Introduction:Ravulizumab replaced eculizumab as the preferred complement inhibitor for Paroxysmal Nocturnal Haemoglobinuria (PNH) in Denmark and Finland after 2020. Data on real-world disease activity after switching are limited. Methods:We conducted a case series of 20 PNH patients who transitioned from eculizumab to ravulizumab, assessing transfusion needs and breakthrough haemolysis episodes (BTH). Results:In 19 of 20 patients, transfusions and BTH were stable or reduced after switching. Particularly, patients with high transfusion or BTH burden had a marked reduction in these parameters after switching. Conclusion:Overall, ravulizumab provided comparable or improved disease control, supporting its use as a long-term treatment in PNH. Trial Registration:The authors have confirmed clinical trial registration is not needed for this submission.

Purpose:Few patients scattered among centers complicate investigation of thrombotic thrombocytopenic purpura (TTP) and Evans syndrome (ES). Routinely collected Danish register data captures the total population and includes lifelong follow-up. We aimed to validate registered TTP and ES diagnoses and to explore clinical characteristics. Patients and Methods:We identified all patients in Denmark with diagnosis registrations indicative of TTP or ES in the Danish National Patient Registry 2000-2019, validated diagnoses through medical record review, and extracted and presented data on initial treatment and complications. Results:Diagnoses for patients registered with TTP and ES were confirmed for 46% and 59%, respectively. Among validated TTP patients the most widespread complications at time of diagnosis were neurological symptoms or deficits, observed in 81% of cases. Other frequent types of complications in TTP patients were any organ failure (32%) and infection (25%). Initial management and complications did not change for patients diagnosed between 2000 and 2009 and 2010 and 2019, and survival remained constant (overall mortality 26%, median follow up of 8.4 years). Treatments and complications also remained unchanged for ES patients. Conclusion:Overall, diagnostic accuracy, complications and prognosis have remained relatively constant for patients over the study period. These now validated cohorts of Danish TTP and ES patients will be utilized in future studies to examine long-term health outcomes.

Prior studies combining pegylated interferon-α to Imatinib and Nilotinib in newly diagnosed CML patients have indicated an additive effect with faster and deeper molecular responses (SPIRIT, TIGER, NordCML002, NiloPEG). In this trial we used a bosutinib (BOS) backbone combined with low-dose ropeginterferon alfa-2b (BESREMi, AOP Health), which in contrast to previously tested interferons has a longer half-life and a more favorable tolerability profile. The aim was to investigate efficacy and tolerability of the combination, with the goal of deepening molecular response to eventually allow a higher proportion of patients to achieve treatment free remission. Patients were in 1st chronic phase and TKI-naïve. Inclusion criteria were standard including good organ function without history of liver, autoimmune or psychiatric disease. Based on clinical experience to improve tolerability, BOS was introduced at 200 mg OD and the dose titrated to 400 mg OD if tolerated. At month 3 (M3), patients who tolerated ≥300 mg OD and had transaminase levels grade ≤1 were randomized 1:1 for addition of ropeginterferon 50 μg every second week or not. The primary endpoint was MR4 at M12 in the intention-to-treat (IIT) population (all randomized patients). Other endpoints were safety and other response levels (e.g. MR4.5). Data up to M12 are presented. We also examined the response and tolerability of BOS up to M3 as the ramp-up dosing is not standard although frequently used in the clinic. 163 patients were included from 2019 to 2023 in 18 hospitals in Denmark (6), Finland (1), Norway (4) and Sweden (7). Despite gradual up-titration of BOS, many patients experienced toxicity as described in the BOS prescribing information, including grade 2, 3 and 4 transaminase elevations (11%; 16%; 3%). Dose reduction or interruption were insufficient to manage transaminase elevations, which frequently recurred upon BOS re-exposure. Compared with data from the BOS registration study (BFORE), GI AEs were less frequent with our present schedule. Twenty-seven % of patients could not be randomized: 15% for transaminitis, 4% for GI AEs and 8% for other reasons including inability to tolerate BOS 300mg OD. Non-randomized patients had M3 responses on par with randomized patients, indicating no harm of the dosing strategy despite the lower or intermittent BOS dose. Their responses at M6, M9 and M12 were similar to the standard arm. At M3, 118 patients were randomized, 58 to BOS and 60 to the combination. AEs were distributed evenly between study arms, but hematological toxicity (grades 3-4, 6.7% vs 0%), neuropsychiatric disorders (grade 2, 13% vs 4%) and infections grade 3-4 (13% vs 0%) were more frequent in the combination arm. Of note, transaminase elevations were similarly distributed, but analysis of attributability to the study drugs is ongoing and will be updated Overall, efficacy in the present study compared favorably with previous experience with BOS. The combination arm demonstrated a clear trend for faster and deeper response at all time points: The combination arm compared with the standard arm showed MR4 or better in 22.0% vs 13.8% at M6, 32.8% vs 17.2% at M9, and 38.3% vs 31.0% at M12. Attainment of MR4.5 or better was at M6, M9 and M12, 11% vs 5,2%, 22,4% vs 6,9% and 31,7% vs 20,7%, respectively. Discontinuation of treatment occurred in 22% of patients in the combination arm and 8,3% in the standard arm, of whom 11,5% and 5% for treatment resistance. The primary endpoint in the IIT dataset was not statistically significantly different between treatment arms; note that all patients were included in the ITT analysis even if no interferon was administered or the TKI was switched. Most switched patients received 1st and 2nd generation TKIs, but some were transplanted or received ponatinib. A per protocol analysis and data on drug exposure will be presented at the meeting. The step-up dosing strategy for BOS reduced GI toxicity, but not transaminitis. Efficacy was excellent in comparison with the registration study (BFORE). The combination of ropeginterferon and BOS was safe and efficacious. Responses occurred earlier and were deeper with the combination.

Chronic myeloid leukemia (CML) is effectively treated with small molecule BCR::ABL1 tyrosine kinase inhibitors (TKIs) but like in all cancers, early identification of suboptimal- and non-responders is a challenge. Through mass cytometry analysis of peripheral blood leukocytes, we collected high-dimensional data from de novo chronic phase CML patients enrolled in two multicenter clinical trials ([clinicaltrials.gov][1] [NCT01725204][2] and [NCT01061177][3]). In leukocytes, dasatinib and nilotinib inhibited intracellular signaling within one or three hours after first per oral dose, and each TKI had a unique signaling signature reflecting its kinase specificity profile beyond BCR::ABL1. An immune and signaling profile was constructed for each patient, predicting the treatment response (BCR::ABL1IS, %) the first 12 months of treatment. These results show that single cell immune and signaling profiles within hours of first dose can predict 12 months treatment response, anticipating future optimalization of kinase inhibitor treatment within days rather than months. ### Competing Interest Statement S.E.G.: Research collaboration with Novartis, H.H.H.: Chairman Nordic CML study group. Study group or institutional support from Bristol-Myers Squibb and Merck (NordCML007); Bristol Myers Squibb (DAStop 2 study), Austrian Orphan health and Pfizer (BosuPeg study); Speakers fees: Incyte and Novartis. B.T.G.: ENEST1st research collaboration with Novartis, collection and shipment of samples; Alden Cancer Therapy AS: Current equity holder in private company; AOP Orphan Pharmaceuticals GmbH: Consultancy; Astellas Pharma: Consultancy; AstraZeneca: Consultancy; Bjorgvin Therapeutic Group AS: Current equity holder in private company; Delbert Pharma: Consultancy; Ha Biotech AS: Current equity holder in private company; Incyte: Consultancy; JAZZ Pharmaceuticals: Consultancy; Kinn Therapeutics AS: Current equity holder in private company; MSD: Consultancy; Novartis: Consultancy; Otsuka Pharma: Consultancy; Sanofi: Consultancy. [1]: https://clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01725204&atom=%2Fbiorxiv%2Fearly%2F2025%2F11%2F11%2F2025.11.10.687542.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01061177&atom=%2Fbiorxiv%2Fearly%2F2025%2F11%2F11%2F2025.11.10.687542.atom

Clinical research has not been able to establish whether the differences between first- and second-generation BCR-ABL 1 kinase inhibitors are clinically relevant with regard to outcome. In the study by Alcazer et al., a relevant difference seems to emerge-paradoxically in the absence of the drugs-as demonstrated by differences in the relapse kinetics after cessation of therapy. Commentary on: Alcazer et al. Kinetics of molecular recurrence after tyrosine kinase inhibitor cessation in chronic phase chronic myelogenous leukaemia patients. Br J Haematol 2024;204:1536-1539.

