Sonja Heibl

Background: Unexplained cytopenia represents a common diagnostic challenge in clinical haematology, reflecting either benign conditions or early manifestations of myeloid neoplasms. Methods: In this retrospective cross-sectional study, we analysed 557 patients with cytopenia who underwent initial diagnostic evaluation. The diagnostic performance of the initial morphological assessment of the bone marrow and ancillary studies excluding genetic analyses was evaluated against a genetically supported reference diagnosis established by a multidisciplinary haematology tumour board. We examined the extent to which the initial morphological assessment could reliably detect or rule out myeloid neoplasia. The analysis was performed for the entire cohort and stratified by specific myeloid neoplasm entities. Results: In the overall cohort, the initial morphological assessment of the bone marrow showed high diagnostic performance (sensitivity, 0.864; specificity, 0.934). The misclassification analysis revealed more false negatives than false positives (31 vs. 21), with no significant asymmetry. In the entity-specific analysis, a sensitivity of 1.0 was observed for acute myeloid leukaemia, with a reduced specificity (0.400). Myelodysplastic neoplasms exhibited a higher rate of false-negative findings, whereas myelodysplastic/myeloproliferative overlap neoplasms were characterised by very high sensitivity (0.982) and limited specificity (0.632). A comparable diagnostic pattern was observed for myelofibrotic neoplasms. Conclusions: Initial morphological assessment demonstrates high overall diagnostic performance in cytopenia but shows important variation across individual entities. These findings highlight the need to consider entity-specific limitations and the role of genetic confirmation in the diagnostic work-up of specific entities.

Background: Unexplained cytopenia presents a common diagnostic challenge in clinical haematology, reflecting either benign conditions or early manifestations of myeloid neoplasms. Although genetic testing is increasingly becoming the standard reference for diagnosis, an initial cellular assessment of the bone marrow is often the first decisive diagnostic step. Methods: In this retrospective cross-sectional study, we analysed 557 patients with cytopenia who underwent initial diagnostic evaluation. The diagnostic performance of the initial cellular assessment defined in this study as morphological and ancillary studies excluding genetic analyses was evaluated against a genetically supported reference diagnosis established by a multidisciplinary haematology tumour board. We examined the extent to which the initial cellular diagnosis can reliably detect or rule out myeloid neoplasia. The analysis was performed for the entire cohort and stratified by specific myeloid neoplasm entities. Results: In the overall cohort, the initial cellular assessment showed high diagnostic performance (sensitivity, 0.864; specificity, 0.934). The misclassification analysis revealed more false negatives than false positives (31 vs. 21), with no significant asymmetry. In the entity-specific analysis, a sensitivity of 1.0 was observed for acute myeloid leukaemia, with a reduced specificity (0.400). Myelodysplastic neoplasms exhibited a higher rate of false-negative findings, whereas myelodysplastic/myeloproliferative overlap neoplasms were characterised by very high sensitivity (0.982) and limited specificity (0.632). A comparable diagnostic pattern was observed for myelofibrotic neoplasms. Conclusion: Initial cellular assessment demonstrates high overall diagnostic performance in cytopenia but shows important variation across individual entities. These findings highlight the need to consider entity-specific limitations and the role of genetic confirmation in the diagnostic work-up of specific entities.

