The influence of t(v;22) sole, major route ACAs all (+8, n = 14; +Ph, n = 10; +19, n = 1), and -Y sole on progression-free survival. Survival curves are compared with those of patients with the standard t(9;22) translocation. Other ACAs or complex karyotypes did not influence survival.

Background: In chronic myeloid leukemia (CML), DNA-based measurable residual disease (MRD) analysis—either combined with RNA MRD (Machova Polakova et al. Leukemia 2020) or with characterization of DNA-positive cell subtypes (Pagani et al. Blood 2023)—has demonstrated predictive value for treatment-free remission (TFR). These strategies form the basis of the TFR traffic light stratification model, previously described in patients undergoing direct tyrosine kinase inhibitor (TKI) cessation. Aim: This study evaluated the applicability of the DNA-/RNA-based TFR traffic light model in a structured, two-step TKI dose de-escalation protocol prior to cessation, as implemented in the HALF trial (NCT04147533). Methods: Between 2020 and 2023, 95 of 207 patients enrolled in the HALF trial underwent genomic breakpoint characterization and optimization of BCR::ABL1 DNA digital PCR assays. To date, DNA and RNA MRD assessments were performed in 83 patients, generating 1,222 paired samples. MRD was monitored throughout the two de-escalation phases: (1) halving the TKI dose for six months, followed by (2) alternate-day dosing for an additional six months. Patients maintaining major molecular response (MMR) proceeded to TKI cessation. Results: At the end of phase 1, 83 patients were stratified as follows: 29 double-negative (green), 26 DNA⁺/RNA⁻ (yellow), and 28 double-positive (red). After phase 2, MRD status shifted to 31 green, 19 yellow, and 33 red. Only red-group patients relapsed during phase 2 (n = 7). By 24 months post-enrolment, MRD dynamics continued to evolve. In the yellow group, 11/19 progressed to double-positive (4 relapsed); 1 reverted to green. Among green patients, 6 converted to red (3 relapsed), and 2 to yellow. In the red group, 11 remained unchanged; 14 relapsed; and 1 improved to yellow. Stratification by MRD status at 12 months significantly predicted molecular recurrence-free survival (MRFS) at 18 months (i.e., 6 months post-TKI cessation): red group, 39% MRFS (HR: 9.71; 95% CI: 2.87–32.78; p = 0.00025); yellow group, 87% MRFS (HR: 1.68; 95% CI: 0.34–8.34; p = 0.56); green group, 90% MRFS. This stratification remained consistent at 36 months (i.e., 24 months post-TKI cessation): red group, 36% MRFS (HR: 8.10; 95% CI: 2.77–23.69; p = 0.00013); yellow group, 74% MRFS (HR: 2.12; 95% CI: 0.57–7.91; p = 0.26); green group, 87% MRFS. Conclusion: Persistent RNA positivity (double-positive MRD) is significantly associated with molecular relapse both during phase 2 of TKI dose reduction and after TKI cessation. DNA MRD analysis is essential to distinguish truly MRD-negative (green) patients from those with DNA⁺/RNA⁻ status (yellow), who carry an intermediate risk of relapse. Importantly, in yellow-group patients, the emergence of RNA expression during either phase of dose reduction indicates an increased risk of relapse. In such cases, we recommend returning to the previous TKI dose rather than proceeding to cessation. For green-group patients, the appearance of DNA positivity should prompt close monitoring, and any subsequent RNA positivity should be considered a warning sign to resume reduced-dose or full-dose TKI therapy. Overall, the two-step TKI de-escalation strategy, when combined with integrated DNA/RNA MRD monitoring in RNA-negative patients through regular follow-up, may reduce the risk of molecular relapse and improve patient selection for safe TKI discontinuation. Supported by Ministry of Health of the Czech Republic NU22-03-00136, MH CZ – DRO (IHBT 0002373), National Institute for Cancer Research Project (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the EuropeanUnion - Next Generation EU

Overall survival of patients classified according to the European LeukemiaNet 2020 classification. Chronic phase (CP), accelerated phase (AP), blast crisis (BC), low risk (LR), intermediate risk (IR), high risk (HR).

