Argiris Symeonidis

Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet

Within the myelodysplastic syndrome (MDS) work package of the European LeukemiaNet, an Expert Panel was selected according to the framework elements of the National Institutes of Health Consensus Development Program. A systematic review of the literature was performed that included indexed original papers, indexed reviews and educational papers, and abstracts of conference proceedings. Guidelines were developed on the basis of a list of patient- and therapy-oriented questions, and recommendations were formulated and ranked according to the supporting level of evidence. MDSs should be classified according to the 2008 World Health Organization criteria. An accurate risk assessment requires the evaluation of not only disease-related factors but also of those related to extrahematologic comorbidity. The assessment of individual risk enables the identification of fit patients with a poor prognosis who are candidates for up-front intensive treatments, primarily allogeneic stem cell transplantation. A high proportion of MDS patients are not eligible for potentially curative treatment because of advanced age and/or clinically relevant comorbidities and poor performance status. In these patients, the therapeutic intervention is aimed at preventing cytopenia-related morbidity and preserving quality of life. A number of new agents are being developed for which the available evidence is not sufficient to recommend routine use. The inclusion of patients into prospective clinical trials is strongly recommended.

Improved survival of patients with multiple myeloma after the introduction of novel agents and the applicability of the International Staging System (ISS): an analysis of the Greek Myeloma Study Group (GMSG).

When the novel agents thalidomide, bortezomib and lenalidomide are administered to patients with myeloma in the context of clinical trials, they are associated with a significant improvement in response, progression-free survival and in some studies, overall survival (OS); however, their effect on the outcome of unselected myeloma patients has not been fully assessed. We compared the outcome of 1376 unselected patients with symptomatic myeloma, who started treatment before or after the introduction of thalidomide. The median OS in patients who started treatment after the introduction of novel agents increased by 12 months (48 vs 36 months, P<0.001). This improvement was more pronounced in patients ⩽70 years (from 39 to 74 months, P<0.001), but less evident in patients >70 years (from 26 to 33 months, P=0.27). In patients treated after the introduction of novel agents, the international staging system (ISS) could discriminate three groups with significantly different outcomes (5-year survival for ISS stage I, II and III was 66, 45 and 18%, respectively, P<0.001). ISS was also valid in patients who actually received upfront treatment with novel drugs (4-year survival rate was 85, 61 and 26% for ISS stage I, II and III patients, P=0.001).

Risk factors for therapy-related myelodysplastic syndrome and acute myeloid leukemia treated with allogeneic stem cell transplantation

After successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems. This study shows that allogeneic stem cell transplantation can cure a significant portion of these patients. See related perspective article on page 542. Background After successful treatment of malignant diseases, therapy-related myelodysplastic syndrome and acute myeloid leukemia have emerged as significant problems. Design and Methods The aim of this study was to investigate outcome and risk factors in patients with therapy-related myelodysplastic syndrome or acute myeloid leukemia who underwent allogeneic stem cell transplantation. Between 1981 and 2006, 461 patients with therapy-related myelodysplastic syndrome or acute myeloid, a median age of 40 years and a history of solid tumor (n=163), malignant lymphoma (n=133), or other hematologic diseases (n=57) underwent stem cell transplantation and their data were reported to the European Group for Blood and Marrow Transplantation. Results The cumulative incidence of non-relapse mortality and relapse at 3 years was 37% and 31%, respectively. In a multivariate analysis significant factors for relapse were not being in complete remission at the time of transplantation (p=0.002), abnormal cytogenetics (p=0.005), higher patients’ age (p=0.03) and therapy-related myelodysplastic syndrome (p=0.04), while higher non-relapse mortality was influenced by higher patients’ age. Furthermore, there was a marked reduction in non-relapse mortality per calendar year during the study period (p<0.001). The 3-year relapse-free and overall survival rates were 33% and 35%, respectively. In a multivariate analysis significant higher overall survival rates were seen per calendar year (p<0.001), for younger age (<40 years) and normal cytogenetics (p=0.05). Using age (<40 years), abnormal cytogenetics and not being in complete remission at the time of transplantation as risk factors, three different risk groups with overall survival rates of 62%, 33% and 24% could be easily distinguished. Conclusions Allogeneic stem cell transplantation can cure patients with therapy-related myelodysplastic syndrome and acute myeloid leukemia and has markedly improved over time. Non-complete remission, abnormal cytogenetics and higher patients’ age are the most significant factors predicting survival.

