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Chronic inflammation is often indicated by a relative increase in the gamma globulin fraction in the serum electrophoresis. In a retrospective study, we analyzed the prevalence of relative hypergammaglobulinemia in 60 patients with chronic myelomonocytic leukemia (CMML), its potential prognostic impact, and potential correlations with laboratory and molecular features. Relative hypergammaglobulinemia ( 20%) was found in 25/60 (42%) patients. The median survival of patients with relative hypergammaglobulinemia was significantly shorter than in patients without hypergammaglobulinemia (10 vs. 24 months, p = 0.018). There was no difference between the groups regarding leukocyte count, hemoglobin value, and platelet count, but a higher prevalence of NRAS mutations and a lower prevalence of ZRSR2 mutations in patients with hypergammaglobulinemia. Our results show that hypergammaglobulinemia is present in a proportion of CMML patients and that this abnormality is associated with poor overall survival. The role of chronic inflammation in the pathophysiology of CMML needs to be further investigated.Eine chronische Entzündung wird häufig durch eine relative Vermehrung der Gammaglobulinfraktion in der Serumelektrophorese angezeigt. In einer retrospektiven Studie wurde die Prävalenz einer relativen Hypergammaglobulinämie bei 60 Patienten mit chronischer myelomonozytärer Leukämie (CMML) analysiert, ihre potenzielle prognostische Bedeutung sowie eine mögliche Korrelation mit laborchemischen und molekularen Parametern. Eine relative Hypergammaglobulinämie ( 20 %) lag bei 25/60 (42 %) CMML-Patienten vor. Das mediane Überleben von Patienten mit relativer Hypergammaglobulinämie war signifikant kürzer als jenes von Patienten ohne Hypergammaglobulinämie (10 vs. 24 Monate; p = 0,018). Keine Unterschiede zwischen beiden Gruppen wurden für Leukozytenzahl, Hämoglobinwerte und Thrombozytenzahl festgestellt jedoch eine höhere Prävalenz von NRAS-Mutationen und eine geringere Prävalenz von ZRSR2-Mutationen bei Patienten mit Hypergammaglobulinämie. Die vorliegenden Ergebnisse zeigen, dass eine relative Hypergammaglobulinämie bei einem Teil der CMML-Patienten vorliegt und dieser auffällige Befund mit einem schlechteren Überleben verbunden ist. Die Rolle einer chronischen Entzündung in der Pathophysiologie der CMML muss noch weiter untersucht werden.

In a retrospective study, we analyzed the prevalence of common cardiovascular comorbidities in 310 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with laboratory and molecular features. 115 (36%) patients had a documented cardiovascular comorbidity. In these patients, coronary heart disease 41/115 (36%), atrial fibrillation 34/115 (29%), and hypertension 75/115 (64%) were documented. None of these conditions had a significant impact on survival. Unexpectedly, patients with cardiovascular comorbidity had a lower number of circulating blasts and a lower prevalence of EZH2 mutations. Moreover, time to transformation was significantly longer in these patients. Cardiovascular comorbidity does not seem to have a major impact on prognosis in CMML patients. The unexpected lower transformation rate in these patients needs to be further investigated.In einer retrospektiven Studie wurde die Prävalenz häufiger kardiovaskulärer Komorbiditäten bei 310 Patienten mit chronischer myelomonozytärer Leukämie (CMML) analysiert, ihr potenzieller prognostischer Einfluss sowie mögliche Korrelationen mit laborchemischen und molekularen Eigenschaften. Bei 115/310 (36 %) Patienten bestand mindestens eine dokumentierte kardiovaskuläre Komorbidität. Unter diesen Patienten wiesen 41/115 (36 %) eine koronare Herzkrankheit, 34/115 (29 %) Vorhofflimmern und 75/115 (64 %) einer arterielle Hypertonie auf. Keine dieser Komorbiditäten hatte einen signifikanten Einfluss auf das Überleben. Unerwarteterweise hatten Patienten mit kardiovaskulärer Komorbidität eine geringere Anzahl zirkulierender Blasten und eine geringere Prävalenz von EZH2-Mutationen. Darüber hinaus war bei diesen Patienten die Zeitdauer bis zur Transformation länger. Kardiovaskuläre Komorbiditäten scheinen keinen wesentlichen Einfluss auf die Prognose bei CMML-Patienten zu haben. Die unerwartete geringere Transformationsrate bei Patienten mit kardiovaskulären Komorbiditäten bedarf weiterer Untersuchungen.