AbstractBackgroundTo evaluate the outcomes of first‐line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML‐CP) in real‐world clinical practice.MethodsA propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated.ResultsNilotinib‐treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib‐treated patients. However, there was no significant difference in 5‐year overall survival (OS) or progression‐free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib‐treated patients had a higher failure‐free survival (FFS) and event‐free survival (EFS) than imatinib‐treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025).ConclusionsThis retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

Background For decades, CML has been considered to be a triphasic disease recognizing 3 distinct stages: chronic phase (CP), accelerated phase (AP), and blast crisis (BC). Since the discovery of TKIs, the prognosis of CML patients has rapidly improved and less than 10% of patients diagnosed in CP experience disease progression on the therapy. Based on low incidence of CML progression and the fact that CML biological behavior seems biphasic, the new WHO 2022 classification of CML deemed AP less relevant and suggested the omission of AP. Many experts, however, still advocate for its inclusion in CML classification (e.g. ELN 2020, ICC 2022, NCCN 2023), even though the universal definition of AP is not established and differs in between publications. Methods This retrospective, real-world study is based on the Czech nationwide CML registry INFINITY with the data of newly diagnosed CML patients who agreed and provided their written consent. Recruited subjects were adult patients diagnosed in years 2005 - 2022 with sufficient data to determine the phase of the disease at diagnosis and follow-ups to assess their overall survival (OS), disease specific survival (DSS) and progression-free survival (PFS). The phase of the disease at the time of diagnosis was determined using the classification according to ELN 2020, ICC 2022, WHO 2016, and WHO 2022. Whenever CP was established, EUTOS Long-Term Survival (ELTS) score was calculated, assigning the patient to low risk (LR), intermediate risk (IR) and high risk (HR) group. OS and PFS are defined according to published guidelines. DSS is defined as the time from diagnosis to death due to CML disease or CML treatment. Results During the studied time period, 1660 new cases of CML were reported in INIFINITY registry. Of them, 1500 patients had data sufficient to classify the phase of the disease at the time of the diagnosis according to ELN 2020 guidelines and WHO 2022 classification and 1395 patients had data to assess the phase according to WHO 2016 and ICC 2022 classifications. When using ELN 2020 guidelines, groups were assigned as follows: LR CP- 784 patients (52.3%), IR CP- 421 patients (28.1%), HR CP- 227 patients (15.1%), AP- 42 patients (2.8%), BC- 26 patients (1.7%). There were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, there were no significant differences. Calculated estimates of 5- and 10- year OS, respectively, were 92.5% and 87.2% for LR CP, 83.5% and 65.9% for IR CP, 76.9% and 65.5% for HR CP, 59.2% and 45.9% for AP, and 32.9% for BC, p= 0.031 for HR CP versus AP (Figure 1). In the case of WHO 2016 and ICC 2022 classifications, 714 (51.2%) patients were diagnosed in LR CP, 374 (26.8%) in IR CP, 154 (11.0%) in HR CP, 125 (9.0%) in AP, and 28 (2.0%) in BC. Again, there were significant differences in representation by gender, age, comorbidities and performance score amongst patient groups. When comparing just HR CP and AP CML patients, only age at the time of diagnosis was significantly different. Calculated estimates of 5- and 10- year OS, respectively, were 93.2% and 87.5% for LR CP, 84.9% and 67.7% for IR CP, 80.0% and 69.5% for HR CP, 65.7% and 55.6% for AP, and 39.7% for BC. We also performed propensity score matching according to age for patients in HR CP and AP and calculated estimates of 5- and 10- year OS, respectively, were 85.4% and 74.4% for HR CP and 60.2%, and 52.0% for AP, p= 0.003 (Figure 2). Similar results were obtained when testing for PFS and DSS. Summary Real-world data obtained from 1500 patients diagnosed in Czechia over 17 years, in our opinion, support the need to recognize the existence of AP at the time of diagnosis, even though a singular definition of AP is not agreed upon. Patients in AP have worse survival scores (OS, DSS, PFS) compared to patients in CP and/or HR CP. Moreover, because ELTS risk score was calculated on patients in CP, it may not be suitable for patients in AP, which would be changed to CP according to the new WHO 2022 classification. In conclusion, based on the real-world data with long-term follow-up, we believe it would be reasonable to keep the AP as part of CML classification of newly diagnosed patients. This publication was supported by the grant number MUNI/A/1224/2022, Programme EXCELES, ID Project No. LX22NPO5102, and by the Ministry of Health of the Czech Republic grant number 00023736.