High serum lactate dehydrogenase adds prognostic value to the international myeloma staging system even in the era of novel agents

Objectives:  High serum lactate dehydrogenase (LDH) is associated with features of advanced disease and inferior survival in multiple myeloma. It is however unclear whether LDH adds to the prognostic value of International Staging System (ISS) and whether it retains its prognostic significance in patients who are exposed to novel agent‐based therapies.

Outcome of pregnancy and disease course among women with aplastic anemia treated with immunosuppression.

Context Little is known about the effects of pregnancy on aplastic anemia and vice versa. Contribution This review of pregnancies in 36 women with aplastic ane-mia indicates that uncomplicated pregnancy is possible after immunosuppressive therapy. Relapse of aplastic anemia, bleeding, eclampsia, and death occurred in 14 of the 36 first pregnancies. Complications were more likely in women with thrombo-cytopenia or paroxysmal nocturnal hemoglobinuria and less likely in women in complete remission. Implications Women with aplastic anemia can have uncomplicated pregnancies, but complications are frequent. The Editors Aplastic anemia is peripheral blood pancytopenia associated with unexplained hypocellularity of the bone marrow. If the disease goes untreated, patients die of bleeding or infection. Immunosuppression is the treatment of choice in patients who are not eligible for bone marrow transplantation (1-3). Hematopoiesis usually improves gradually in patients who respond to therapy, but blood counts never completely normalize in many patients (4, 5). In contrast to patients treated with bone marrow transplantation, patients given immunosuppressive therapy experience autologous hematopoietic reconstitution and have persistent damage to the stem-cell compartment. As a consequence, these patients remain at risk for relapse of aplasia or may develop paroxysmal nocturnal hemoglobinuria, a myelodysplastic syndrome, or acute leukemia (6-8). The first case of aplastic anemia described in the literature occurred in a pregnant woman (9). Numerous case reports of aplastic anemia during pregnancy have since followed (10-14). However, the relationship between aplastic anemia and pregnancy remains unclear. It has been suggested that pregnancy causes aplastic anemia, since aplasia may remit spontaneously after abortion or delivery (15-17) and preexisting marrow insufficiency may worsen during pregnancy (18, 19). The effect of pregnancy on the disease after immunosuppressive treatment is poorly understood, but concern about relapse during pregnancy is justified. Recurrent episodes of aplastic anemia have been reported in consecutive pregnancies (20-22). We report on the experience of the European Group for Blood and Marrow Transplantation (EBMT) Severe Aplastic Anaemia Working Party with outcome of pregnancy and disease course among women with aplastic anemia who previously received immunosuppressive therapy. Methods Data Collection European centers participating in the EBMT that specialize in the treatment of aplastic anemia were asked to provide information on all women with aplastic anemia who had become pregnant after immunosuppressive treatment. Twelve centers with experience in the treatment of aplastic anemia that were involved in the long-term follow-up of these patients and were members of the Severe Aplastic Anaemia Working Party of the EBMT participated (Appendix). We sent a questionnaire to the centers that requested details on pregnancy outcomes, including early spontaneous abortions and deliberate termination, and the course of aplastic anemia during pregnancy. We contacted centers to obtain missing data. We also collected demographic information, pretreatment blood values, type and date of first-line immunosuppressive therapy, response to treatment, and type and date of clonal complications. Obstetric data included the number of pregnancies, abortions, and deliveries; the method of delivery; complications during pregnancy, at delivery, and after delivery; and maternal and fetal outcomes. Blood counts were collected before pregnancy, at least once per trimester, and once 1 to 6 months after delivery. In most cases, blood counts of the children at delivery were not available. Patients were followed through 15 January 2000. Data Evaluation and Definitions We collected data on all pregnancies reported by the centers but analyzed first and subsequent pregnancies separately. We obtained information on pregnancy outcomes and complications observed during pregnancy, at delivery, and immediately after delivery for the first observed pregnancy. Information was also requested on the postnatal development of the infants. We compared women who had complicated pregnancies with those who experienced no complications. Blood counts of the women during and after pregnancy were compared with counts obtained before pregnancy. Severity of aplastic anemia was defined according to the criteria of Camitta and colleagues (23) and Bacigalupo and associates (1). Complete remission was defined as a hemoglobin concentration greater than 120 g/L, a neutrophil count of 1.5 109 cells/L or greater, a platelet count of 150 109 cells/L or greater, and