off VKA (P=0.03). In patients receiving VKA, the IR of recurrent thrombosis per 100 pt-years was 5.3 (95% CI: 3.2-8.4) among 108 patients on long-term VKA and 12.8 (95% CI: 7.3-20.7) after discontinuation among the 47 who ceased treatment (P=0.008), with a doubled risk of recurrence after stopping VKA (hazard ratio: 2.21, 95% CI: 1.19-5.30). The IR of major bleeding per 100 pt-years was 2.4 (95%: CI: 1.1-4.5) on VKA and 0.7 (95% CI: 0.08-2.5) off VKA (P=0.08). In conclusion, in MPN patients with VTE recurrent thrombosis is significantly reduced by VKA and caution should be adopted in discontinuation; however, the incidence of recurrence on treatment remains high, calling for clinical trials aimed to improve prophylaxis in this setting.

Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients.

We retrospectively studied 181 patients with polycythaemia vera (n=67), essential thrombocythaemia (n=67) or primary myelofibrosis (n=47), who presented a first episode of splanchnic vein thrombosis (SVT). Budd-Chiari syndrome (BCS) and portal vein thrombosis were diagnosed in 31 (17.1%) and 109 (60.3%) patients, respectively; isolated thrombosis of the mesenteric or splenic veins was detected in 18 and 23 cases, respectively. After this index event, the patients were followed for 735 patient years (pt-years) and experienced 31 recurrences corresponding to an incidence rate of 4.2 per 100 pt-years. Factors associated with a significantly higher risk of recurrence were BCS (hazard ratio (HR): 3.03), history of previous thrombosis (HR: 3.62), splenomegaly (HR: 2.66) and leukocytosis (HR: 2.8). Vitamin K-antagonists (VKA) were prescribed in 85% of patients and the recurrence rate was 3.9 per 100 pt-years, whereas in the small fraction (15%) not receiving VKA more recurrences (7.2 per 100 pt-years) were reported. Intracranial and extracranial major bleeding was recorded mainly in patients on VKA and the corresponding rate was 2.0 per 100 pt-years. In conclusion, despite anticoagulation treatment, the recurrence rate after SVT in myeloproliferative neoplasms is high and suggests the exploration of new avenues of secondary prophylaxis with new antithrombotic drugs and JAK-2 inhibitors.

Plasma fibrin D-dimer levels and risk of stable coronary artery disease: results of a large case-control study.

Increased levels of fibrin D-dimer are indicative of a hypercoagulable state, as found in acute coronary syndromes. Few well-controlled studies have assessed D-dimers in patients with stable coronary artery disease (CAD). We measured levels of D-dimers (in ng/mL by enzyme-linked immunosorbent assay) in 312 patients with angiographically proved CAD and stable angina pectoris and in 477 age- and sex-matched healthy blood donors. Demographic characteristics were assessed by a standardized questionnaire, and a complete lipid profile was performed for all subjects. In addition, a variety of other markers of hemostasis and inflammation were measured. The distribution of D-dimer levels was skewed to the right, and plasma median levels were higher in cases than in controls (median: 11.2 vs 2.8 ng/mL; P<0.001). In controls, correlations of D-dimer were found with fibrinogen, plasma viscosity, and interleukin-6. In logistic regression analysis, the age- and sex-adjusted odds ratio (OR) for the presence of CAD was 2.6 (95% confidence interval [CI], 1.9 to 3.5) when the highest quartile of the D-dimer distribution was compared with the combined lower 3 quartiles. The OR did not change appreciably after controlling for nonlipid risk factors (OR, 2.7; 95% CI, 1.9 to 3.9) and remained significant after further adjustment for other hemostatic parameters (OR, 2.4; 95% CI, 1.7 to 3.3) and markers of inflammation (OR, 2.1; 95% CI, 1.5 to 2.9). Plasma D-dimer levels are strongly and independently associated with the presence of CAD in patients with stable angina pectoris. These results support the concept of a contribution of intravascular fibrin to atherothrombogenesis.