Next-generation sequencing technology, including whole-exome or whole-genome sequencing and target gene sequencing, has allowed the molecular characterization of somatic mutation spectrums in hematologic diseases. Mutations in Additional sex combs-like 1 (ASXL1), a chromatin regulator, are identified in clonal hematopoiesis of indeterminate potential (CHIP), indicating ASXL1 mutations as early events in leukemogenesis. Not surprisingly, they occur at high frequency in myeloid malignancies and are associated with poor prognosis. Therefore, understanding how mutant ASXL1 drives clonal expansion and leukemogenesis will serve as the basis for the future development of preventative and/or therapeutic strategies for myeloid diseases with ASXL1 mutations. Here, we discuss the biology of ASXL1 and its role in controlling normal and malignant hematopoiesis. In addition, we review the clinical relevance of ASXL1 mutations in CHIP and myeloid diseases.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers.Significance:This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275

Background: A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients. ----- Methods: Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14). ----- Results: Median survival was 90, 45, and 9 months, respectively (p = .001). Whereas no patient in the T and TS group transformed into acute myeloid leukemia (AML), 6/14 patients in the TSN group had AML at study entry or transformed during follow-up. Leukocyte counts, blast cell counts, and LDH levels were significantly higher in TSN vs. TS and T, respectively, whereas hemoglobin and platelet values were not significantly different. Increased growth factor-independent myeloid colony formation was restricted to TSN but not found in T and TS, respectively. The proportion of patients showing in vitro myelomonocytic skewing in T, TS, and TSN was 0%, 56%, and 100%, respectively (p = .010). ----- Conclusion: Our results demonstrate that the model of multistep pathogenesis in CMML can be recapitulated in patients regarding clinical, phenotypic, and biologic features.

Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular ∼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1−/− accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1−/− (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.

Pancytopenia is a condition in which there is a lower-than-normal number of red and white blood cells and platelets in the blood. The spectrum of causes for the decrease of one or more blood cell lineages is broad including increased destruction, pooling by spleen, loss of blood cells, decreased production due to toxic and/or immune-mediated mechanisms and abnormalities due to clonal/malignant hematopoiesis. In this article common and/or typical causes of pancytopenia are presented with special emphasis on more or less disease specific features that may be useful clues in the differential diagnosis of this blood picture abnormality.

Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. Significance: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age‐related groups

Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes and a substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34+/CD38– fraction of the malignant clone. Whereas CD34+/CD38– cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34+/CD38+ progenitors or the bulk of CD34– monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34+/CD38– cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.

Background Myelomonocytic skewing is considered as a key pathophysiologic phenomenon in chronic myelomonocytic leukemia (CMML), but its prevalence and potential correlation with phenotypic, genotypic, and clinical features are poorly defined. Methods Skewed differentiation toward the myelomonocytic over erythroid commitment as indicated by an inverse ratio of myelomonocytic/erythroid colonies was investigated in 146 patients with CMML by semisolid in vitro cultures. Results There was a high prevalence of myelomonocytic skewing in patients with CMML (120/146, 82%); whereas, this phenomenon was rare in normal individuals (1/98, 1%). Patients with CMML with myelomonocytic skewing had higher white blood cell and peripheral blast cell counts, and lower platelet values. The number of mutations in genes of the epigenetic and/or splicing category was higher in CMML patients with as compared with patients without skewing. Patients with myelomonocytic skewing had more frequently mutations in RASopathy genes and higher growth factor independent myeloid colony formation. Interestingly, the lack of myelomonocytic skewing discriminated patients with CMML with a particularly favorable prognosis (60 vs 19 months, P = .003) and a minimal risk of transformation. Conclusion Myelomonocytic skewing as determined by semisolid cultures can discriminate subgroups of patients with CMML with a different phenotype, a different genotype, and a different prognosis.

