Immunomodulation with romiplostim as a second-line strategy in primary immune thrombocytopenia: The iROM study.

Thrombopoietin receptor agonists (TPO-RAs) stimulate platelet production, which might restore immunological tolerance in primary immune thrombocytopenia (ITP). The iROM study investigated romiplostim's immunomodulatory effects. Thirteen patients (median age, 31 years) who previously received first-line treatment received romiplostim for 22 weeks, followed by monitoring until week 52. In addition to immunological data, secondary end-points included the sustained remission off-treatment (SROT) rate at 1 year, romiplostim dose, platelet count and bleedings. Scheduled discontinuation of romiplostim and SROT were achieved in six patients with newly diagnosed ITP, whereas the remaining seven patients relapsed. Romiplostim dose titration was lower and platelet count response was stronger in patients with SROT than in relapsed patients. In all patients, regulatory T lymphocyte (Treg) counts increased until study completion and the counts were higher in patients with SROT. Interleukin (IL)-4, IL-9 and IL-17F levels decreased significantly in all patients. FOXP3 (Treg), GATA3 (Th2) mRNA expression and transforming growth factor-ß levels increased in patients with SROT. Treatment with romiplostim modulates the immune system and possibly influences ITP prognosis. A rapid increase in platelet counts is likely important for inducing immune tolerance. Better outcomes might be achieved at an early stage of autoimmunity, but clinical studies are needed for confirmation.

[Acquired Stomatocytosis in Hyperosmolar Hyperglycemic Derangement]. / Erworbene Stomatozytose beihyperosmolarer, hyperglykämer Entgleisung.

Acquired Stomatocytosis in Hyperosmolar Hyperglycemic Derangement Abstract. In the context of a suicidally motivated suspension of insulin therapy, a massive hyperosmolar hyperglycemic derailment occurred in pancreoprivic diabetes mellitus most likely due to aethyltoxicity. In the blood picture differentiation stomatocytes could be detected, the development of which will be discussed in more detail below.

The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results of phase II study SAKK 33/14.

The ß-3 sympathomimetic agonist BRL37344 restored nestin-positive cells within the stem cell niche, and thereby normalized blood counts and improved myelofibrosis in a mouse model of JAK2-V617F-positive myeloproliferative neoplasms. We therefore tested the effectiveness of mirabegron, a ß-3 sympathomimetic agonist, in a phase II trial including 39 JAK2-V617F-positive patients with myeloproliferative neoplasms and a mutant allele burden more than 20%. Treatment consisted of mirabegron 50 mg daily for 24 weeks. The primary end point was reduction of JAK2-V617F allele burden of 50% or over, but this was not reached in any of the patients. One patient achieved a 25% reduction in JAK2-V617F allele burden by 24 weeks. A small subgroup of patients showed hematologic improvement. As a side study, bone marrow biopsies were evaluated in 20 patients. We found an increase in the nestin+ cells from a median of 1.09 (interquartile range 0.38-3.27)/mm2 to 3.95 (interquartile range 1.98-8.79)/mm2 (P<0.0001) and a slight decrease of reticulin fibrosis from a median grade of 1.0 (interquartile range 0-3) to 0.5 (interquartile range 0-2) (P=0.01) between start and end of mirabegron treatment. Despite the fact that the primary end point of reducing JAK2-V617F allele burden was not reached, the observed effects on nestin+ mesenchymal stem cells and reticulin fibrosis is encouraging, and shows that mirabegron can modify the microenvironment where the JAK2-mutant stem cells are maintained. (Registered at clinicaltrials.gov identifier: 02311569).

[Chronic myeloid leukemia - update 2020]. / Chronische Myeloische Leukämie ­ Update 2020.

Chronic myeloid leukemia - update 2020 Abstract. The discovery of specific inhibitors of the BCR-ABL tyrosine kinase more than 20 years ago has revolutionized the treatment of patients with chronic myeloid leukemia (CML). Prognosis and outcome of patients considerably improved and progress in the use of the tyrosine kinase inhibitors is ongoing. In comparison to imatinib, second generation inhibitors used in first line lead to faster and deeper molecular remissions accompanied by different adverse event profiles. An essential part of the management of CML patients is to assess regularly the remaining tumor load by standardized molecular methods. Based on several clinical trials definitions of optimal response to treatment and of treatment failure have been put forward and help guide the treatment of the patients. The concept of treatment free remission was investigated extensively and is now part of the management of CML patients. Advanced stages of CML are diagnosed less frequently but are still challenging to treat. In these cases, allogeneic transplantation still plays an important role in the attempt to control the disease.

Dyslipidemia and lipid-lowering treatment in a hematopoietic stem cell transplant cohort: 25 years of follow-up data.