Background: Stopping TKI treatment in patients with CML is getting more frequent but many questions remain unanswered. It is not even known the proportion of patients who do not actually want to stop the TKI treatment although they are in the long-term deep molecular response. Aims: To determine how many patients with CML in deep molecular response do not wish to stop TKI treatment. To explore any differences between the cohort of patients that agree and disagree with TKI stopping. To evaluate the reasons for the decision not to stop TKI treatment. Methods: In Czechia, by law, the care for adult CML patients is centralized into eight centres. All the centres collaborate within the Czech Leukemia Study Group for Life (CELL) and contribute to the detailed database of CML patients. The Czech nation-wide clinical trial HALF (ClinicalTrials.gov Identifier: NCT04147533), which started in June 2020, tests to stop TKIs in CML patients after the two-step dose reduction. The TKI stopping in the clinical trial HALF is being offered to all suitable CML patients in Czechia. An integral part of the clinical trial was the questionnaire Anti-HALF. All patients who did not want to enter the HALF project were asked to complete this questionnaire. Anti-HALF consists of 20 questions regarding sex, age, occupation, socioeconomic status, TKI therapy and its side effect, compliance, and finally, the reasons for decision not to stop the TKI. The project Anti-HALF was finished at the end of 2022, the HALF project continues. Results: In June 2020, the number of living patients with CML registered in CELL database was 1751. By the end of 2022, the stopping of TKI treatment was offered to 246 of them (14%/1751 pts); 190 of 246 pts (77.2%) were enrolled (HALF patients, H pts), 45 (18.3%) did not want to participate, but completed the Anti-HALF questionnaire (Anti-HALF patients, AH pts), and 11 (4.5%) refused even to complete the survey. There were 143 H pts vs. 36 AH pts on imatinib, 31 H pts vs. 9 AH pts on nilotinib, and 16 H pts vs. 0 AH pts on dasatinib. AH pts were more frequently of female sex (64.4% vs. 46.8%; p=0.046), elderly (median 67.5y vs. 61.8y; p =0.0342), more frequently retired or unemployed (75.6% vs. 54.5%; p=0.0171) and with already reduced dosing of imatinib (55.6% vs. 34.3%; p=0.0223). The factors which did not seem to play a role were the type of TKI and, unexpectedly, the presence of subjective side effects, or the average distance to travel to treating physician. The AH pts took longer their current TKI, but this difference had a borderline statistical significance (median 9.2y vs. 8.0y; p=0.0764). The AH pts were minimally or not stressed during the regular follow up (82.2%), they felt the TKI as effective and safe treatment (57.8%), were very compliant (80.0%), mostly without any subjective side effects of TKI (62.2%). The decision to enter or not the trial was rather difficult for AH pts (53.3%), with serious concern about the disease recurrence (62.2%) and less effective re-treatment (55.6%). Summary/Conclusion: Surprisingly, there is a high proportion of patients with CML who do not wish to stop TKI treatment despite fulfilling the generally accepted stopping criteria. We believe that this is clinically important and so far underexplored phenomenon deserving further study, and this fact has to be taken into the account when counselling the patients. Detailed data will be presented. Supported by the national budget through MEYS, RI CZECRIN (LM2018128) and from ERDF Project CZECRIN_4 PATIENTS (CZ.02.1.01/0.0/0.0/16_013/0001826) and by Ministry of Health of the Czech Republic, grant no. NU22-03-00136 and by National Institute for Cancer Research Project (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the EuropeanUnion - Next Generation EU. Keywords: Tyrosine kinase inhibitor, treatment-free remission, Chronic myeloid leukemia