Funder: MUG (within the PhD program Molecular Medicine), Funder: Austrian Society of Internal Medicine (Joseph-Skoda Award), Austrian Science Fund (grant P32783), Austrian Society of Hematology and Medical Oncology (Clinical Research Grant) and MEFOgraz, Funder: Austrian Science Fund (grant P 31430-458 B26) and Leukämiehilfe Steiermark, Funder: Austrian Society of Internal Medicine (Joseph-Skoda Award)and Leukämiehilfe Steiermark

BACKGROUND: Approval of hypomethylating agents in patients with chronic myelomonocytic leukaemia is based on trials done in patients with myelodysplastic syndromes. We aimed to investigate whether hypomethylating agents provide a benefit in subgroups of patients with chronic myelomonocytic leukaemia compared with other treatments. METHODS: For this retrospective cohort study, data were retrieved between Nov 30, 2017, and Jan 5, 2019, from 38 centres in the USA and Europe. We included non-selected, consecutive patients diagnosed with chronic myelomonocytic leukaemia, who received chronic myelomonocytic leukaemia-directed therapy. Patients with acute myeloid leukaemia according to 2016 WHO criteria at initial diagnosis (ie, =20% blasts in the bone marrow or peripheral blood) or with unavailability of treatment data were excluded. Outcomes assessed included overall survival, time to next treatment, and time to transformation to acute myeloid leukaemia. Analyses were adjusted by age, sex, platelet count, and Chronic myelomonocytic leukaemia-Specific Prognostic Scoring System (CPSS). Patients were grouped by first received treatment with either hydroxyurea, hypomethylating agents, or intensive chemotherapy, and stratified by risk according to blast count, French-American-British subtype, CPSS, WHO 2016 subtype, and the eligibility criteria of the DACOTA trial (NCT02214407). FINDINGS: 949 patients diagnosed with chronic myelomonocytic leukaemia between April 13, 1981, and Oct 26, 2018, were included. Median follow-up was 23·4 months (IQR 11·5-42·3) from diagnosis and 16·2 months (6·6-31·6) from start of first-line treatment. 412 (43%) of 949 patients received hypomethylating agents as first treatment, 391 (41%) hydroxyurea, and 83 (9%) intensive chemotherapy. Adjusted median overall survival for patients treated with hydroxyurea versus hypomethylating agents was 15·6 months (95% CI 13·1-17·3) versus 20·7 months (17·9-23·4); hazard ratio (HR) 1·39 (1·17-1·65; p=0·0002) and 14·0 months (9·8-17·2) versus 20·7 months (17·9-23·4; HR 1·55 [1·16-2·05]; p=0·0027) for those treated with intensive chemotherapy versus hypomethylating agents. In patients with myeloproliferative chronic myelomonocytic leukaemia (myeloproliferative CMML), median overall survival was 12·6 months (10·7-15·0) versus 17·6 months (14·8-21·5; HR 1·38 [1·12-1·70]; p=0·0027) for patients treated with hydroxyurea versus hypomethylating agents, and 12·3 months (8·4-16·6) versus 17·6 months (14·8-21·5; HR 1·44 [1·02-2·03]; p=0·040) for intensive chemotherapy versus hypomethylating agents. Hypomethylating agents did not confer an overall survival advantage for patients classified as having lower-risk disease (ie, myelodysplastic chronic myelomonocytic leukaemia with

Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease. Diagnosis of IPF requires considerable expertise and experience. Since the publication of the international IPF guideline in the year 2011 and the update 2018 several studies and technical advances have occurred, which made a new assessment of the diagnostic process mandatory. The goal of this guideline is to foster early, confident, and effective diagnosis of IPF. The guideline focusses on the typical clinical context of an IPF patient and provides tools to exclude known causes of interstitial lung disease including standardized questionnaires, serologic testing, and cellular analysis of bronchoalveolar lavage. High-resolution computed tomography remains crucial in the diagnostic workup. If it is necessary to obtain specimens for histology, transbronchial lung cryobiopsy is the primary approach, while surgical lung biopsy is reserved for patients who are fit for it and in whom a bronchoscopic diagnosis did not provide the information needed. After all, IPF is a diagnosis of exclusion and multidisciplinary discussion remains the golden standard of diagnosis.

According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative neoplasms (MPN). The classical term MPN covers the subcategories of MPN: ET, polycythemia vera (PV), primary myelofibrosis (PMF), and prefibrotic PMF (pPMF). ET is marked by clonal proliferation of hematopoietic stem cells, leading to a chronic overproduction of platelets. At the molecular level a JAK2 (Janus Kinase 2), calreticulin, or MPL mutation is found in the majority of patients. Typical ongoing complications of the disease include thrombosis and hemorrhage. Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.