Tyrosine kinase inhibitor (TKI) discontinuation in chronic myeloid leukemia (CML) has become part of routine care for patients with a sustained deep molecular response (DMR). Approximately 50% experience a molecular relapse upon TKI cessation. Most of them quickly regain DMR upon TKI resumption. Whether these patients can achieve a second treatment-free remission (TFR) remains unclear. DAstop2 (ClinicalTrials.gov ID: NCT03573596) is a prospective study including patients with a failed first TFR attempt re-treated with any TKI for ≥ one year. Upon entering the study, patients received the TKI dasatinib for additional two years. Patients with sustained DMR for ≥1 year qualified for a second TKI stop. Ninety-four patients were included between Oct 2017-Dec 2021. At the time of data analysis, 62 patients had attempted a 2nd stop. After a median follow-up of 27 months from 2nd stop, TFR rates were 61%, 56% and 46% at 6, 12 and 24 months respectively. No progression to advanced stage disease was seen and 87% had re-achieved MR4 within a median of 3 months from TKI re-initiation. In summary, we show that a 2nd TFR attempt after dasatinib treatment is safe, feasible and TFR rates seem in the range of those reported in trials of a first TKI stop.

Background: Hydroxyurea (HU) is the most commonly used first-line cytoreductive treatment option for patients with myeloproliferative neoplasms (MPN) worldwide. However, increasing evidence on the efficacy and safety of pegylated interferon-alpha2 (IFNα) is emerging, and optimal first-line treatment is to be established. Aims: To compare the efficacy and safety of HU vs. low-dose IFNα in patients with MPN over five years. Methods: DALIAH (NCT01387763) was a randomized phase III trial of HU vs. IFNα in newly diagnosed or untreated patients with MPN (essential thrombocythemia (ET), polycythemia vera (PV), prefibrotic myelofibrosis (PreMF), and primary myelofibrosis (PMF)). Patients > age 60 were randomized (1:1:1) to HU, IFNα-2a, or IFNα-2b whereas patients ≤ age 60 were randomized to IFNα-2a or IFNα-2b. The primary outcome was the JAK2V617F molecular response (MR) rate at 18, 36, and 60 months per 2009 European LeukemiaNetwork (ELN) (ET, PV, PreMF) or 2005 European Myelofibrosis Network (EUMNET) (PMF) criteria. Secondary outcomes included the complete clinicohematologic response (CHR) rate at 12 months. The JAK2V617F allele burden was measured using quantitative polymerase chain reaction (qPCR) on peripheral blood (assay sensitivity: 0.1%). Primary and secondary outcomes were compared between groups (HU vs. IFNα or HU vs. IFNα > 60 years) using Fisher's exact test (categorical variables) or Wilcoxon rank-sum test (continuous variables). Paired comparisons (within groups) were made using Wilcoxon signed-rank test. Serial JAK2V617F measurements were compared by unadjusted mixed-effects linear regression analysis. Results: We included 203 patients (ET: 73 (36%), PV: 89 (44%), PreMF: 16 (8%), and PMF: 25 (12%)) in the modified intention-to-treat (ITT) population. Baseline characteristics were well balanced except for median age (HU: 68 years vs. IFNα: 59 years, p<0.0001) ( Table 1). The MR rate by ITT analysis was similar between HU and IFNα (18 months: 19% vs. 21%, p=1.00; 36 months: 19% vs. 26%, p=0.64; 60 months: 23% vs. 24%, p=1.00) (Figure 1A). However, the JAK2V617F allele burden was significantly lower in the IFNα group at month 36 and beyond (Figure 1B) and the absolute median (IQR) change in JAK2V617F allele burden (baseline to 60 months) was greater with IFNα (-20% (-9;-49) vs. -7% (3;-15), p=0.0053) (Figure 1C). Two patients (IFNα: n=2) were in complete molecular remission (undetectable JAK2V617F) at 60 months. The CHR rate by ITT analysis was higher with HU at 18 months (58% vs. 38%, p=0.03) but similar at all other time points (12 months: 50% vs. 36%, p=0.21; 60 months: 24% vs. 22%, p=0.83) ( Figure 1D). A post hoc subgroup analysis comparing HU with IFNα > age 60 showed comparable efficacy results. Among patients remaining on treatment (per-protocol analysis), the MR and CHR rates were superior in the IFNα group compared to the HU group at 36 months and beyond. The MR and CHR rates (HU vs. IFNα) by per-protocol analysis were: MR at 36 months: 23% vs. 56%, p=0.01; MR at 48 months: 27% vs. 59%, p=0.02; MR at 60 months: 35% vs. 67%, p=0.03; CHR at 36 months: 33% vs. 67%, p=0.002; CHR at 60 months: 38% vs. 62%, p=0.05. Overall treatment discontinuation at 60 months was 60% (HU: 37% vs. IFNα: 65%, p=0.0019). The most common cause of treatment discontinuation was adverse events (HU: 6/38 (16%); IFNα: 71/165 (43%)). Adverse events ≥ grade 3 occurred in 46% (HU: 58% vs. IFNα: 45%, p=0.15). Nineteen major thrombotic events were reported in 16 patients (HU: 4 events in 4 patients; IFNα>60: 12 events in 10 patients; IFNα≤60: 3 events in 2 patients), corresponding to an incidence rate of 2.6 per 100 person-years for HU and 3.4 per 100 person-years for IFNα (IFNα>60: 6.2; IFNα≤60: 1.2). None of the patients transformed into secondary acute myeloid leukemia. Five patients died during follow-up (HU: 2; IFNα: 3). Bone marrow histologic remission rates at 36 and 60 months will be presented at the meeting. Conclusion: ITT analysis detected no significant difference in the MR or CHR rates between HU and IFNα with long-term treatment (5 years) among patients with MPN, reflecting a higher treatment discontinuation rate in the IFNα group (65%). Thus, using the per-protocol principle, the MR and CHR rates were superior in the IFNα group at 36 months and beyond.