Chronic myelogenous leukemia: recent developments in prognostic evaluation and chemotherapy. The German CML Study Group.

Recent developments in CML research are illustrated by the results of one large randomized multicenter study carried out by the German CML Study Group. From July 1983 to January 1991, a total of 703 CML patients were recruited; 624 patients were randomized to compare hydroxyurea and interferon alpha (IFN) with busulfan. The median survival of Ph+ patients by now is 3.95 years, that of Ph- patients 1.1 years. Some difference in survival is recognizable between the treatment arms, but this is not yet significant. Fewer adverse effects are being observed in the hydroxyurea group. Ph-negative patients tend to have lower white blood cell and platelet counts. Patients (164) were randomized to receive IFN. In 50 patients (30%) IFN had to be terminated because of adverse effects, therapy resistance, or other reasons. Reduction of the Ph-chromosome was observed in 20% of evaluable patients. In 3 patients complete cytogenetic remissions were observed. Clinically relevant neutralizing antibodies were detected in 9 cases. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, erythroblasts, and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined and compared to Sokal's score. It is expected that the study results will allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.

Randomized comparison of interferon alpha and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II): prolongation of survival by the combination of interferon alpha and hydroxyurea.

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1:2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n=194) to the HU control group. Therefore, a total of 534 patients were evaluable (226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile (new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU-treated patients (59 vs 32%). Of 169 evaluable IFN/HU-treated patients (75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% (n=21), major in 14% (n=24), and at least minimal in 35% (n=59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU (P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P=0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.

Karyotype abnormalities and their clinical significance in blast crisis of chronic myeloid leukemia.

We examined karyotypes and their prognostic significance in a series of 122 patients with chronic myeloid leukemia in blast crisis. Of 73 patients cytogenetically examined at the onset of blast crisis 63% had developed secondary cytogenetic abnormalities in addition to the Philadelphia chromosome. These newly emerging abnormalities included a double Philadelphia chromosome in 20 patients, a trisomy 8 in 17, and an isochromosome 17q in 11 patients. Development of such additional karyotypic abnormalities was significantly associated with a shorter median survival and less response to cytoreductive treatment and was significantly more common in nonlymphoid blast crisis than in the lymphoid-type blast crisis. Thus, assessment of karyotypes at the onset of chronic myeloid leukemia blast crisis appears to be of prognostic significance for both remission duration and survival.

Clinical end points for drug treatment trials in BCR-ABL1-negative classic myeloproliferative neoplasms: consensus statements from European LeukemiaNET (ELN) and Internation Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).

The discovery of somatic mutations, primarily JAK2V617F and CALR, in classic BCR-ABL1-negative myeloproliferative neoplasms (MPNs) has generated interest in the development of molecularly targeted therapies, whose accurate assessment requires a standardized framework. A working group, comprised of members from European LeukemiaNet (ELN) and International Working Group for MPN Research and Treatment (IWG-MRT), prepared consensus-based recommendations regarding trial design, patient selection and definition of relevant end points. Accordingly, a response able to capture the long-term effect of the drug should be selected as the end point of phase II trials aimed at developing new drugs for MPNs. A time-to-event, such as overall survival, or progression-free survival or both, as co-primary end points, should measure efficacy in phase III studies. New drugs should be tested for preventing disease progression in myelofibrosis patients with early disease in randomized studies, and a time to event, such as progression-free or event-free survival should be the primary end point. Phase III trials aimed at preventing vascular events in polycythemia vera and essential thrombocythemia should be based on a selection of the target population based on new prognostic factors, including JAK2 mutation. In conclusion, we recommended a format for clinical trials in MPNs that facilitates communication between academic investigators, regulatory agencies and drug companies.

Indication and management of allogeneic stem cell transplantation in primary myelofibrosis: a consensus process by an EBMT/ELN international working group.