Background: Low – dose fludarabine, cyclophosphamide, and rituximab (LDFCR) regimen showed promising activity in treatment-naïve elderly / comorbid patients (pts) with chronic lymphocytic leukemia (CLL) (Smolej et al., Br J Haematol. 2021). However, no data are available regarding comparison to bendamustine and rituximab (BR), which has been one of the predominant first - line options for CLL patients ineligible for full – dose FCR. Aims: To perform a historical comparison of the efficacy and safety of LDFCR and BR regimens used as the first - line therapy of CLL within routine practice. Patients with 17p deletion and/or TP53 mutation were not included in this analysis because chemoimmunotherapy is no longer indicated in this extremely unfavourable subgroup due to very low activity. Methods: The analysis included 237 pts treated with LDFCR and 320 pts treated with BR (median age, 69 vs 70 years; males, 70 vs 61%; median CIRS score, 6 vs 7; Rai stage III/IV, 57 vs 59%; bulky lymphadenopathy > 5cm, 35 vs 35%; unmutated IGHV, 74 vs 70%, deletion 11q, 28 vs 26%) treated between March 2009 and December 2019 at 17 centers cooperating within the Czech CLL Study Group. LDFCR consisted of fludarabine 20 mg/m2 orally or 12 mg/m2 on days 1-3, cyclophosphamide 150mg/m2 orally or iv on days 1-3, and rituximab 500 mg/m2 D1 (375 mg/m2 in Cycle 1). BR included bendamustine 90 mg/m2 iv on days 1-2 and rituximab 500 mg/m2 D1 (375 mg/m2 in Cycle 1). Median follow – up was 98 months for LDFCR and 57 months for BR. Results: Distribution of demographic data and prognostic factors was comparable between LDFCR and BR groups. The overall response rate / complete remissions were similar for LDFCR vs BR (84/46% vs. 88/51%, p=n.s.). The median progression – free survival (PFS) was 30 vs 34 months (hazard radio [HR] 0.90; p=n.s.); PFS was markedly longer in pts with mutated IGHV and absence of del 11q (LDFCR vs BR, median 58 vs 59 months, HR 0.84; p=n.s.; Fig. 1a). Median overall survival (OS) was 73 vs 77 months for LDFCR vs BR (HR 1.09; p=n.s.) but markedly longer (median 116 months vs not reached) in patients with mutated IGHV without del 11q (HR 0.90; p=n.s.; Fig. 1b). Grade ≥ 3 neutropenia occurred in 55% (LDFCR) vs 51% (BR) pts but serious infections developed in 15% vs 20% pts only. Image:Summary/Conclusion: Our data indicate that both low-dose FCR and BR are well – tolerated regimens with similar efficacy and safety and represent a suitable first - line treatment alternative for elderly / comorbid CLL patients with favourable biological prognosis. Detailed results including multivariate analysis will be presented.

SummaryTherapeutic options used to be very limited for treatment‐naïve elderly/comorbid patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) before the introduction of chemo‐immunotherapy. Because dose‐reduced fludarabine‐based regimens yielded promising results, the Czech CLL Study Group initiated a prospective observational study to assess safety and efficacy of low‐dose fludarabine and cyclophosphamide combined with rituximab (FCR) in elderly/comorbid patients. Between March 2009 and July 2012, we enrolled 107 patients considered ineligible for full‐dose FCR (median age, 70 years; median Cumulative Illness Rating Scale score, 5; median creatinine clearance, 69 ml/min). Notably, 77% patients had unfavourable biological prognosis [unmutated immunoglobulin heavy‐chain variable‐region gene (IGHV), 74%; deletion 17p, 9%). Fludarabine was reduced to 12 mg/m2 intravenously (iv) or 20 mg/m2 orally on days 1–3 and cyclophosphamide to 150 mg/m2 iv/orally on days 1–3. Grade 3–4 neutropenia occurred in 56% of the patients, but there were serious infections in only 15%. The median progression‐free survival was 29 months, but was markedly longer in patients with mutated IGHV (median 53 months), especially in absence of del 11q or 17p (median 74 months). Low‐dose FCR is a well‐tolerated and effective first‐line regimen for selected elderly/comorbid patients with CLL/SLL with favourable biology. The study was registered at clinicaltrials.gov (NCT02156726).