BACKGROUND:Patients with myeloproliferative neoplasms (MPNs) suffer from substantial symptoms and risk of debilitating complications, yet observational data on their labor market affiliation are scarce.MATERIAL AND METHODS:We conducted a descriptive cohort study using data from Danish nationwide registries, including patients diagnosed with MPN in 2010-2016. Each patient was matched with up to ten comparators without MPN on age, sex, level of education, and region of residence. We assessed pre- and post-diagnosis labor market affiliation, defined as working, unemployed, or receiving sickness benefit, disability pension, retirement pension, or other health-related benefits. Labor market affiliation was assessed weekly from two years pre-diagnosis until death, emigration, or 31 December 2018. For patients and comparators, we reported percentage point (pp) changes in labor market affiliation cross-sectionally from week -104 pre-diagnosis to week 104 post-diagnosis.RESULTS:The study included 3,342 patients with MPN and 32,737 comparators. From two years pre-diagnosis until two years post-diagnosis, a larger reduction in the proportion working was observed among patients than comparators (essential thrombocythemia: 10.2 [95% CI: 6.3-14.1] vs. 6.8 [95% CI: 5.5-8.0] pp; polycythemia vera: 9.6 [95% CI: 5.9-13.2] vs. 7.4 [95% CI: 6.2-8.7] pp; myelofibrosis: 8.1 [95% CI: 3.0-13.2] vs. 5.8 [95% CI: 4.2-7.5] pp; and unclassifiable MPN: 8.0 [95% CI: 3.0-13.0] vs. 7.4 [95% CI: 5.7-9.1] pp). Correspondingly, an increase in the proportion of patients receiving sickness benefits including other health-related benefits was evident around the time of diagnosis.CONCLUSION:Overall, we found that Danish patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN had slightly impaired labor market affiliation compared with a population of the same age and sex. From two years pre-diagnosis to two years post-diagnosis, we observed a larger reduction in the proportion of patients with MPN working and a greater proportion receiving sickness benefits compared with matched individuals.

Topic: 32. Platelet disorders Background: Early recognition and treatment of Thrombotic Thrombocytopenic Purpura (TTP) is vital for patients’ prognoses. Plasma exchange (PEX) has improved survival and introduction of Rituximab has reduced risk of relapse, but patients are still susceptible to a number of complications and late effects, which are yet to be studied in depth across entire populations. While possible in Denmark due to routinely collected health data, the diagnosis has not been validated. In our own register based studies of Evans syndrome (ES), we have seen few patients diagnosed with both ES and TTP, raising concerns of diagnostic misclassification. Aims: We aimed to validate diagnoses of TTP and ES, and described initial treatment, complications, and health outcomes of confirmed patients. Methods: Patients ≥18 years were identified in the Danish National Registry of Patients through ICD codes indicative of TTP or Evans syndrome 2000-2019. Medical journals were reviewed and data collected by local hematologists at 9 centres. Positive predictive values (PPV) were estimated for TTP and ES diagnosis registrations. Descriptive statistics were estimated for baseline information, initial treatment, complications, relapses and survival (follow-up until May 2022), both overall and compared for patients diagnosed 2000-2009 and 2010-2019. Results: In total, 355 eligible patients were identified in the nationwide register. Journal Data was available for 149 patients registered with TTP and 110 with ES. Unavailable journals were predominantly from 2000-2009. PPV was 46.3% [95%CI 38.1; 54.7] for TTP and 59.1% [49.3; 68.4] for ES, and most frequent misclassified diagnoses were cancer-associated TMA and ITP, respectively. Only 1.3% of patients registered with TTP were misclassified ES patients, and 1.8% of registered ES patients misclassified TTP patients. For confirmed TTP patients, 79% had ADAMTS13 activity analysed. Proportion presenting with neurological symptoms was comparable from 2000-2009 to 2010-2019 (75 vs 81%), as was median duration of PEX (15 vs 13 days). Median duration of steroid course increased from 46.0 [17.5; 76.0] to 87.0 [47.5; 141.5] days (P = 0.04), and proportion treated with Rituximab increased from 46.2% [19.2; 74.9] to 62.1% [48.4; 74.5] (P = 0.29). Intensive care was required for 25 vs 28% of patients, organ failure decreased from 53.8% [25.1; 80.8] to 27.6% [16.7; 40.9] (P = 0.07), and CNS failure fell from 38.5% [13.9; 68.4] to 17.2% [8.6; 29.4] (P = 0.09). Infection occurred in 31 vs 22% of patients, and relapse in 25 vs 14%. Early mortality remained high between the two time periods (figure). For confirmed ES patients, median duration of steroid course (days) decreased from 144.5 [30.0; 306.0] to 106.5 [42.0; 169.5] from 2000-2009 to 2010-2019 (P = 0.24). Rituximab use was constant at 57%, as was infection at 21%, while 33 vs 38% suffered from relapse during follow up. Summary/Conclusion: Register-based studies of TTP and ES should be supported with medical journal validation or other supportive measures (e.g. ADAMTS13 data), as diagnosis code alone is unreliable, although misclassification between the two is not a concern. While no signs of reduced early mortality was observed, some acute clinical complications such as organ failure and CNS failure showed trends of improvement across study periods among TTP patients. However, analyses lacked precision. Increased measurement of ADAMTS13 activity will likely improve timely detection and treatment of more TTP patients, which continue to be a priority. Figure: Survival of TTP and Evans syndrome patients by diagnosis periodKeywords: Autoimmune hemolytic anemia (AIHA), Clinical outcome, Thrombotic thrombocytopenic purpura (TTP), Immune thrombocytopenia (ITP)