Background: The MOMENTUM study met all key endpoints at week 24, demonstrating symptom, spleen, and anaemia benefits with momelotinib versus danazol in patients with myelofibrosis. In this updated analysis, we report duration of week 24 responses and new responses with momelotinib through week 48. Methods: MOMENTUM is an international, double-blind, randomised, phase 3 study done at 107 sites across 21 countries. Patients were 18 years or older with primary, post-polycythaemia vera, or post-essential thrombocythaemia myelofibrosis, previously treated with an approved Janus kinase (JAK) inhibitor for 90 days or more (≥28 days with haematological complications), and had an Eastern Cooperative Oncology Group performance status of 2 or less. Patients were randomly assigned (2:1) to either the momelotinib group (200 mg orally once per day) or danazol group (300 mg orally twice per day) through week 24 via non-deterministic biased coin minimisation and an interactive response system. Stratification factors were Total Symptom Score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), transfusion burden (0 units vs 1–4 units vs ≥5 units), and study site. After week 24, all patients initially randomly assigned to either group who remained on the study received open-label momelotinib [...]. Findings: Between April 24, 2020, and Dec 3, 2021, a total of 195 patients were randomised (130 [67%] in the momelotinib group and 65 [33%] in the danazol group). 93 (72%) of 130 patients in the momelotinib group and 41 (63%) of 65 in the danazol group entered the momelotinib open-label extension period. Median follow-up was 48·4 weeks (IQR 40·6–55·7). Among TSS-evaluable patients at week 48, 30 (45%) of 67 patients in the momelotinib group who continued treatment and 15 (50%) of 30 in the danazol group who crossed over were responders. TSS responders at any time during the open-label period by week 48 were 46 (61%) of 75 evaluable patients in the momelotinib group who continued and 19 (59%) of 32 in the danazol group who crossed over, including most week 24 responders plus new responders after week 24. No new safety signals emerged with long-term follow-up. The most common non-haematological treatment-emergent adverse events in momelotinib-treated patients over the entire study period as of the data cutoff were diarrhoea (45 [26%] of 171) and asthenia (28 [16%]); the most common grades 3–4 treatment-emergent adverse events were thrombocytopenia (33 [19%]) and anaemia (19 [11%]). Serious treatment-emergent adverse events were reported in 79 (46%) of 171 patients, and fatal treatment-emergent adverse events were reported in 30 (18%); two fatal treatment-emergent adverse events were considered possibly related to momelotinib (rotaviral enteritis and Staphylococcus pneumonia). Interpretation: Momelotinib was associated with durable symptom, spleen, and anaemia benefits, late responses after week 24, and favourable safety through week 48. These results highlight the potential benefits of treatment with momelotinib in patients with myelofibrosis, particularly those with anaemia. Funding: Sierra Oncology, a GSK company.

Introduction: Controlled randomized trials, molecular analytics, and guideline recommendations have so far been irreplaceable tools to ensure appropriate treatment and decision-making for physicians and patients. Individual patient models are increasingly complementing these methods, particularly in the case of advanced cancers, rare cancers, and cancers of unknown primary (CUP), as in these cases comprehensive clinical evidence is unavailable, often resulting in poor treatment success, even after stratification. Case Presentation: Here we report a 53-year-old patient with CUP with axillary lymph node metastases for whom patient-derived 3D (PD3D®) tumor organoids successfully guided personalized treatment. PD3D tumor models were used to screen drugs that are effective at the suspected primary tumor site. The screen revealed sensitivity to doxorubicin, which is not indicated for CUP treatment but hinted toward breast cancer that was subsequently confirmed as triple-negative breast cancer (TNBC). The patient showed partial remission to first-line doxorubicin and cyclophosphamide, which were followed by docetaxel. Subsequent radiotherapy eventually led to a complete remission, which is still ongoing. Conclusion: We conclude that pre-therapeutic drug sensitivity screening with PD3D tumor models can be essential in guiding and enabling an effective personalized treatment for patients with hard-to-treat cancers, like CUP or TNBC.

Mutant calreticulin (CALR) proteins resulting from a −1/+2 frameshifting mutation of the CALR exon 9 carry a novel C-terminal amino acid sequence and drive the development of myeloproliferative neoplasms (MPNs). Mutant CALRs were shown to interact with and activate the thrombopoietin receptor (TpoR/MPL) in the same cell. We report that mutant CALR proteins are secreted and can be found in patient plasma at levels up to 160 ng/mL, with a mean of 25.64 ng/mL. Plasma mutant CALR is found in complex with soluble transferrin receptor 1 (sTFR1) that acts as a carrier protein and increases mutant CALR half-life. Recombinant mutant CALR proteins bound and activated the TpoR in cell lines and primary megakaryocytic progenitors from patients with mutated CALR in which they drive thrombopoietin-independent colony formation. Importantly, the CALR-sTFR1 complex remains functional for TpoR activation. By bioluminescence resonance energy transfer assay, we show that mutant CALR proteins produced in 1 cell can specifically interact in trans with the TpoR on a target cell. In comparison with cells that only carry TpoR, cells that carry both TpoR and mutant CALR are hypersensitive to exogenous mutant CALR proteins and respond to levels of mutant CALR proteins similar to those in patient plasma. This is consistent with CALR-mutated cells that expose TpoR carrying immature N-linked sugars at the cell surface. Thus, secreted mutant CALR proteins will act more specifically on the MPN clone. In conclusion, a chaperone, CALR, can turn into a rogue cytokine through somatic mutation of its encoding gene.