no need for transfusion. Patients who did not fulfill the hematologic criteria for complete remission but did not require transfusion and had no evidence of paroxysmal nocturnal hemoglobinuria or myelodysplastic syndrome were considered to have partial remission. Relapse of aplastic anemia was defined as a decrease in blood counts to a platelet count less than 20 109 cells/L or to counts necessitating regular red blood cell or platelet transfusions. Patients who needed transfusions only during delivery and had sustained platelet counts greater than 20 109 cells/L were not considered to have relapse. Paroxysmal nocturnal hemoglobinuria was defined as a positive result on the Ham or sucrose test; presence of glycosyl phosphatidylinositolanchored protein deficiency; and typical clinical symptoms of paroxysmal nocturnal hemoglobinuria, such as hemolytic crisis or history of thrombosis. Patients who had only laboratory signs of paroxysmal nocturnal hemoglobinuria (positive results on the Ham or sucrose test or glycosyl phosphatidylinositolanchored protein deficiency) were not considered to have paroxysmal nocturnal hemoglobinuria. Statistical Analysis Women with and without complicated pregnancies were compared by using the chi-square test or the Fisher exact test for categorical data and the MannWhitney U test for continuous unrelated variables. We evaluated blood counts of the pregnant women before pregnancy; during the first, second, and third trimesters; and 1 to 6 months after delivery. When several measurements were available for a particular period, the lowest value was chosen. Because of heterogeneity of blood counts among patients, fluctuations during pregnancy are shown as a percentage deviation from prepregnancy values. Results are presented as the median with quartiles and confidence intervals. Differences in blood counts during various periods with initial counts were analyzed by using the Wilcoxon signed-rank test. A P value of 0.05 or less was considered statistically significant. Statistical analysis was performed by using SPSS statistical software (SPSS for Windows, release 9.0, SPSS, Inc., Chicago, Illinois). The global Fisher exact test was performed by using StatXact statistical software (release 3, Cytel Software Corp., Cambridge, Massachusetts). Results Patients Thirty-six women treated with immunosuppression had at least one pregnancy. Table 1 shows baseline characteristics at diagnosis and at first pregnancy. The median age of the participants was 20 years (range, 7 to 33 years) at diagnosis and 28 years (range, 19 to 41 years) at delivery. Women became pregnant a median of 7.2 years (range, 1.5 to 19 years) after initial immunosuppressive therapy. The median interval between pregnancy and last follow-up was 38 months (range, 4 to 149 months). Aplastic anemia was not severe in 16 patients, severe in 16 patients, and very severe (neutrophil count < 0.2 109 cells/L) in 3 patients. Information on disease severity was missing for 1 patient. Table 1. Characteristics of Women with Aplastic Anemia Who Received Immunosuppressive Therapy before Pregnancy Before pregnancy, 11 women had complete remission, 21 patients had partial remission, and 4 patients had clinical paroxysmal nocturnal hemoglobinuria. The median hemoglobin concentration before pregnancy was 122 g/L (range, 47 to 150 g/L), the median neutrophil count was 2.5 109 cells/L (range, 1.1 to 6.2 109 cells/L), and the median platelet count was 140 109 cells/L (range, 20 to 294 109 cells/L). Two patients with paroxysmal nocturnal hemoglobinuria (patients 9 and 17) required red blood cell transfusion. One patient with paroxysmal nocturnal hemoglobinuria (patient 3) had a low platelet count (20 109 cells/L) and was classified as not in hematologic remission. The fourth patient with paroxysmal nocturnal hemoglobinuria (patient 36) was assigned to the paroxysmal nocturnal hemoglobinuria group even though she met the criteria for partial remission. Three patients in partial remission (patients 1, 19, and 22) received cyclosporine, and one patient with paroxysmal nocturnal hemoglobinuria (patient 9) received corticosteroids. One patient with paroxysmal nocturnal hemoglobinuria (patient 36) received prophylactic anticoagulation with low-molecular-weight heparin during pregnancy and after delivery. Pregnancy Outcomes The 36 first pregnancies resulted in 34 live births (one set of twins), 2 elective abortions, and 1 spontaneous abortion. There were 18 vaginal deliveries (54% [95% CI, 36% to 72%]) and 15 deliveries by cesarean section (46% [95% CI, 28% to 64%]). The course of pregnancy was uneventful for the mother and the child in 19 of the 36 pregnancies (53% [95% CI, 35% to 70%]), including the twin pregnancy. Seventeen pregnancies (47% [95% CI, 30% to 65%]) involved a complication in the mother (n = 11), the child (n = 3), or both (n = 3). Five children were born 2 to 4 weeks prematurely. Three of the five premature births occurred in women who had had relapse or developed progressive thrombocytopenia, and one occurred in a woman receiving cyclosporine during pregnancy. One of the premature infants (born to patient 3) had neonatal alloimmune thrombocytopenia (Table 2). One spontaneous abortion occurred in a woman who had four pregnanci

Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial

BACKGROUND In the era of widespread rituximab use for Waldenströms macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenströms macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. METHODS This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenströms macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. FINDINGS Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenström Macroglobulinaemia, median number of previous therapies was four (IQR 2-6), and all were rituximab-refractory. At a median follow-up of 18·1 months (IQR 17·5-18·9), the proportion of patients with an overall response was 28 [90%] of 31 (22 [71%] of patients had a major response), the estimated 18 month progression-free survival rate was 86% (95% CI 66-94), and the estimated 18 month overall survival rate was 97% (95% CI 79-100). Baseline median haemoglobin of 10·3 g/dL (IQR 9·3-11·7) increased to 11·4 g/dL (10·9-12·4) after 4 weeks of ibrutinib treatment and reached 12·7 g/dL (11·8-13·4) at week 49. A clinically meaningful improvement from baseline in FACT-An score, anaemia subscale score, and the EQ-5D-5L were reported at all post-baseline visits. Time to next treatment will be presented at a later date. Common grade 3 or worse adverse events included neutropenia in four patients (13%), hypertension in three patients (10%), and anaemia, thrombocytopenia, and diarrhoea in two patients each (6%). Serious adverse events occurred in ten patients (32%) and were most often infections. Five (16%) patients discontinued ibrutinib: three due to progression and two due to adverse events, while the remaining 26 [84%] of patients are continuing ibrutinib at the time of this report. INTERPRETATION The sustained responses and median progression-free survival time, combined with a manageable toxicity profile observed with single-agent ibrutinib indicate that this chemotherapy-free approach is a potential new treatment choice for patients who had heavily pretreated, rituximab-refractory Waldenströms macroglobulinaemia. FUNDING Pharmacyclics LLC, an AbbVie Company.

Recurrent ETNK1 mutations in atypical chronic myeloid leukemia

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.

Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation

The results of allogeneic stem cell transplantation (allo‐SCT) in chronic myelomonocytic leukaemia (CMML) are usually reported together with other categories of myelodysplastic syndrome. We analysed transplantation outcome in 513 patients with CMML, with a median age of 53 years reported to the European Group for Blood and Marrow Transplantation. Conditioning was standard (n = 249) or reduced‐intensity (n = 226). Donors were human leucocyte antigen‐related (n = 285) or unrelated (n = 228). Disease status at transplantation was complete remission (CR) in 122 patients, no CR in 344, and unknown in 47. Engraftment was successful in 95%. Grades 2–4 acute graft‐versus‐host disease (GvHD) occurred in 33% of the patients and chronic GvHD was reported in 24%. The 4‐year cumulative incidence of non‐relapse mortality was 41% and 32% for relapse, resulting in a 4‐year estimated relapse‐free and overall survival (OS) of 27% and 33%, respectively. Patients transplanted in CR had lower probability for non‐relapse death (P = 0·002) and longer relapse‐free and OS (P = 0·001 and P = 0·005, respectively). In multivariate analysis the only significant prognostic factor for survival was the presence of CR at transplantation (P = 0·005). Allo‐SCT remains a curative treatment option for patients with CMML and should preferably be performed early after diagnosis or after establishing the best possible remission status.