Background. Treatment-free remission (TFR) has become a new treatment goal for chronic myeloid leukemia (CML) patients. However, usually abrupt tyrosine kinase inhibitors (TKIs) therapy discontinuation has been successful only in about half of eligible patients and it can cause burdening TKI withdrawal syndrome (TWS) in about 30% of them. Moreover, any robust clinical or biological factor predictive for successful TFR has not been identified yet. On top of that, sustainable deep molecular response (DMR) as the main prerequisite for TKI discontinuation attempt is achieved only in 20-40% of patients. The majority of CML patients, therefore, need to be treated with the effective and well-tolerated drug for a long time or even life-long. Study design and methods. With the recognition of all these aspects, we designed a nationwide prospective investigator-initiated phase II clinical trial HALF (ClinicalTrials.gov NCT04147533) in order to evaluate efficacy and safety of TKI discontinuation after previous two-step dose reduction in patients with CML in DMR (Fig. 1). Step-wise TKI dose reduction, i.e. half of the standard during the first 6 months after study entry, and the same dose given alternatively (every other day) during the next 6 months, was derived from pharmacokinetics and experimental data as well as from clinical trials' results. We assume that the step-wise and eventually meaningful TKI dose reduction enables a higher rate of patients achieving successful TFR with less pronounce TWS, or even would represent a more reasonable and safer alternative to the complete and sudden TKI interruption. This unique nationwide academic project has been facilitated by hematological patients care centralization in the Czech Republic. A primary study objective is to evaluate the proportion of patients in major molecular response (MMR) at 6 and 12 months and in TFR at 18, 24, and 36 months after the study enrollment, respectively, and molecular recurrence-free survival at all mentioned time points as well. Main secondary and exploratory objectives are: to evaluate the proportion of patients loosing MMR and in whom MMR and MR4.0 would be re-achieved after TKI re-introduction, time to MMR and MR4.0 re-achievement, FFS, PFS, OS, TWS, and QoL assessment, predictive factors for successful TFR identification, quantification of BCR-ABL1 using digital droplet PCR at both the DNA and mRNA levels, immunological profiling, BCR-ABL1 kinetics mathematical modeling, assessment of TKI pharmacokinetics, clonal hematopoiesis and pharmaco-economics. Results. The study was launched in December 2019; however, due to the COVID-19 outbreak, patients' recruitment started on June 16, 2020. Here, characteristics of the first 74 patients included in the study until April 2021 are presented. There were 37 males and 37 females, with median age at the time of diagnosis of 53 years (range, 23-74) and at the time of the study entry of 67 years (range, 35-86). A median time of CML disease, TKI treatment, and DMR duration before the study initiation was as follows: 9.9 years (range, 4.4-22.5), 9.8 years (range, 4.2-20.2), and 7.3 years (range, 3.2-18.3), respectively. The ELTS score was low, intermediate, high and unknown in 62.2%, 21.6%, 13.5%, and 2.7% of patients, respectively. At the time of study entry, 58 patients (79.5%) were treated with imatinib, 10 (13.7%) with nilotinib, and 5 (6.8%) with dasatinib, respectively, whereas in 63 patients (86.3%) it was in the first line of therapy. With almost half of patients (48.6%), the TKI dose was already reduced at the time of study entry. With 10 (13.5%) patients, interferon-α treatment preceded TKI administration. At the time of this abstract preparation, on July 26, 2021, altogether 102 patients (from planned 150) have been enrolled in the study; 48 of them (47.1%) have already moved to the second de-escalation phase and 9 (8.8%) patients to the TFR phase. There were 2 cases of confirmed MMR loss (both in month 8 after the study entry) and no patient experienced symptoms resembling TWS. Conclusions. Despite the COVID-19 pandemic, the HALF study was successfully launched and initiated in the majority of centers, with 102 already included patients and continuing intensive enrolment. Based on our very preliminary results, the step-wise dose reduction seems to be an effective and safe approach. More included patients, longer follow-up and further analyses are needed in order to reach all set up objectives. Figure 1 Figure 1. Žácková: Angelini: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Faber: Angelini: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Novartis: Consultancy, Other: conference fees, Research Funding, Speakers Bureau; Pfizer: Other: conference fees; TERUMO: Other: conference fees. Bělohlávková: Novartis: Consultancy; BMS/Celgene: Consultancy. Horňák: Angelini: Honoraria. Svobodník: Roche: Speakers Bureau; Janssen-Cilag: Speakers Bureau. Machová Poláková: Incyte: Consultancy; Angelini: Consultancy; Novartis: Research Funding. Mayer: Principia: Research Funding.

Observational study in comorbid patients with CLL receiving first-line rituximab-bendamustine, Observational study in comorbid patients with CLL receiving first-line rituximab-bendamustine