BACKGROUND: Dyslipidemia is common after hematopoietic stem cell transplantation (HSCT). Few data regarding the time course of lipid profiles after HSCT, the effect of multiple transplantations, and efficacy and safety of lipid-lowering treatments are available. OBJECTIVE: The objective of the study was to determine the prevalence and treatment of dyslipidemia over a 25-year period in a large, single-center cohort. METHODS: One thousand one hundred ninety-six adult patients (≥16 years) who underwent HSCT during 1973 to 2013 and who survived ≥100 days were studied retrospectively. RESULTS: The prevalence of dyslipidemia before transplantation was 36% and 28% in the autologous and allogeneic groups, respectively (P < .001). Three months after HSCT, the prevalence rose to 62% and 74% (P < .001), and at 25 years, it was 67% and 89%. Lipid profiles were similar after first and subsequent transplants. Baseline dyslipidemia (odds ratio [OR] = 2.72), allogeneic transplant (OR = 2.44), and age ≥ 35 years (OR = 2.33) were independent risk factors for dyslipidemia at 1 year. Lipid-lowering treatment was given to 223 (19%) patients, primarily in the form of statins (86%) and was associated with a decrease in total cholesterol from 246 to 192 mg/dL (P < .01) and from 244 to 195 mg/dL (P < .001) in the autologous and allogeneic groups, respectively. There were 10 cases (4%) of muscle symptoms prompting cessation of lipid-lowering therapy, including 1 case of rhabdomyolysis. The OR for dyslipidemia among patients who suffered a cardiovascular event (conditional logistic regression) was 3.5 (95% confidence interval = 1.6-7.7, P = .002). CONCLUSION: This study confirms that dyslipidemia is a common and long-lasting phenomenon among both allogeneic and autologous HSCT patients. Statins are effective, generally well-tolerated and should be highly recommended for the management of post-HSCT dyslipidemia.

Severe events in donors after allogeneic hematopoietic stem cell donation.

BACKGROUND: The risk for donors of allogeneic hematopoietic stem cells transplants is generally considered negligible. Scattered reports of severe complications and a recent controversy on hematopoietic malignancies after granulocyte colony-stimulating factor administration have challenged this opinion. DESIGN AND METHODS: Three hundred and thirty-eight allogeneic transplant teams from 35 primarily European countries were asked to report numbers of fatalities, severe adverse events and hematologic malignancies occurring among their hematopoietic stem cell donors. RESULTS: Two hundred and sixty-two of the 338 teams (77.5%) responded to a first survey (1993-2002) and 169 of the 262 responder teams (65%) to a second survey (2003-2005). They had performed a total of 51,024 first allogeneic hematopoietic stem cell transplantations, of which 27,770 were bone marrow and 23,254 peripheral blood. They observed five donor fatalities, one after a bone marrow donation and four after peripheral blood donation (incidence 0.98 per 10,000 donations; 95% CI 0.32-2.29), 37 severe adverse events (7.25/10,000; 95% CI 5.11-9.99), of which 12 in bone marrow donors (4.32/10,000; 95% CI 2.24-7.75) and 25 in peripheral blood donors (10.76/10,000; 95% CI 6.97-15.85; p<0.05) and 20 hematologic malignancies (3.92/10,000; 95% CI 2.39-6.05), of which 8 after donating bone marrow and 12 after donating peripheral blood stem cells. The observed incidence rate of hematologic malignancies did not exceed the expected incidence in an age- and sex-adjusted general population. CONCLUSIONS: Hematopoietic stem cell donation is associated with a small but definite risk of fatalities and serious adverse events. True incidences might be higher, due to potential underreporting by study design. A continuous, standardized donor follow-up is needed to define donor risk groups and to monitor intermediate and long-term sequelae.

Quality-adjusted survival analysis shows differences in outcome after immunosuppression or bone marrow transplantation in aplastic anemia.

Bone marrow transplantation (BMT) and immunosuppression (IS) have improved the prognosis of aplastic anemia; both treatments have specific advantages and drawbacks but similar survival rates. Analysis of additional endpoints may help in treatment decisions. In a single-center study, patients with aplastic anemia treated with IS (n=155) or BMT (n=52) were compared for survival, event-free survival, and quality-adjusted time without symptoms and toxicity (Q-TWiST). Probability of overall and event-free survival at 15 years was similar among both groups (BMT 51+/-15% and 25+/-14%, IS 53+/-10% and 27+/-8%), with more early deaths in the transplant group and more late deaths in the IS group. There were differences in terms of mean duration of seven analyzed health states: time with symptoms from treatment-related toxicity (IS 0.36 years, BMT 0.27), transfusion dependency (IS 0.66 years, BMT 0.1 years), partial remission (IS 3.27 years, BMT 1.42), and secondary clonal disorder (IS 0.68 years, BMT 0.04) was significantly longer for IS compared to BMT (p< or =0.001). Patients treated with BMT spent more time with extensive chronic graft-versus-host disease (GvHD) (IS 0 years, BMT 0.96, p<0.023) and in CR without drugs (IS 1.22 years, BMT 2.43, p=0.056). In conclusion, survival, event-free survival, and Q-TWiST are similar. BMT-treated patients had longer periods free from symptoms, while IS-treated patients needed closer medical care, transfusion support, and medications.