Background: Azacitidine is the treatment backbone for patients with acute myeloid leukemia, myelodysplastic syndromes and chronic myelomonocytic leukemia who are considered unfit for intensive chemotherapy. Detailed reports on adverse events in a real-world setting are lacking. Aims: To analyze the frequency of adverse events in the Austrian Registry of Hypomethylating agents. To compare real-world data with that of published randomized clinical trials. Results: A total of 1406 patients uniformly treated with a total of 13,780 cycles of azacitidine were analyzed. Hematologic adverse events were the most common adverse events (grade 3–4 anemia 43.4%, grade 3–4 thrombopenia 36.8%, grade 3–4 neutropenia 36.1%). Grade 3–4 anemia was significantly more common in the Registry compared to published trials. Febrile neutropenia occurred in 33.4% of patients and was also more common in the Registry than in published reports. Other commonly reported adverse events included fatigue (33.4%), pain (29.2%), pyrexia (23.5%), and injection site reactions (23.2%). Treatment termination due to an adverse event was rare (5.1%). Conclusion: The safety profile of azacitidine in clinical trials is reproducible in a real-world setting. With the use of prophylactic and concomitant medications, adverse events can be mitigated and azacitidine can be safely administered to almost all patients with few treatment discontinuations.

Purpose of Review: To review available data on the relationship of MDS and aging and to address the question if biological changes of (premature) aging are a prerequisite for the development of MDS. Recent Findings: Whereas the association of MDS with advanced age and some common biologic features of aging and MDS are well established, additional evidence for both, especially on the role of stem cells, the stem cell niche, and inflammation, has been recently described. Summary: Biologically, many but not all drivers of aging also play a role in the development and propagation of MDS and vice versa. As a consequence, aging contributes to the development of MDS which can be seen as an interplay of clonal disease and normal and premature aging. The impact of aging may be different in specific MDS subtypes and risk groups.

The goal of current management of patients with chronic phase chronic myeloid leukemia (CML) is to reach treatment‐free remission with sustained deep molecular remission (DMR) being the prerequisite therefor. Second‐generation tyrosine kinase inhibitors can induce deeper and faster remission than imatinib, but are often associated with severe adverse events (AEs). The combination of pegylated interferon (IFN) with imatinib was shown to induce higher molecular remissions than imatinib alone in two studies. Treatment discontinuation rates due to IFN induced AEs were high in both studies. To investigate safety, tolerability (primary objective), and efficacy (secondary objective) of the combination of imatinib with ropeginterferon alpha‐2b this phase I study was initiated. Twelve patients were planned to be enrolled. Nine patients completed the study according to protocol. Three patients terminated the study early, one due to occurrence of a dose‐limiting toxicity (neutropenia grade 3), one due to an AE (panic attacks grade 2) and one due to the patient's decision. Tolerability was good, non‐hematologic AEs were mainly grade 1/2, hematologic AEs were mainly neutropenias. No new AEs were reported for the combination of imatinib and ropeginterferon alpha‐2b. In a nondose‐dependent manner the addition of ropeginterferon alpha‐2b led to the achievement of a DMR in four out of nine patients after a treatment duration of 18 months. The combination of imatinib and ropeginterferon alpha‐2b is safe and showed in this phase I study the ability to deepen the molecular response in patients with chronic phase CML not achieving a DMR with imatinib alone.