We retrospectively evaluated the role of age and dosage in 372 CML patients (170 women, 202 men) treated with first-line imatinib (IMA) from the records of the CAMELIA registry. The median follow-up of the patients was 82.3 (18.0-177.3) months. The treatment results of 80 elderly patients aged over 65 years at diagnosis were compared in analysis "A" with those of 292 younger patients and in analysis " B" with those of 90 patients younger than 40 and 202 patients aged 40-64. The elderly patients had statistically adverse values of the Sokal, ELTS, and ECOG scores and Charlson comorbidity index in both analyses (p from= 0.012 to <= 0.001). Despite a more frequent use of a daily dose lower than 400 mg - in 31 elderly patients (38.8%) than in 45 younger ones (15.4%) (p < 0.001), there were no statistically significant differences in the achievement of optimal haematological, cytogenetic, and molecular responses according to the ELN criteria in both the analyses, A and B. The comparisons of overall survival with CML-related death (OSCML) and event-free survival (EFS) were insignificant inanalysis A (p = 0.07 and 0.396, respectively) but progression-free survival (PFS) differed significantly (p = 0.007). In analysis B OSCML and PFS differed significantly (p = 0.027 and 0.003) but EFS was similar (p = 0.351). Elderly patients with a sustained dose of IMA of 400 mg/day have insignificantly better OS, PFS, and EFS compared to patients treated with a lower dosage of IMA. The results in the treatment of the elderly CML patients were comparable with those of the younger ones in terms of the probabilities of the achievement of optimal ELN responses. However, the results for the survival probabilities were influenced by age and the IMA dosage.

Patients with newly diagnosed chronic myeloid leukemia (CML) frequently receive imatinib. Although initial response rates are high, imatinib fails in up to 40% of patients because of disease resistance, frequently because of BCR-ABL kinase domain mutations, or side effects. Patients who discontinue imatinib may have a response to second-generation tyrosine kinase inhibitors (TKIs). Ponatinib (PON) is a potent oral TKI active against unmutated and mutated BCR-ABL kinase. PON is indicated also in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) patients. Clinical activity of PON was confirmed in the phase II PACE trial, however lack of real world data is evident. The aim of this non-interventional study was to analyze data on PON treatment and its efficacy in the Czech patients with CML / Ph+ ALL. The study was designed as a one-off retrospective data collection from 3 national registry databases INFINITY, CAMELIA and DATOOL ALL in the period 2014-2018. In total, the study comprised 27 patients treated with PON at 7 centers; 16 (59.3%) patients were treated for chronic phase (CP) CML, 4 (14.8%) patients for accelerated- or blast-phase (AP/BP) CML and 7 (25.9%) patients for Ph+ ALL. The 16 CP CML patients (68.8% males) had median age at the start of PON treatment 59.7 years (range 28.6-81.4), were heavily pretreated (75% with ≥ 3 TKIs) with median time from diagnosis to start of PON treatment 4.8 (0.2-16.8) years; 37.5% of them had mutations (18.8% with T315l), 75.0% had comorbidities. The 11 AP/BP CML / Ph+ ALL patients (54.5% males) were younger with median age 56.6 (31.2-74.7) years, were less pretreated (36.4% with ≥ 3 TKIs) with a shorter time from diagnosis to start of PON treatment 2.0 (0.4-22.0) years; almost twice as many (72.7%) of them had mutations (54.5% with T315l), 63.6% had comorbidities. The most common reason for switching to ponatinib was hematologic resistance (37.5% of CP CML and 54.5% of AP/BP CML / Ph+ ALL patients). The other most frequent indications were cytogenetic resistance, non-hematologic and hematologic intolerance (18.8%, 12.5% and 12.5% of CP CML patients and 9.1%, 9.1% and 0% of AP/BP CML / Ph+ ALL patients, respectively). Interestingly, starting dose of PON was 45 mg/day as recommended in the product SmPC only in of about half of the patients (43.8% of CP CML and 54.5% of AP/BP CML / Ph+ ALL patients). Median treatment duration was 16.1 (0.8-49.9) months in CP CML patients and only 2.9 (0.2-36.1) months in AP/BP CML / Ph+ ALL patients. Early (in the first 3 months) and late termination of the treatment occurred in 12.5% and 31.3% of CP CML and 54.5% and 27.3% of AP/BP CML / Ph+ ALL patients, respectively. Disease progression was the major reason for treatment termination (50%). In terms of safety, only 1 patient discontinued therapy due to congestive heart failure, and 1 due to vascular adverse event although more than half of the patients had cardiovascular comorbidities and history of cardiovascular disease. PON efficacy was evaluated in 14 CP CML patients and 5 AP/BP CML / Ph+ ALL who were treated beyond 3 months (Figure 1). More than half of CP CML patients achieved MMR (57.1%) and 40% of AP/BP CML / Ph+ ALL achieved undetectable disease. Estimated percentage of CHR, CCyR and MMR in CP CML patients after one year of treatment was 85.7%, 50% and 50%, respectively. Nevertheless, 5 (35.7%), 2 (14.3%) and 1 (7.1%) patients had CHR, CCyR and MMR at start of PON treatment, respectively. In AP/BP CML / Ph+ ALL patients, estimated percentage of CR and CMR after one year was 100% and 40%, respectively. However, 2 patients (20%) had CR at the start of PON treatment. Despite limited number of patients, our analysis confirmed PON efficacy in real-life setting with a significant proportion of heavily pre-treated patients achieving durable molecular responses in both CP and AP/BP CML / Ph+ ALL groups. Our data are comparable to the PACE trial results. This study partially fills the gap in RWE data and significantly contributes to the evaluation of real-life clinical practice in rare disease area. Figure 1. Cumulative incidence of responses on ponatinib treatment in A) CP CML (N=14) and B) AP/BP CML / Ph+ ALL (N=5) patients that continued ponatinib treatment beyond 3 months. Figure 1 Disclosures Žáčková: Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Angelini: Consultancy; Incyte: Consultancy. Kellnerová:Angelini Pharma: Employment.