Background Limited data on the relation between quality of life (QoL) and the type of cytoreductive therapy in patients with myeloproliferative neoplasms (MPN) exists. Methods DALIAH (NCT1387763) was a randomized controlled phase 3 clinical trial. Newly diagnosed patients with MPN ≥ 18 years of age were eligible to enroll. Patients > age 60 were randomized (1:1:1) to receive HU, IFNα-2a, or IFNα-2b and patients ≤ age 60 were randomized (1:1) to receive IFNα-2a or IFNα-2b. HU pre-treatment was allowed from screening and until enrollment. Symptom burden and overall QoL was measured by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) on a scale from 0 (absent/as good as it can be) to 10 (worst-imaginable/as bad as it can be) at baseline, 4, 8, 12, 18, 24, 30, and at data-cutoff at 36 months. Wilcoxon rank-sum test or Fisher's exact test were used for two-group comparisons, and a Wilcoxon signed-rank test was used for within-group comparisons. To avoid age-bias the following groups were compared: HU>60 vs IFNα>60 and IFNα-2a vs IFNα-2b. Analyses followed the per-protocol principle. Results At baseline, the MPN-SAF survey was completed by 199 (98%) of 203 included patients (HU: 38, IFNα-2a/2b>60: 37/37, IFNα-2a/2b≤60: 45/46). Seventy (35%) had ET, 88 (44%) had PV, 16 (8%) had Pre-MF, and 25 (13%) had overt PMF. Median age was 62 years (IQR 50-69) and 113 (55%) were males. Twenty-one (10%) patients had received HU pre-treatment for a median of 19 days (min: 3, max: 44). Burden of MPN-symptoms at baseline Mean Total Symptom Score (TSS, scale 0 [absent]-100 [worst imaginable]) was 15.0 (standard deviation [SD]: 14.3, range 0-69.0). Clinical deficient overall QoL (≥ 4 of 10) was reported in 42% (ET: 46%, PV: 41%, Pre-MF: 38%, PMF: 44%). Fatigue (one-item Brief Fatigue Inventory [BFI]) was the most common symptom (82%) and also carried the highest mean symptom intensity (3.5, SD: 2.8). One or more moderate or severe symptoms (≥ 4 of 10) were reported by 70% of the patients with the most common symptoms (prevalence ≥ 20%) being fatigue (BFI score, 25%) followed by concentration (21%), and insomnia (20%). Severe symptoms (≥ 7 of 10) were reported by 46%. Baseline characteristics as well as TSS and individual symptoms were balanced between groups (HU>60 vs IFNα>60 and IFNα-2a vs IFNα-2b) except abdominal pain, which was higher among IFNα-2b than IFNα-2a, p=0.02. Burden of MPN-symptoms during treatment A total of 179 (88%) patients on randomized therapy completed at least one MPN-SAF survey during follow-up, and 96 of 105 (91%) completed the survey at 36 months (HU: 27, IFNα-2a/2b>60: 21/12, IFNα-2a/2b≤60: 22/14). Overall treatment discontinuation rate at 36 months was 48% (HU: 21%, IFNα-2a/2b>60: 43%/65%, IFNα-2a/2b≤60: 47%/63%). On HU, patients experienced transient or persistent worsening of individual symptoms in fatigue (BFI score), abdominal pain, abdominal discomfort, sexuality problems, itching, and bone pain whereas those receiving IFNα (irrespective of age) experienced worsening in fatigue (BFI score), early satiety, abdominal pain, abdominal discomfort, inactivity, headache, concentration problems, numbness, dizziness, insomnia, sexuality problems, cough and itching (all, p<0.05). Of note, sad mood and fever was only significantly worsened at 4 months. On IFNα, weight loss was improved (Table 1). TSS increased within the first year in all treatment groups but was only significantly elevated at 36 months compared to baseline among those receiving HU>60 (mean 10.4 to 14.6, p=0.02) (Table 1). At 36 months, the proportion of patients (baseline TSS>0) achieving a reduction in TSS was similar between groups (HU>60: 23% vs IFNα>60: 30%, p=0.57; IFNα-2a: 33% vs IFNα-2b: 38%, p=0.80), and no significant difference in TSS was observed (HU>60: 14.6 [SD: 13.9] vs IFNα>60: 16.8 [SD: 13.5], p=0.47; IFNα-2a: 17.7 [SD: 13.3] vs IFNα-2b: 15.4 [SD: 15.1], p=0.38) (Table 1, Figure 1A/B). At 36 months, one or more moderate or severe symptoms were reported by 63%. Fatigue (one-item BFI) remained the most common symptom across groups and no significant differences in individual symptom scores or proportion of moderate or severe symptoms were detected between groups (Figure 1C/D). Conclusion HU and IFNα increased total symptom burden initially in patients with MPN with no significant difference between HU>60 vs IFNα>60 or IFNα-2a vs IFNα-2b. However, at 36 months only patients on HU had significantly increased TSS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Few studies have assessed healthcare resource utilization (HRU) in patients with Philadelphia-negative myeloproliferative neoplasms (MPN) using a matched cohort design. Further, no detailed assessment of HRU in the years preceding an MPN diagnosis exists. We conducted a registry-based nationwide Danish cohort study, including patients with essential thrombocythemia, polycythemia vera, myelofibrosis, and unclassifiable MPN diagnosed between January 2010 and December 2016. HRU data were summarized annually from 2 years before MPN diagnosis until emigration, death, or end of study (December 2017). We included 3342 MPN patients and 32 737 comparisons without an MPN diagnosis, matched on sex, age, region of residence, and level of education. During the study period, the difference in HRU (rate ratio) between patients and matched comparisons ranged from 1.0 to 1.5 for general practitioner contacts, 0.9 to 2.2 for hospitalizations, 0.9 to 3.8 for inpatient days, 1.0 to 4.0 for outpatient visits, 1.3 to 2.1 for emergency department visits, and 1.0 to 4.1 for treatments/examinations. In conclusion, MPN patients had overall higher HRU than the matched comparisons throughout the follow-up period (maximum 8 years). Further, MPN patients had substantially increased HRU in both the primary and secondary healthcare sector in the 2 years preceding the diagnosis.

In chronic myeloid leukemia (CML), combination therapies with tyrosine kinase inhibitors (TKIs) aim to improve the achievement of deep molecular remission that would allow therapy discontinuation. IFN-α is one promising candidate, as it has long-lasting effects on both malignant and immune cells. In connection with a multicenter clinical trial combining dasatinib with IFN-α in 40 patients with chronic-phase CML (NordCML007, NCT01725204), we performed immune monitoring with single-cell RNA and T cell receptor (TCR) sequencing (n = 4, 12 samples), bulk TCRβ sequencing (n = 13, 26 samples), flow cytometry (n = 40, 106 samples), cytokine analyses (n = 17, 80 samples), and ex vivo functional studies (n = 39, 80 samples). Dasatinib drove the immune repertoire toward terminally differentiated NK and CD8+ T cells with dampened functional capabilities. Patients with dasatinib-associated pleural effusions had increased numbers of CD8+ recently activated effector memory T (Temra) cells. In vitro, dasatinib prevented CD3-induced cell death by blocking TCR signaling. The addition of IFN-α reversed the terminally differentiated phenotypes and increased the number of costimulatory intercellular interactions and the number of unique putative epitope-specific TCR clusters. In vitro IFN-α had costimulatory effects on TCR signaling. Our work supports the combination of IFN-α with TKI therapy, as IFN-α broadens the immune repertoire and restores immunological function.

Recent studies have shown the Philadelphia-negative myeloproliferative neoplasms (MPN) to be massively underdiagnosed and often preceded by a long pre-diagnostic phase of several years, in which many patients suffer serious vascular events. In this review, we focus on the urgent need for earlier diagnosis and treatment of MPN. Such efforts are foreseen to decrease morbidity and mortality for the individual patients and potentially reduce costs for health and social care systems.