The aim of this work is to produce recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles released from 1999 to 2015 (January) was used as a source of scientific evidence. Recommendations were produced using a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention and management of relapse after transplant. Patients with intermediate-2- or high-risk disease and age <70 years should be considered as candidates for allo-SCT. Patients with intermediate-1-risk disease and age <65 years should be considered as candidates if they present with either refractory, transfusion-dependent anemia, or a percentage of blasts in peripheral blood (PB) >2%, or adverse cytogenetics. Pre-transplant splenectomy should be decided on a case by case basis. Patients with intermediate-2- or high-risk disease lacking an human leukocyte antigen (HLA)-matched sibling or unrelated donor, should be enrolled in a protocol using HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for HLA-matched sibling and unrelated donor transplants. The optimal intensity of the conditioning regimen still needs to be defined. Strategies such as discontinuation of immune-suppressive drugs, donor lymphocyte infusion or both were deemed appropriate to avoid clinical relapse. In conclusion, we provided consensus-based recommendations aimed to optimize allo-SCT in PMF. Unmet clinical needs were highlighted.

Pregnancy and renal failure: the case for application of dosage guidelines.

Pregnancies in women with renal disease, undergoing dialysis treatment or with kidney transplants are increasingly observed. Serious problems with drug dose adjustment may arise in pregnant women with renal impairment. This review gives a practical overview on the risks of drug use during gestation, the recommended drugs of choice (e.g. methyldopa, cyclosporin), and provides some proposals for dosage adjustments in pregnant women with renal impairment. In normal pregnancy, the glomerular filtration rate and plasma volume increase, whereas plasma protein binding and liver function may be impaired. An increase in dosage is needed for cyclosporin and for methadone because of increased hepatic clearance. The dosage of erythropoetin must be increased because of lower potency in pregnant women. Little more is known on the impact of gestation on drug dose, since pharmacokinetic studies are rarely done in pregnant women. The dosages of magnesium, lithium and morphine must be reduced in renal impairment. Dose adjustment to renal function is critical and is essential for anti-infective agents (e.g. ceftazidime, ganciclovir). Basing drug dose on estimated creatinine clearance might be the most practical solution in pregnant women with renal impairment.

Randomized study of the combination of hydroxyurea and interferon alpha versus hydroxyurea monotherapy during the chronic phase of chronic myelogenous leukemia (CML Study II). The German CML Study Group.

It is the long-term goal of the German CML Study Group and of the Süddeutsche Hämoblastosegruppe (SHG) to improve survival of patients with chronic myelogenous leukemia (CML). In a first randomized study (CML Study I) monotherapies with hydroxyurea or interferon alpha (IFN-alpha) were compared with a standard busulfan regimen with regard to duration of the chronic phase and survival. The main results of this study were published, 1-3 and a long-term follow up is planned. In a second randomized study the effect of the combination of IFN-alpha and hydroxyurea versus hydroxyurea monotherapy on survival is being investigated. This paper provides a first preliminary report on the study concept, patient recruitment, state of documentation and initial patients' characteristics 9 months after closure of the study.

Effects of the tyrosine kinase inhibitor imatinib mesylate (STI571) on bone marrow features in patients with chronic myelogenous leukemia.