Lenalidomide therapy represents meaningful progress in the treatment of anemic patients with myelodysplastic syndromes with del(5q). We present our initial lenalidomide experience and the positive effect of combining erythropoietin and steroids with lenalidomide in refractory and relapsed patients. We treated by lenalidomide 55 (42 female; 13 male; median age 69) chronically transfused lower risk MDS patients with del(5q) (45) and non-del(5q) (10). Response, meaning transfusion independence (TI) lasting ≥ eight weeks, was achieved in 38 (90%) of analyzed patients with del(5q), of whom three achieved TI only by adding erythropoietin ± prednisone. Another five patients responded well to this combination when their anemia relapsed later during the treatment. In the non-del(5q) group only one patient with RARS-T reached TI. Cytogenetic response was reached in 64% (32% complete, 32% partial response). The TP53 mutation was detected in 7 (18%) patients; four patients progressed to higher grade MDS or acute myeloid leukemia (AML). All seven RAEB-1 patients cleared bone marrow blasts during lenalidomide treatment and reached complete remission (CR); however, three later progressed to higher grade MDS or AML. Lenalidomide represents effective treatment for del(5q) group and combination with prednisone and erythropoietin may be used for non-responders or therapy failures.

In 2008, the WHO combined the former categories RCMD (refractory cytopenia with multilineage dysplasia) and RCMD-RS (ring sideroblasts ≥15%). We studied the clinical impact and genetic background of RARS, RCMD, and RCMD-RS in 1082 patients. Good karyotypes (IPSS) were similarly frequent in RARS, RCMD, and RCMD-RS. 2-year overall survival (OS) rates were similar in RARS, RCMD, and RCMD-RS (85.9%/89.0%/91.7%; n.s.). The 2-year OS rate was better in good than intermediate or poor karyotypes (p < 0.001). These results support to combine RCMD and RCMD-RS as performed by WHO and emphasize the prognostic power of cytogenetic criteria for these MDS subtypes.

Controversies still exist regarding definition of the thrombotic risks in Ph- (BCR/ABL1-) myeloproliferative disorders with thrombocythemia (MPD-T). Platelet counts at diagnosis are currently not taken as a risk factor of thrombosis. In our cohort of 1179 patients with MPD-T, prospectively registered for anagrelide treatment, we found that the median platelet count prior to the thrombotic event was significantly higher than at time points without any ensuing thrombosis (453 vs. 400 × 10(9)/L, P < 0.001), albeit higher platelet counts at diagnosis tended to be connected with fewer thrombotic events (in contrast to WBC counts at diagnosis). The JAK2(V617F) mutation predicted both arterial and venous events, while age >65 yr, hypertension, diabetes mellitus, smoking, elevated triglyceride and homocysteine levels predicted arterial events only. For venous events, the specific thrombophilic risk factors (factor V 'Leiden' and others), antiphospholipid antibodies, and elevated factor VIII levels played a major role. During anagrelide treatment (± aspirin), we documented a decrease in both venous (6.7-fold) and arterial events (1.8-fold), while bleeding (mostly minor events) increased twofold compared to history. Our results suggest that keeping platelet counts at low levels may be a meaningful therapeutic measure to prevent thrombosis, although their counts at diagnosis lack any prognostic value.