Abstract BACKGROUND Myeloproliferative neoplasms (MPNs) are characterized by a substantial symptom burden, risk of debilitating complications (e.g., thrombosis), and increased comorbidity. Recently, three comprehensive questionnaire studies (Mesa 2016, Harrison 2017, Jingbo 2018) have reported a high impact of MPNs on patients' ability to work. However, no registry-based studies have assessed labor market attachment (LMA) of MPN patients and matched nonMPN comparisons. AIM To assess the pre- and post-diagnostic LMA of MPN patients and matched nonMPN comparisons. METHODS We conducted a descriptive, registry-based nationwide cohort study, using data from the Danish National Chronic Myeloid Neoplasia Registry including all Danish MPN patients diagnosed between January 2010 and December 2016. Population-based cohorts of nonMPN comparisons were constructed by 1:10 matching on age, sex, level of education, and region of residence. Data on LMA were retrieved from the Danish Register for Evaluation of Marginalization, which holds information on all public transfer payments in Denmark. Data were linked using the unique civil registration number, which identifies all Danish citizens. The LMA endpoints were defined for each individual as working (not receiving any type of transfer payment), unemployed, receiving transfer payment for either sick leave, disability pension, age pension, or other health-related benefits (e.g., wage-subsidized employment). We assessed LMA weekly for each individual from two years before diagnosis until death, emigration, or two years after the diagnosis. For each cohort, we presented LMA as proportions with 95% confidence intervals (CIs), as well as the proportion of individuals who died during follow-up. RESULTS The study included 3,342 MPN patients (1,140 essential thrombocythemia [ET]; 1,109 polycythemia vera [PV]; 533 myelofibrosis [MF]; and 560 unspecified MPN [MPN-U]) and 32,737 nonMPN comparisons (11,181 nonET; 10,873 nonPV; 5,217 nonPMF; and 5,466 nonMPN-U). The median age at time of diagnosis was: ET 67 years (interquartile range [IQR], 55-76); PV, 69 years (IQR, 61-77); PMF, 73 years (IQR, 66-79); and MPN-U, 72 years (IQR, 63-80). At time of MPN diagnosis, the majority of MPN patients and nonMPN comparisons received age pension (range: ET, 52.1% [95% CI, 49.2-55.0] to nonMF, 70.3% [95% CI, 69.1-71.6]). The proportions working were: ET, 35.1% (95% CI, 32.3-37.9) vs. nonET, 37.3% (95% CI, 36.5-38.2); PV, 22.6% (95% CI, 20.2-25.1) vs. nonPV, 30.8% (95% CI, 29.9-31.7); MF, 23.8% (95% CI, 20.2-27.4) vs. nonMF, 23.6% (95% CI, 22.5-24.8); and MPN-U, 22.1% (95% CI,18.7- 25.6) vs. nonMPN-U, 27.8% (95% CI, 26.6-29.0). Across MPN subtypes, a larger proportion of patients than comparisons were on sick leave: ET, 3.5% (95% CI, 2.4-4.6) vs. nonET, 1.3% (95% CI, 1.1-1.5); PV, 5.5% (95% CI, 4.2-6.8) vs. nonPV, 0.9% (95% CI, 0.7-1.1); MF (not applicable due to small numbers) vs. nonMF, 0.6% (95% CI, 0.4-0.8); and MPN-U, 3.0% (95% CI, 1.6- 4.5) vs. nonMPN-U, 1.0% (95% CI, 0.7-1.3). Regarding disability pension, the proportions ranged from 4.1% (95% CI, 2.4-5.8) to 5.0% (95% CI, 3.7-6.3) among patients and from 3.1% (95% CI, 2.6-3.6) to 4.7% (95% CI, 4.3-5.1) among comparisons. For both MPN patients and nonMPN comparisons, few were unemployed (≤3.3%) or received other health-related benefits (≤1.6%). Two years preceding diagnosis, the proportion of PV and MPN-U patients working was slightly lower than the matched comparisons: PV, 31.0% (95% CI, 28.4-33.8) vs. nonPV, 34.3% (95% CI, 33.5-35.2) and MPN-U, 28.2% (95% CI, 24.6-32.1) vs. nonMPN-U, 32.0% (95% CI, 30.7-33.2), while this difference was not observed between ET and MF patients and their respective comparisons. From two years before to two years after diagnosis, we observed slightly larger reductions in the proportion working among MPN patients than among comparisons. Among MPN patients, the proportion on sick leave including other health-related benefits, increased during the study period, while it remained unchanged among comparisons. The proportion of patients and comparisons on disability pension remained stable. CONCLUSION Overall, our findings showed that Danish patients with ET, PV, MF, and MPN-U had slightly impaired LMA already two years before diagnosis and up to two years after diagnosis. Thus, fewer patients were working and more patients transferred to sick leave compared with matched individuals without MPN. Figure 1 Figure 1. Disclosures Stenling: Novartis: Current Employment. Paulsson: Novartis: Current Employment. Frederiksen: Novartis: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding. Hasselbalch: Novartis, AOP Orphan: Consultancy, Other: Advisory Board.

Objectives Treatment-free remission (TFR) has emerged as a treatment goal in chronic myeloid leukemia in the chronic phase (CML-CP). Attempts to increase proportion of patients achieving TFR include combination of tyrosine kinase inhibitors (TKI) and other drugs. Interferon-alpha in addition to TKI has shown promising efficacy but with dose-dependent toxicity and discontinuations. NordCML007 was initiated to study the efficacy and safety of low dose pegylated IFN-alpha (PegIFN-alpha) in combination with dasatinib (DAS) in CML-CP. Methods Forty patients with newly diagnosed CML-CP were given DAS upfront. After month 3 (M3) 15 mu g/wk of PegIFN-alpha was added and increased to 25 mu g/wk from M7 until M15. DAS treatment was continued and adverse events and BCR-ABL1 qRT-PCR values were reported yearly after M24. Results from M1 to M18 have previously been published, and here we present long-term data. Results After 5 years of follow-up, there were no suspected unexpected serious adverse reactions, no increase in serosal effusions, no disease progressions and no CML-related deaths. Rates of MR3.0 (MMR), MR4.0 and MR4.5 were 84.6%, 64.1% and 51.3% respectively at M60, and 95% of patients reached MMR at some point during the study. Conclusion Initial addition of PegIFN-alpha to DAS shows good long-term efficacy without increased toxicity.

The ENESTfreedom trial assessed the feasibility of treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) following frontline nilotinib treatment. Results for long-term outcomes after a 5-year follow-up are presented herein. Patients who had received ≥2 years of frontline nilotinib therapy and achieved MR 4.5 underwent a 1-year nilotinib treatment consolidation phase before attempting TFR. At the 5-year data cut-off, 81/190 patients entering the TFR phase (42.6%) were still in TFR, with 76 (40.0%) in MR 4.5 . Patients who lost major molecular response (MMR) entered a treatment re-initiation phase; 90/91 patients entering this phase (98.9%) regained MMR and 84/91 patients (92.3%) regained MR 4.5 . The Kaplan–Meier estimated treatment-free survival rate at 5 years was 48.2%. No disease progression or CML-related deaths were reported. Whereas the incidence of adverse events (AEs) declined from 96 weeks following the start of TFR, an increase in AE frequency was observed for patients in the treatment re-initiation phase. Low Sokal risk score, BCR-ABL1 IS levels at 48 weeks of TFR and stable MR 4.5 response for the first year of TFR were associated with higher TFR rates. Overall, these results support the efficacy and safety of attempting TFR following upfront nilotinib therapy of >3 years in patients with CML-CP.