Preliminary data are available about bone marrow (BM) changes in patients with chronic myeloid leukemia (CML) who received the molecularly targeted and highly effective tyrosine kinase inhibitor Imatinib mesylate (STI571). This review is focused on a systematic assessment of BM features detectable at different stages of CML (stable, accelerated, blastic) following long-term (more than 10 months) treatment. By applying enzyme- and immunohistochemistry including monoclonal antibodies visualizing proliferating cell nuclear antigen (PCNA) and apoptosis (anti-apostatin), a more elaborate insight into alterations affecting hematopoiesis and the stroma compartment was gained. In patients with stable-phase CML therapy resulted in a significant reduction in cellularity, neutrophil granulopoiesis and number of megakaryocytes, accompanied by a retrieval of erythroid precursors. In patients with Imatinib as the only treatment morphometric analysis of CD61+ megakaryopoiesis was in keeping with a significant decrease in maturation defects implying a lesser amount of atypical micromegakaryocytes almost consistent with normalization. Moreover, a reduction of the initially enhanced (CD34+) microvessel density was detectable associated with a decrease in luminal distension. Regression of marked to moderate myelofibrosis was recognizable in about 70% of patients especially in the accelerated and blastic phases. The amount of myeloblasts, CD34+ progenitor cells and lysozyme-expressing immature myelomonocytic cells declined with treatment, but recurred in about 19% of patients that developed a leukemic relapse after 21+/-6 months of therapy. Data on proliferative activity and apoptosis in general supported in vitro findings concerning the inhibitory effect of this agent on growth associated with a tendency for stimulated apoptosis, at least in responding patients.

Usefulness of FDG-PET in diagnosing primary lymphoma of the liver.

This case report shows for the first time the usefulness of positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) in the diagnosis of primary non Hodgkin's lymphoma of the liver. Results of FDG-PET, which in contrast to other imaging techniques offers the advantage of screening the whole body, demonstrated a high glycolytic activity of a solitary mass in the liver with central necrosis (loss of glycolytic activity), but no spread of lymphoma to the body. These results were confirmed by ultrasound, computed tomography, magnetic resonance imaging and were biopsy proven. From our findings we conclude that in patients with liver masses with high uptake of FDG, lack of liver dysfunction and absence of signs indicating other malignancies, a primary lymphoma of the liver should be considered as a possible diagnosis.

Interferon-alpha in the treatment of essential thrombocythemia.

Interferon alpha (IFN) inhibits the growth of megakaryocytic progenitors in normal hematopoiesis and in patients with essential thrombocythemia (ET) leading to a reduction of peripheral platelet counts. The effectiveness in the induction therapy of patients with ET is demonstrated in 11 international studies including 212 patients. With an average dose of about 3 mill IU IFN daily, the response rate was about 90%. Further studies investigated the practicability and the success of IFN maintenance therapy. The results show that IFN can effectively control platelet counts over a period of several years. During maintenance the IFN dose could be reduced in the majority of patients. However, sustained unmaintained complete remissions were obtained in only 12% of the patients. Side effects were frequently the limiting factors in treatment with IFN especially in older patients. Analyzing a total of 273 patients, IFN therapy was terminated in 25% against the primary treatment plan. Of the currently effective drugs in controlling the platelet counts in ET, IFN is the only antiproliferative agent with immuno-modulating properties. Thus far, no leukemogenic or significant gonadotoxic effects have been observed. In a subset of the patients off all therapy, the sustained remissions support a long-term tumor load reduction effect by IFN. Thus, IFN is a promising agent in cytoreductive treatment of ET especially in younger patients.

Essential thrombocythemia and pregnancy.

A review of the literature disclosed 106 pregnancies (preg.) in 57 women with essential thrombocythemia (ET). The success rate (baby alive) was 57% (60 live births/106 preg.), the rate of miscarriage 43% (46 miscarriages/106 preg.). The most frequent complication was spontaneous abortion during the first trimester in 36% (38 abortions/106 preg.). Other complications such as intrauterine death and stillbirth after the 28th week, which occurred in 5% (7/106), premature delivery in 8% (8/106), pre-eclampsia in 4% (4/106), and fetal growth retardation in 4% (4/106) were rarer events. Placental infarction due to thrombosis seems to be the most consistent pathological event as far as the fetus is concerned. Maternal hemorrhage occurred in 4% (3 minor and 1 major bleeding) and only 2 minor maternal thrombotic episodes have been observed. Interestingly, a decline in platelet count has been observed in 14 women and was associated with a successful preg, in 13/14 cases (93%). Aspirin (ASS) was the most frequently used drug in 47 of 93 recorded cases (51%). In 16 evaluable women treated with ASS the live birth rate was higher (12/16 preg., 75%) than for 21 untreated women (9/21 preg., 43%). In 5 cases interferon alpha (IFN) has been used successfully. In summary, 57% of women with ET had a live birth, maternal complications happened in 6%. Promising treatment modalities might be ASS and IFN. However, no definitive answer can be given on the ideal management for women with ET during pregnancy. A European register should be set up.