Background: Tumor-stroma ratio (TSR) is an independent prognosticator in colon cancer.Objective: We set out to investigate the predictive power, as well as to validate the prognostic power of TSR in stage II colon cancer patients. Better identification of patients who could benefit from adjuvant chemotherapy remains an important issue in stage II disease.Methods: TSR was microscopically determined on haematoxylin and eosin-stained primary tumor tissue slides of 212 patients who received either adjuvant chemotherapy or surveillance after curative resection in a prospective randomized clinical trial (ABCSG-91).Results: Stroma-high tumors were associated with significantly more cancer-related death ((CaDeath) HR 2.30, 95% CI 1.05−5.03; p=0.037) and significantly shorter distant recurrence-free survival ((DRFS) HR 2.32, 95% CI 1.10−4.87; p=0.027) compared to stroma-low tumors. Backward multivariate Cox-regression analysis demonstrated TSR as an independent prognosticator for DRFS (p=0.027) and CaDeath (p=0.031). TSR did not validate as a predictive biomarker; CaDeath (HR 0.87, 95% CI 0.18−4.17; p=0.87), DRFS (HR 0.76, 95% CI 0.17−3.36; p=0.71) and OS (HR 0.96, 95% CI 0.29−3.21; p=0.95) for the type of chemotherapy given in ABCSG-91.Conclusions: TSR, an easily applicable and inexpensive observer-based method, is an independent predictor of poor prognosis in stage II colon cancer. Predictive value for adjuvant 5-FU/leucovorin could not be demonstrated.

In a retrospective study, we analyzed the prevalence of increased creatinine levels in 166 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with laboratory and molecular features. Increased creatinine values ( 1.1 mg/dl) were found in 71 of 166 (43%) patients. The median survival of patients with increased creatinine values was significantly shorter than in patients without impairment of renal function (20 vs. 52 months, p 0.001). Patients with increased creatinine values were older, were more often male, had higher leukocyte counts, higher monocyte counts, and higher lactatdehydrogenase (LDH) values. There was a trend toward a higher prevalence of CBL and ASXL1 mutations in patients with renal impairment. Our findings show a high prevalence of renal abnormalities in patients with CMML. Increased creatinine values were identified as a new prognostic marker. These findings may be important for the individualized management of this heterogenous group of patients.In einer retrospektiven Studie wurde die Prävalenz erhöhter Kreatininwerte bei 166 Patienten mit chronischer myelomonozytärer Leukämie (CMML), ihr potenzieller prognostischer Einfluss und ihre potenzielle Korrelation mit laborchemischen und molekularen Parametern untersucht. Erhöhte Kreatininwerte ( 1,1 mg/dl) wurden bei 71 von 166 (43 %) Patienten festgestellt. Das mediane Überleben von Patienten mit eingeschränkter Nierenfunktion war signifikant kürzer als bei Patienten ohne Einschränkung der Nierenfunktion (20 vs. 52 Monate; p 0,001). Patienten mit erhöhten Kreatininwerten waren älter, waren häufiger männlich, hatten höhere Leukozytenwerte, höhere Monozytenzahlen und höhere Laktadehydrogenase(LDH)-Werte. Bei Patienten mit gestörter Nierenfunktion zeigte sich ein Trend zu einem höheren Anteil von CBL- und ASXL1-Mutationen. Nach den vorliegenden Ergebnissen zeigte sich eine hohe Prävalenz von Nierenfunktionsstörungen bei Patienten mit CMML. Erhöhte Kreatininwerte wurden als neuer prognostischer Parameter entdeckt. Die beschriebenen Ergebnisse könnten für ein individuelles Management dieser heterogenen Patientengruppe wichtig sein.