Treatment with bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group

Plasma cell leukemia (PCL) is a rare and aggressive plasma cell disorder, with poor outcome. Bortezomib‐based regimens (BBR) are highly effective in myeloma, but there is limited information about their efficacy and safety in PCL. Thus, we retrospectively collected data from 42 consecutive PCL patients (25 with primary PCL‐pPCL and 17 with secondary PCL‐sPCL) to explore the role of BBR in this entity. BBR were administered in 29 of 42 patients, while 6 of 25 patients with pPCL underwent autologous transplantation. Objective response (≥partial response) was significantly higher in patients treated with BBR versus conventional therapies (69% vs. 30.8%, P = 0.04); 27.5% of patients treated with BBR achieved at least very good partial response (vgPR). The highest ORR was observed in pPCL patients treated with BBR (88.9%; ≥vgPR: 33.3%). In BBR‐group, grade 3 of 4 hematological, neurological and renal toxicity and neutropenic infections were observed in 41.4%, 7%, 3.4%, and 31%, respectively. With a median follow‐up of 51 months, median overall survival (OS) for patients treated with BBR versus conventional therapies was 13 versus 2 months (P < 0.007). Median OS of patients with pPCL and sPCL treated with BBR was 18 and 7 months, respectively (P < 0.001). In the multivariate analysis normal PLTs, treatment with BBR and high quality response were the only powerful predictors for survival. Our study carrying the longest reported median follow‐up, demonstrated that treatment of PCL with BBR induces high response rates and prolongs survival over conventional therapies, regardless of additional autologous transplantation rescue or established high risk features, with manageable toxicity. Am. J. Hematol. 89:145–150, 2014.

Allogeneic stem cell transplantation for myelodysplastic syndromes with bone marrow fibrosis

Background Bone marrow fibrosis in patients with myelodysplastic syndrome is associated with a poor outcome, but whether the outcome after allogeneic stem cell transplantation is related to the degree of bone marrow fibrosis is unknown. Design and Methods Patients with myelodysplastic syndrome and known bone marrow histology (n=721) who underwent hematopoietic stem cell transplantation were classified according to the degree of bone marrow fibrosis into those without fibrosis (n=483), those with mild or moderate fibrosis (n=199) and those with severe fibrosis (n=39) and analyzed regarding engraftment, treatment-related mortality, relapse and survival. Results The degree of fibrosis was not associated with disease status or abnormal cytogenetics. The cumulative incidence of engraftment achieved at day +30 in non-fibrotic patients was 93% and was significantly lower in those with mild or moderate fibrosis (89%) and severe fibrosis (75%) (P=0.009). Neutrophil engraftment occurred later in patients with mild or moderate fibrosis and severe fibrosis than in patients without fibrosis (median 17 versus 20 versus 16 days, respectively; P=0.002). The cumulative incidence of relapse at 3 years was significantly higher in patients with severe fibrosis than in those with a lesser degree of fibrosis or no fibrosis (47% versus 28% versus 27%, respectively; P=0.04), resulting in comparable 3-year disease-free survival rates in patients without fibrosis and in those with mild or moderate fibrosis (42% versus 38%, respectively) but a lower disease-free survival rate in those with severe fibrosis (18%; P=0.002). Severe fibrosis remained an independent factor for reduced survival (hazard ratio, 1.9; P=0.006). Conclusions Among patients with myelodysplastic syndromes, only severe fibrosis affects survival after hematopoietic stem cell transplantation while patients with mild or moderate fibrosis have an outcome comparable to that of patients without bone marrow fibrosis.