As haematologists, we always seek to follow standardized guidelines for practice and apply the best treatment within our means for our patients with blood diseases. However, treatment can never follow an exact formula. Opinions differ as to the best approach; sometimes more than one treatment approach results in identical outcomes, or treatments differ only by the manner in which they fail. Furthermore, the haematologist is faced with constraints relating to the local economic environment. Patients, too, are not the same the world over. Early presentation is more common in the developed world, as is the patient's understanding of the disease process. This in turn has an impact on the way patients are managed, the rigorousness of patient adhesion to the treatment schedule and the outcome. For these reasons, given the same starting conditions, patients will be treated differently according to the institute and the country they are in. In this series of global views, we have tasked experts from around the world to describe their management plan and rationale for a specific disease presentation. Here we explore the management of autoimmune thrombocytopenia (ITP) in institutions six different nations. We conclude with an expert in the field comparing and contrasting these different management styles and considering their merits and limitations. The case history and questions posed to the experts are shown in the Box 1 and their responses are summarized in Table 1. Oral prednisolone Occasionally patients can afford IvIg Treatment will be based on platelet counts. Treatment only if platelet counts < 30 × 109/l Second line treatment will consist of dapsone, azathioprine or a splenectomy. If failure: Danazol is an option for those with economic constraints otherwise Rituximab or TPO-RAs Repeated IvIg, splenectomy, rituximab*, romiplostim* If breastfeeding: Remove accessory spleens, rituximab*, romiplostim* If not breastfeeding: No limitations Prednisolone Start with 1 mg/kg/day for few days than reduce to 20–25 mg/day or even less according to platelet response I would advise the patient of the risk of ITP recurrence or worsening during the second pregnancy and possible complications for the mother and for the fetus. In women with active ITP wanting pregnancy, I would consider 'preparing' the woman to have a safe pregnancy using treatments with possible long-term benefits I would treat the mother only if symptomatic and/or platelet count < 20 × 109/l. Repeated course of IvIg In case of no response to IvIg: Romiplostim In case of no response to IvIg and romiplostim only in case of bleeding: rituximab splenectomy Observation If breastfeeding: Check platelet count in the baby. Treatment only if platelet count < 20 × 109/l or bleeding. If not breastfeeding. Splenectomy or TPO-RAs or rituximab according to previous treatments and patient's expectations Prednisolone IvIg Prednisolone IvIg Platelet concentrate Eltrombopag, romiplostim, rituximab We hope that this exercise brings home to practicing clinicians that there is more than one 'right' way to manage patients. There are always things to learn from the way other experts' practice. Moreover, there is much to learn from our colleagues working in lower-resourced economies. This teaches us that we should be nuanced in our perception of how and why treatments differ worldwide. A 26-year woman sees her general practitioner because of petechiae on her lower extremities. She has an unremarkable history with no prior episodes of bleeding and with a normal menstruation pattern. A laboratory workup reveals nothing out of the ordinary except a platelet count of 5 × 109/l but a positive pregnancy test (hitherto unknown to the patient). She is referred to the local haematology department. I would inform the patient of the pregnancy test result! The history points toward this being newly diagnosed ITP at an early stage in pregnancy, although it is important to be alert for alternative diagnoses, which may or may not be pregnancy related. A spurious thrombocytopenia is unlikely given the petechiae, but the blood film should be examined urgently and the blood count should be repeated, along with the routine ITP baseline investigations.1 Thrombotic thrombocytopenic purpura (TTP) seems unlikely given that thrombocytopenia is the only finding on clinical-laboratory work-up, but both acquired and hereditary TTP present more commonly in pregnancy and should be rapidly excluded with blood film review and a haemolytic screen. It is unusual, but not unreported, for TTP to present with isolated thrombocytopenia. The gestation should be accurately assessed with a dating ultrasound scan as the pregnancy-related disorders, haemolysis, elevated liver enzymes and low platelets, (HELLP), pre-eclampsia and acute fatty liver of pregnancy, would not be seen in the first trimester and are extremely rare in the second trimester. Hereditary thrombocytopenia with severe thrombocytopenia may also present in adult life. While I would not initially screen for this in the absence of any pre-existing personal or family history, it is important to keep this in mind if the response to treatment subsequently proves to be unsatisfactory. Assuming that we are early in the first trimester, and based on what would appear to be a low bleeding score, my initial treatment would be oral prednisolone. Doses of 1 mg/kg/day are routinely used in non-pregnant patients with newly diagnosed ITP, but in the non-pregnant state, the aim would be to taper steroids to cessation in around 6 weeks. In pregnancy, ongoing steroids are likely to be needed, and as there is no bleeding manifestation other than petechiae, I would start with a lower dose of prednisolone. For convenience, I would start at 25 mg daily (one tablet) and adjust the dose either up or down, depending on the response. Although there is no high level evidence to support this strategy, expert opinion2 and personal experience guide this decision. After a satisfactory effect of the therapy you instituted and an uneventful birth of a healthy boy, she is without symptoms for 3 years, when she seeks your advice because she is planning to become pregnant. I would support the patient in her wish for a pregnancy, but counsel that recurrence of thrombocytopenia is possible, and a 'high-risk pregnancy' monitoring schedule would be required from confirmation of the pregnancy (assuming that the ITP presentation in the first pregnancy was confirmed to be at an early stage). Published reports3 and personal experience indicate that the risk of exacerbation of ITP is acceptable and pregnancy outcomes are nearly always favourable. After the patient succeeds in becoming pregnant, she once more displays a pronounced drop in platelet counts, this time to 58 × 109/l, but without symptoms or signs of bleeding. After you institute the initial therapeutic option again, you discover that its effectiveness is not nearly as pronounced as the first time with the platelet counts increasing only to 70–90 × 109/l. I would not have started any treatment with the platelet count at this level in the absence of bleeding or impending delivery. I would monitor the patient closely. If the platelet count dropped below the threshold for treatment (<20 × 109/l or < 30 × 109/l with petechiae/bruising), I would reinstate the treatment used successfully in the first pregnancy (prednisolone at doses previously indicated). Nearer delivery, the goals of treatment change such that a platelet count of > 50 × 109/l is required for delivery (irrespective of method) and if epidural anaesthesia is desired, the platelet count should be > 80 × 109/l. To achieve the platelet counts above, if there were enough time, I would first aim to adjust the prednisolone dose to increase the platelet count. If this were not successful, or if there was urgency to increase the platelet count, I would use intravenous immunoglobulin (IvIg). The dose would be 1g/kg daily for up to 2 days if very urgent or 0·4 g/kg daily for up to 5 days if less urgent (there are more complications with a higher dose, so preference is for a lower dose schedule). Therapeutic strategies beyond corticosteroids and IvIg are rarely needed for ITP in pregnancy. Anti-D is not available for ITP treatment in Australia. If further measures are needed, azathioprine is safe in pregnancy4 and can be useful in steroid sparing, if higher doses of steroids are needed for prolonged periods. Splenectomy is an option in the second trimester,5 but I have never resorted to this. Thrombopoietin receptor agonists (TPO-RAs) in short term use in pregnancy are probably safe,6 but data are limited so, currently, this would be a last resort. The patient once more has an uneventful birth, but at a follow-up with you 30 days post-partum, platelets are now on two consecutive occasions 20–30 × 109/l. Generally, ITP with exacerbation during pregnancy remits to some degree post-partum. This might still occur, so unless there was bleeding, or risk factors for bleeding, I would monitor the situation and not treat. If the platelet count declined or bleeding developed, the next step would depend on breastfeeding status and the mother's willingness to switch to formula feeding. If not breastfeeding or if willing to cease, then choices are not limited. A bleeding risk assessment would determine whether to start a treatment that is likely to increase the platelet count swiftly (corticosteroids, IvIg) or whether a slower recovery of the platelet count was a reasonable goal. In the latter case, rituximab 100 mg weekly × 4 would be my choice. Younger females, particularly those with a broader autoimmune diathesis, are the group who respond best to rituximab (Bird, manuscript in preparation). Rituximab is not funded nationally in Australia for ITP, but using the low dose and generic drug, local funding or self-funding is generally feasible. Full hepatitis B serology should always be checked before