In a retrospective study, we analyzed the prevalence of subnormal prothrombin time (PT) values in 104 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with clinicolaboratory features. Reduced PT values ( 70%) were found in 45/104 (43%) patients. The median survival of patients with reduced PT values was significantly shorter than in patients with normal PT (19 vs. 49 months, p = 0.006). Patients with reduced PT had higher leukocyte counts, a higher proportion of circulating blast cells, and lower platelet counts. In patients for whom clinical information was available, there was no difference in the incidence of bleeding complications between patients with or without reduced PT. Our results show a high prevalence of plasmatic coagulation abnormalities in patients with CMML, which were associated with laboratory features of advanced disease. Moreover, subnormal PT values were identified as a new prognostic marker. Reduced PT values do not seem to have a clinical impact regarding bleeding complications.In einer retrospektiven Studie wurde die Prävalenz einer verminderten Prothrombinzeit (PTZ) bei 104 Patienten mit chronischer myelomonozytärer Leukämie (CMML), ihr potenzieller prognostischer Einfluss und ihre potenzielle Korrelation mit klinischen und laborchemischen Parametern untersucht. Eine verminderte PTZ ( 70 %) wurde bei 45/104 (43 %) Patienten gefunden. Das mediane Überleben von Patienten mit verminderten PTZ-Werten war signifikant kürzer als jenes von Patienten mit normalen PTZ-Werten (19 vs. 49 Monate, p = 0,006). Patienten mit verminderten PTZ-Werten wiesen höhere Leukozytenwerte, einen höheren Anteil zirkulierender Blasten und geringere Thrombozytenzahlen auf. Bei Patienten, bei denen klinische Informationen vorlagen, bestand kein Unterschied im Hinblick auf Blutungskomplikationen zwischen beiden Gruppen. Die vorliegenden Ergebnisse zeigen eine hohe Prävalenz plasmatischer Gerinnungsstörungen bei Patienten mit CMML, die mit Laborparametern einer fortgeschrittenen CMML assoziiert waren. Darüber hinaus wurde die PTZ als neuer prognostischer Parameter bei dieser Erkrankung identifiziert. Verminderte PTZ-Werte scheinen jedoch keinen Einfluss auf Blutungskomplikationen zu haben.

The impact of treatment on the outcome of chronic myelomonocytic leukemia (CMML) patients over a longer period of time and the potential role of predictive factors are not well defined. In a retrospective observational study, we analyzed 168 CMML patients regarding treatment options and survival during the past three decades. The proportion of patients treated with hydroxyurea (HU), intensive chemotherapy, and azacitidine (AZA) was 65/19/0% before 2000, 51/25/32% from 2000-2010, and 36/12/53% after 2010, respectively. Median overall survival (OS) increased from 10 months before 2000 to 23 months thereafter (p = 0.021). AZA-treated patients but not patients treated with other treatment options had improved survival as compared to CMML patients without AZA therapy (19 vs. 25 months, p = 0.041). When looking at subgroups, the following patient cohorts had a significant survival benefit in association with AZA therapy: patients with Hb 10 g/dL, patients with monocytosis 10 G/L, and patients with mutations in RASopathy genes.Der Einfluss einer Behandlung bei Patienten mit chronischer myelomonozytärer Leukämie (CMML) über einen längeren Beobachtungszeitraum und die Rolle möglicher prädiktiver Faktoren wurde bisher nur unzureichend untersucht. In einer retrospektiven Beobachtungsstudie wurden 168 CMML-Patienten im Hinblick auf Therapieoptionen und Überleben während der letzten 3 Jahrzehnte untersucht. Vor dem Jahr 2000 betrug der Anteil von Patienten, die mit Hydroxyurea, Zytostatika und Azacitidin therapiert wurden, 65/19/0 %, zwischen 2000 und 2010 lag er bei 51/25/32 % und nach 2010 bei 36/12/53 %. Das mediane Überleben stieg von 10 Monaten vor dem Jahr 2000 auf 23 Monate danach (p = 0,021). Insgesamt wiesen die Patienten, die mit Azacitidin therapiert wurden, eine längere Überlebenszeit auf als CMML-Patienten ohne Azacitidintherapie (19 vs. 25 Monate; p = 0,041). Im Hinblick auf Untergruppen hatten folgende Faktoren einen signifikanten Überlebensvorteil in Verbindung mit einer Azacitidintherapie: Patienten mit Hämoglobinwerten ≥ 10 g/dl, mit Monozytose ≥ 10 G/l und Patienten mit Mutationen in den RAS-Genen.