Serum erythropoietin and thrombopoietin levels in patients with essential thrombocythaemia.

In 40 patients with essential thrombocythaemia (ET) serum erythropoietin (EPO) and thrombopoietin (TPO) concentrations were determined and compared with the EPO and TPO values of a healthy control group. The mean EPO serum concentration for 24 control patients was 9.4 mU/ml +/- 3.7 (range 2-17.9), for 32 untreated ET patients at diagnosis 6.6 mU/ml +/- 7.6 (range 0.5-44.3) and for 8 ET patients treated with cytoreduction 14.1 mU/ml +/- 8.0 (range 4.5-26.1). Serum EPO levels in untreated ET patients at diagnosis were significantly lower compared with serum EPO levels in healthy control patients (p=0.002). Serum EPO levels in treated ET patients were not different from serum EPO levels in healthy controls (p=0.13) but were significantly higher compared with untreated ET patients (p=0.003). Serum TPO levels were determined in 18 of 40 ET patients, the mean TPO serum concentration was 211 pg/ml +/- 109 (range 62,5-345). The mean TPO serum concentration for 10 untreated ET patients at diagnosis was 162 pg/ml +/- 87 (range 62,5-302) and for 8 ET patients who had received cytoreductive treatment 272 pg/ml +/- 106 (range 96-345), respectively (p=0.04). Both serum TPO levels for treated and untreated ET patients were significantly higher (p<0.001) compared with serum TPO levels for healthy controls. The results of our study suggest a difference in the regulation of serum EPO and TPO in patients with ET. While the mean serum EPO level is decreased in untreated ET patients, the corresponding mean serum TPO level is increased. Treatment with cytoreduction, results in normalisation of the mean serum EPO level, whereas the mean TPO serum level remains elevated.

The German CML study, comparison of busulfan vs. hydroxyurea vs. interferon alpha and establishment of prognostic score 1.

From July 1983 to January 1991 a total of 622 patients were randomized (585 eligible) to compare the effects of hydroxyurea, interferon alpha (IFN), and busulfan on the duration of chronic phase, and survival. Further goals included the determination of prognostic parameters. 598 CML patients were documented and 575 evaluable. The Ph-status was known for 547 patients. 89.4% of the patients were Ph-positive (+). 11% had additional chromosome aberrations. The median survival of Ph+ patients by now is 4.2 years, that of Ph-patients 1.4 years. Ph-negative patients are older, tend to have lower cell counts and, as a group are more ill at diagnosis. A survival difference of about one year is expected between busulfan and hydroxyurea treated patients. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, number of erythroblasts and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined which was superior to Sokal's score in the study population. 164 patients were randomized to receive IFN. In 54 patients (33%) IFN had to be terminated because of adverse effects, therapy resistance or other reasons. Clinically relevant neutralizing antibodies were detected in 9 cases. Most frequent adverse events were flu-like symptoms in 74%, gastrointestinal symptoms in 52%, and neurologic-psychiatric symptoms in 30% of patients. Reduction of the Ph-chromosome was observed in 13% of evaluable patients (10 of 75). In 4 patients complete cytogenetic remissions were observed, in three of these ongoing. Cytogenetic responders have a survival advantage. Interferon treated Philadelphia-negative CML patients have no survival disadvantage. The study is expected to allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.