starting rituximab. Breastfeeding would not be a barrier to using rituximab.7 Government funding restrictions for TPO-RAs in Australia require splenectomy or a medical contraindication to splenectomy (patient preference not considered). Unfortunately, this essentially precludes their use as the cost would be around 60% of the average annual gross income. Numerous other 'traditional' treatments with little evidence base are available, but my preference, if the patient is not breastfeeding and all other inclusion/exclusion criteria are met, would be to invite the patient to participate in a clinical trial. Other treatments not previously mentioned that I use if trials or TPO-RAs cannot be accessed include (most commonly) mycophenolate mofetil and other corticosteroids (dexamethasone, high-dose methylprednisolone) and, very uncommonly, danazol, dapsone, vincristine or ciclosporin. Arrangements exist for hospital funding for individual patients if the drugs are not on the Australian Government Pharmaceutical Benefits Scheme. In the Australian context, I have never found H. pylori screening and eradication to be a useful strategy, but I would test and treat if the patient were of East Asian (particularly Japanese) ethnicity. The most likely cause of severe isolated thrombocytopenia in early pregnancy is ITP.8 According to her unremarkable history and clinical-laboratory work-up, this patient should be treated for primary ITP. The initiation of therapy for ITP in pregnancy in Thailand depends on platelet count and bleeding. If a patient develops bleeding related to thrombocytopenia (usually platelet count of < 50 × 109/l), therapy will be started. If the gestational stage is less than 36 weeks, I would start the therapy when the platelet count was less than 30 × 109/l. However, if the gestational stage is 36 weeks or more, therapy would be started at a platelet count of less than 50 × 109/l to prepare for caesarean delivery if required. The initial therapy for ITP in pregnancy is corticosteroids, either prednisolone or dexamethasone. However, if there is life-threatening bleeding, the initial therapy would include IvIg, high-dose dexamethasone and platelet transfusion. In addition, in cases of intracerebral haemorrhage, emergency splenectomy may be considered in some centres. In Thailand, the cost of IvIg can be reimbursed only in the case of life-threatening bleeding. In this patient, I would recommend prednisolone with a dose of 1 mg/kg/day for initial therapy because of less transplacental transfer than with dexamethasone.9 Dexamethasone may be used when approaching delivery to promote fetal lung maturity. Because tuberculosis is prevalent in Thailand, I would suggest a baseline chest X-ray (with shield) after counselling the patient about the risks and benefits. In addition, initial testing of stool for parasites and intermittent fasting blood sugar while taking corticosteroids would be recommended. After a satisfactory effect of the therapy you instituted and an uneventful birth of a healthy boy, she is without symptoms for 3 years, when she seeks your advice because she is planning to become pregnant. First, I would counsel the patient and her husband about the effect of pregnancy on ITP and vice versa, including the risk from ITP therapy. Platelet count may fall, be stable or increase during pregnancy. Judging from her previous pregnancy, her platelet count tends to decrease during pregnancy. However, hopefully, she will respond well to therapy with the uneventful birth of a child, as in the previous pregnancy; also, the mortality rate of ITP in pregnancy is generally very low.10 The effects of ITP on pregnancy that have been reported include increased risk of stillbirth, fetal loss, preterm birth and post-partum haemorrhage.10, 11 In addition, the treatment of ITP with corticosteroids may add some maternal and fetal risks, such as infection, hyperglycaemia, hypertension, and osteopenia in the mother and cleft palate in fetus.9, 12 If the patient and her husband accept the risk and she decides to become pregnant, before conception I would request a chest X-ray, if it has not been done within the previous 5 years, consult a dentist for general dental care, and check her full blood count (FBC) as baseline investigations. After conception, I would check her FBC every 1–2 months or more frequently if the results were abnormal. After the patient succeeds in becoming pregnant, she once more displays a pronounced drop in platelet counts, this time to 58 × 109/l, but without symptoms or signs of bleeding. After you institute the initial therapeutic option again, you discover that its effectiveness is not nearly as pronounced as the first time with platelet counts increasing to only 70–90 × 109/l. The target level of platelet count during pregnancy is 30–50 × 109/l or more without bleeding. Hence, this patient has achieved the target level already. I would continue the initial therapy to keep her platelet count at 50 × 109/l or above. However, if she did not respond to prednisolone, I would discuss other options including their risks and benefits. Selection of other options depends on gestational stage, severity of bleeding, possible adverse effects, co-morbidity and cost. The common options after the first trimester include high-dose dexamethasone, dapsone, azathioprine and ciclosporin. IvIg is reserved for life-threatening bleeding. In some cases without significant bleeding, observation may be offered if the platelet count is 10 × 109/l or higher and the risk of therapy is concerning. The patient once more has an uneventful birth, but at a follow-up with you 30 days post-partum, platelets are now on two consecutive occasions 20–30 × 109/l. The duration of her ITP is more than 1 year, making the diagnosis that of chronic ITP.13 Thus, the target platelet count may be decreased to 20 × 109/l or above in the absence of bleeding. The initial option is corticosteroids, if not currently used. If she needed moderate-dose prednisolone to maintain a platelet count, I would consider other options, depending on whether she is breastfeeding or not, the potential adverse effects and the cost. If she stops breastfeeding, the options include dapsone, azathioprine, cyclophosphamide and danazol. If the patient can afford the high-cost options, rituximab (low-dose or standard-dose) and eltrombopag would be offered. If she wants to continue breastfeeding, a possible option is azathioprine (breastfeeding only after at least 4 h from ingestion of azathioprine14). Finally, if the patient does not respond to the above options or develops unacceptable adverse effects, elective splenectomy would be considered with appropriate preoperative vaccination. I would confirm the diagnosis of ITP with a bone marrow examination and send off relevant tests, including a viral screen for blood borne viruses, prothrombin time and activated partial thromboplastin time and a screen for systemic lupus erythematosus. A bone marrow examination is generally done because I would like to rule out other possibilities, such as non-severe aplastic anaemia, hypocellular myelodysplastic syndrome and tuberculous granulomas involving the bone marrow. The patient should be counselled that pregnancy can be continued, but she will need to remain on close follow-up. A detailed conversation would be had regarding whether she can come for regular follow-up during the ante-natal period. Since she is clinically very stable, even with a platelet count of 5 × 109/l, I would start her on oral prednisolone 1 mg/kg/day for 4 weeks. If she showed a good response to corticosteroids, I would consider tapering the steroids slowly down to the lowest dose that would maintain the platelet count above 30 × 109/l in the first and second trimester and a platelet count above 50 × 109/l towards the end of the third trimester and at the time of delivery and then stop the oral corticosteroids 2–4 weeks after delivery.15 After a satisfactory effect of the therapy you instituted and an uneventful birth of a healthy boy, she is without symptoms for 3 years, when she seeks your advice because she is planning to become pregnant. I would warn her that there is a 30% possibility that she will have either a relapse of her ITP if her present platelet counts are normal or will have worsening of a stable platelet count requiring further treatment during the next pregnancy. Therefore, she would need to continue to remain on close follow-up once she became pregnant. I would check her present platelet count. If the counts are above 30 × 109/l, she only needs to remain under close monitoring. If the platelet counts are < 30 × 109/l, she will be started on either azathioprine or dapsone.16 After the patient succeeds in becoming pregnant, she once more displays a pronounced drop in platelet counts, this time to 58 × 109/l, but without symptoms or signs of bleeding. After you institute the initial therapeutic option again, you discover that its effectiveness is not nearly as pronounced as the first time with platelet counts increasing only to 70–90 × 109/l. This patient has received corticosteroids and presently has platelet counts of 70–90 × 109/l. During the first and second trimester, I would continue the dose of oral steroids that is able to maintain the same platelet count. During the third trimester, I would reconsider the option of increasing the dose of corticosteroids if the patient does not have hypertension or gestational diabetes. If it is not possible to increase the dose of corticosteroids, I would initiate second line therapy with either azathioprine (2–3 mg/kg/day) with close monitoring of blood counts, or dapsone (1–2 mg/kg/day) with close monitoring of haemoglobin and watching for development of a skin rash. Based upon our experience with both drugs, I would expect a rise in the platelet count to > 100 × 109/l in about 50% of patients. In general, it will take between 8 and 12 weeks for