Summary In the Austrian biodatabase for chronic myelomonocytic leukemia (ABCMML) clinicolaboratory real-life data have been captured from 606 CMML patients from 14 different hospitals over the last 30 years. It is the only large biodatabase worldwide in which functional methods such as semisolid in vitro cultures complement modern molecular methods such as next generation sequencing. This provides the possibility to comprehensively study the biology of CMML. The aim of this study was to compare patient characteristics with published CMML cohorts and to validate established prognostic parameters in order to examine if this real-life database can serve as a representative and useful data source for further research. After exclusion of patients in transformation characteristics of 531 patients were compared with published CMML cohorts. Median values for age, leukocytes, hemoglobin, platelets, lactate dehydrogenase (LDH) and circulating blasts were within the ranges of reported CMML series. Established prognostic parameters including leukocytes, hemoglobin, blasts and adverse cytogenetics were able to discriminate patients with different outcome. Myeloproliferative (MP) as compared to myelodysplastic (MD)-CMML patients had higher values for circulating blasts, LDH, RAS-pathway mutations and for spontaneous myelomonocytic colony growth in vitro as well as more often splenomegaly. This study demonstrates that the patient cohort of the ABCMML shares clinicolaboratory characteristics with reported CMML cohorts from other countries and confirms phenotypic and genotypic differences between MP-CMML and MD-CMML. Therefore, results obtained from molecular and biological analyses using material from the national cohort will also be applicable to other CMML series and thus may have a more general significance.

TPS7075 Background: A novel genomically defined subset of higher-risk MDS (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive (RARA+) by a blood-based biomarker test (Vigil, 2017). Biologically targeted therapy with tamibarotene, an oral selective RARα agonist, has potential to provide clinical benefit for RARA+ HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA+ R/R HR-MDS patients treated with tamibarotene showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene in combination with azacitidine (aza) showed high complete response rates (CR) with rapid onset of response in RARA+ newly diagnosed (ND) unfit AML patients, including those with low blast count (≤ 30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/aza was generally well tolerated with no increase in myelosuppression compared to aza alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and AML, particularly low blast count AML (Estey 2021), supports further development of tamibarotene/aza in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). Methods: This Phase 3, multi-center, randomized, double-blind, placebo-controlled study will compare activity of tamibarotene/aza to placebo/aza in RARA+ patients with ND HR-MDS. The primary objective is to characterize and compare the CR rate of tamibarotene/aza vs placebo/aza, with secondary objectives to characterize ORR, EFS, OS, transfusion independence rate, time to and duration of initial and complete responses, and safety. Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms, with a one-sided alpha of 0.025. Patients must be RARA+ based on the investigational biomarker test, ND with HR-MDS by WHO classification (Arber 2016), classified by IPSS-R risk category as very high, high, or intermediate risk with a blast count > 5% at study entry. Patients suitable for transplant at screening, or with prior treatment for MDS with any HMA, chemotherapy or transplant are excluded. Aza will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally days 8-28 of each 28-day cycle. Response will be assessed per modified IWG MDS criteria (Cheson 2006). The SELECT-MDS-1 trial opened in February 2021, recruitment is ongoing, with sites located in North America, Israel, and Europe. Clinical trial information: NCT04797780.

Background Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. Methods CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m(2) given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. Findings Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19.2 months (IQR 7.4-28.8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21.5 months (95% CI 17.8-33.0) versus 13.8 months (10.2-17.5; hazard ratio 0.52 [95% CI 0.39-0.69]; p, Bayer, Bayer.

Background Corticosteroid therapy (CST) prior to biopsy may hinder histopathological diagnosis in primary central nervous system lymphoma (PCNSL). Therefore, preoperative CST in patients with suspected PCNSL should be avoided if clinically possible. The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST. Methods A multicenter retrospective study including all immunocompetent patients diagnosed with PCNSL between 1/2004 and 9/2018 at four neurosurgical centers in Austria was conducted and the results were compared to literature. Results A total of 143 patients were included in this study. All patients showed visible contrast enhancement on preoperative MRI. There was no statistically significant difference in the rate of diagnostic surgeries with and without preoperative CST with 97.1% (68/70) and 97.3% (71/73), respectively (p = 1.0). Tapering and pause of CST did not influence the diagnostic rate. Including our study, there are 788 PCNSL patients described in literature with an odds ratio for inconclusive surgeries after CST of 3.3 (CI 1.7–6.4). Conclusions Preoperative CST should be avoided as it seems to diminish the diagnostic rate of biopsy in PCNSL patients. Yet, if CST has been administered preoperatively and there is still a contrast enhancing lesion to target for biopsy, surgeons should try to keep the diagnostic delay to a minimum as the likelihood for acquiring diagnostic tissue seems sufficiently high.

ObjectivesJanus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.MethodsExisting data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.ResultsThe Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.ConclusionThe consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

We have originally reported that colony-forming units granulocyte/macrophage (CFU-GM) formation is an in vitro feature of chronic myelomonocytic leukemia (CMML) and a strong predictor for short survival. Elucidation of the molecular basis underlying this in vitro phenomenon could be helpful to define molecular features that predict inferior outcome in patients. We studied the correlation between the mutational landscape and spontaneous colony formation in 164 samples from 125 CMML patients. As compared to wildtype samples, spontaneous in vitro CFU-GM formation was significantly increased in samples containing mutations in NRAS, CBL and EZH2 that were confirmed as independent stimulatory factors by multiple regression analysis. Inducible expression of mutated RAS but not JAK2 was able to induce growth factor independence of Ba/F3 cells. Whereas high colony CFU-GM growth was a strong unfavorable parameter for survival (p &lt, 0.00001) and time to transformation (p = 0.01390), no single mutated gene had the power to significantly predict for both outcome parameters. A composite molecular parameter including NRAS/CBL/EZH2, however, was predictive for inferior survival (p = 0.00059) as well as for increased risk of transformation (p = 0.01429). In conclusion, we show that the composite molecular profile NRAS/CBL/EZH2 derived from its impact on spontaneous in vitro myeloid colony formation improves the predictive power over single molecular parameters in patients with CMML.

Normal hematopoietic function is maintained by a well-controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations which may be skewed during pathologic conditions. Using semisolid in vitro cultures supporting the growth of myelomonocytic (CFU-GM) and erythroid (BFU-E) colonies, we investigated skewed differentiation towards the myelomonocytic over erythroid commitment in 81 patients with myelofibrosis (MF). MF patients had significantly increased numbers of circulating CFU-GM and BFU-E. Myelomonocytic skewing as indicated by a CFU-GM/BFU-E ratio &ge, 1 was found in 26/81 (32%) MF patients as compared to 1/98 (1%) in normal individuals. Patients with myelomonocytic skewing as compared to patients without skewing had higher white blood cell and blast cell counts, more frequent leukoerythroblastic features, but lower hemoglobin levels and platelet counts. The presence of myelomonocytic skewing was associated with a higher frequency of additional mutations, particularly in genes of the epigenetic and/or splicing machinery, and a significantly shorter survival (46 vs. 138 mo, p &lt, 0.001). The results of this study show that the in vitro detection of myelomonocytic skewing can discriminate subgroups of patients with MF with a different phenotype, a different mutational profile and a different prognosis. Our findings may be important for the understanding and management of MF.

Background Chronic myelomonocytic leukemia (CMML) is an aggressive hematopoietic malignancy that arises from hematopoietic stem and progenitor cells (HSPCs). Patients with CMML are frequently treated with epigenetic therapeutic approaches, in particular the hypomethylating agents (HMAs), azacitidine (Aza) and decitabine (Dec). Although HMAs are believed to mediate their efficacy via re-expression of hypermethylated tumor suppressors, knowledge about relevant HMA targets is scarce. As silencing of tumor-suppressive micro-RNAs (miRs) by promoter hypermethylation is a crucial step in malignant transformation, we asked for a role of miRs in HMA efficacy in CMML. Results Initially, we performed genome-wide miR-expression profiling in a KrasG12D-induced CMML mouse model. Selected candidates with prominently decreased expression were validated by qPCR in CMML mice and human CMML patients. These experiments revealed the consistent decrease in miR-125a, a miR with previously described tumor-suppressive function in myeloid neoplasias. Furthermore, we show that miR-125a downregulation is caused by hypermethylation of its upstream region and can be reversed by HMA treatment. By employing both lentiviral and CRISPR/Cas9-based miR-125a modification, we demonstrate that HMA-induced miR-125a upregulation indeed contributes to mediating the anti-leukemic effects of these drugs. These data were validated in a clinical context, as miR-125a expression increased after HMA treatment in CMML patients, a phenomenon that was particularly pronounced in cases showing clinical response to these drugs. Conclusions Taken together, we report decreased expression of miR-125a in CMML and delineate its relevance as mediator of HMA efficacy within this neoplasia.