the improvement in the platelet count to be apparent. If there is a contraindication to the above drugs, I would consider using low-dose ciclosporin at 3 mg/kg/day in two divided doses, monitoring the blood pressure and renal function. We occasionally find a patient who is unresponsive to any medical therapy and maintains platelet counts of only 10–20 × 109/l. In such patients, if a caesarean section is planned for an obstetric indication, we would consider performing a splenectomy at the same time.16 The patient once more has an uneventful birth, but at a follow-up with you 30 days post–partum, platelets are now on two consecutive occasions 20–30 × 109/l. This patient has chronic ITP which warrants initiation of treatment, since the current platelet counts are < 30 × 109/L. The second line of treatment will be either azathioprine (2–3 mg/kg/day) or dapsone (1–2 mg/kg/day). Corticosteroids at 0·5 mg/kg/day may be added if the patient is clinically symptomatic with mucocutaneous bleeding. Either azathioprine or dapsone should be given for a period of 3–6 months before considering therapy to have failed; if there is a failure of one drug, the other can still be considered. If the patient is a non-responder to both azathioprine and dapsone, initiation of further therapy will be dependent upon clinical signs and symptoms and the platelet count. If the platelet count is stable around 30 × 109/l with no clinical features of bleeding, the patient could be kept on close follow-up till a further drop in the platelet count or the development of clinical manifestations of bleeding. If there is a need for further therapy, there would be a detailed discussion with the patient regarding surgical versus non-surgical options. My personal preference would be for a splenectomy since published data from our centre show long-term remission rates of 70% with 5- and 10-year overall survival of > 90%. This is a one-time procedure and cheaper than most of the other therapeutic options that can be offered. In patients who are not willing to have a surgical procedure, further treatment options will depend upon economic resources. If there are resource constraints, one can consider danazol or pulse cyclophosphamide. If there are no resource constraints, options available would include the use of four doses of rituximab or the TPO-RAs – eltrombopag or romiplostim. Generic romiplostim is presently available in India and is a cheaper option that can be considered.17 It is reasonable to regard this as an acquired bleeding disorder due to the lack of previous symptoms and the absence of information on family members with bleeding disorders. There is no suggestion of other medical conditions underlying the findings (acute conditions like sepsis with disseminated intravascular coagulation or pre-eclampsia/HELLP syndrome, chronic manifestations suggestive of collagenosis, or peripheral blood changes with signs of microangiopathy or a malignant haematological disease). According to the finding of normal blood counts apart from thrombocytopenia, we would diagnose ITP after having tested the patient for human immunodeficiency virus (HIV) and hepatitis C infection. Pregnancy unnoticed by the patient is unusual and I assume that it is very early, in which case the thrombocytopenia is most likely to be unrelated. Gestational thrombocytopenia occurs much more frequently than ITP, but usually later and very rarely, if ever, with such low counts. Since the only bleeding manifestation is petechiae, the patient has serious, but not life-threatening ITP. The initial therapy would be corticosteroids. Two regimens could be suggested: prednisolone 1 mg/kg/day, tapered after some weeks, or dexamethasone 40 mg, fixed dose, for 4 days, for one–three courses. The latter is increasingly popular here in 'common' ITP, even though there is no firm evidence of the superiority of dexamethasone over prednisolone in ITP with regard to overall response.18 A lower prednisolone dosage, (0·25 mg/kg/day), has been investigated in ITP,19 but not recently. Dexamethasone confers a much higher steroid exposure to the fetus, and its use in the first trimester has been suggested as a risk factor for cleft palate. However, a very large Danish cohort study, involving 832 636 live births, did not find an increased risk of cleft palate in the infants of women who were prescribed corticosteroids.20 Nevertheless, as a precaution, I would use prednisolone 1 mg/kg/day, and taper as soon as possible, thus minimizing the exposure – with the additional benefit of minimizing more obvious disadvantages of steroids in the pregnant patient. After a satisfactory effect of the therapy you instituted and an uneventful birth of a healthy boy, she is without symptoms for 3 years, when she seeks your advice because she is planning to become pregnant. The information on the patient allows for both the possibility that she had had a single ITP episode or that she has mild chronic ITP. This problem must be unravelled before counselling and planning, but in both cases, I would encourage the patient to proceed with her plans. There is a significant risk of relapse/progression in the case of a further pregnancy,3 but I would be reluctant to give an accurate number. There is no indication for pre-emptive therapy. Hence, monitoring of the platelet count at regular intervals, for example once a month, is indicated in order to avoid undetected relapse at a crucial time point of the pregnancy. After the patient succeeds in becoming pregnant, she once more displays a pronounced drop in platelet counts, this time to 58 × 109/l, but without symptoms or signs of bleeding. After you institute the initial therapeutic option again, you discover that its effectiveness is not nearly as pronounced as the first time with platelet counts increasing only to 70–90 × 109/l. I would probably not institute any therapy in this situation. The level of the platelet count (58 × 109/l) is safe,1, 21 and there is no bleeding tendency. I would probably arrange more frequent monitoring. The patient should be informed that epidural anaesthesia requires a platelet count over 80 × 109/l. Most obstetrical manoeuvers, including caesarean section, and perhaps excluding vacuum extraction and scalp electrodes, can be performed with platelet counts over 50 × 109/l.21 Let us assume that the platelet count later dropped below 20 × 109/l, and that the patient then started the same regimen of corticosteroids as before. Moreover, that the maximum response was 90 × 109/l, and that the count dropped significantly when the prednisolone dose was reduced to 40 mg/day. Under such circumstances, the peripartum bleeding risk is significant and the steroid exposure is expected to be high, depending on the scheduled time of delivery. However, none of the novel, second line medical interventions is attractive, because of the lack of experience, except for high-dose IvIg, which would be my choice. This intervention needs to be repeated every 3 weeks, it is quite expensive, might be a challenge due to expansion of the plasma volume and is burdened with the risk of haemolytic anaemia and complicating aseptic meningitis. Hence, I would discuss the option of splenectomy with the patient. The chance of a remission lasting for 5 years is about 70%, even allowing for additional pregnancies. Laparoscopic splenectomy confers minimal risk to otherwise healthy individuals. The optimum timing is the second trimester. Medical alternatives could be a TPO-RA and rituximab, which would have a quite high rate of success. However, very few cases have been reported, and fetal risk estimates, would thus, be unreliable. Both drugs cross the placental barrier and the fetus would, therefore, be exposed to the 'physiological' side effects of the drugs, megakaryocyte hyperplasia and B-cell depletion. The time to response, often several weeks, needs to be taken into consideration in this specific clinical context. Oral immunosuppressants, such as azathioprine and mycophenolate mofetil, are regarded as safe in pregnancy, but their success rate is uncertain and the response is expected to be late. A British retrospective study of ITP in pregnancy in a 20 month cohort of 107 pregnancies reported uniformly successful outcome, with manageable post-partum haemorrhage (defined as > 500 ml blood loss) being the only problem.10 Eighty per cent of patients received medical therapy, either corticosteroids, IvIg or both. One patient received azathioprine and one anti-D immunoglobulin; the latter is not available in Denmark. The need for therapy beyond corticosteroids and IvIg seems to be minimal. The patient once more has an uneventful birth, but at a follow-up with you 30 days post-partum, platelets are now on two consecutive occasions 20–30 × 109/l. In this situation, I would probably stay calm. In case of deterioration and/or bleeding, I would need to know whether the patient is breastfeeding and wants to continue that. If so, the options are restricted, as during pregnancy. You may speculate that rituximab and romiplostim probably will be inactivated and not absorbed from the child's gastrointestinal channel. If the spleen was not removed during pregnancy, you now have more reasons to consider splenectomy, and if it was removed, you may consider investigating the patient for accessory spleens that could be eliminated. If the patient is not breastfeeding, the use of steroid-saving immunosuppression, preferably rituximab, or of a TPO-RA is feasible. Provan et al. recently published an updated international consensus report on ITP in which medical therapy beyond corticosteroids1 and IvIg was classified as having 'robust' evidence (TPO-RAs rituximab, and fostamatinib) or 'less robust' evidence (other immunosuppressants, danazol and vinca alkaloids). The need for 'less robust' evidence drugs in Denmark is minimal, but admittedly, these drugs have a long record of usefulness and are far less expens