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Eculizumab is an antibody targeting the C5 complement protein. Clinical trials suggest that eculizumab significantly reduces transfusion requirements and prevents disease complications in patients with paroxysmal nocturnal hemoglobinuria (PNH).To analyze the outcome of pregnancies among Polish women with PNH treated with eculizumab as a part of the Polish National Health Fund program.We report the outcomes of 3 pregnancies among women treated with eculizumab between 2017 and 2020. For 1 of these woman, it was the 1st pregnancy, while the remaining 2 patients had previously had 1 previous successful pregnancy each.All 3 mothers survived pregnancy, and all children were born alive. One of the patients had a vaginal delivery. Another required cesarean delivery at the 34th week due to a decreasing platelet count. In 1 case, premature rupture of the fetal membranes occurred at week 36, followed by artificial labor induction. All children were born without any inborn defects. The 2 prematurely born babies required a prolonged hospital stay.Treatment with eculizumab seems to reduce the risk to a mother and a child associated with PNH. However, more data are necessary to confirm this notion.

Systemic mastocytosis (SM) is a rare hematological malignancy characterized by an abnormal expansion and accumulation of pathological mast cells in bone marrow and other organs including skin, liver, spleen and lymph nodes. The clinical manifestation can be extremely heterogeneous, from limited skin changes to multi-organ involvement or mast cell tumors. The median survival of patients diagnosed with indolent form is comparable to healthy population, while prognosis for patients with advanced disease is poor, with an estimated survival ranging from several months to several years. In most patients (> 90%), a somatic mutation in codon 816 of the c-KIT gene encoding tyrosine kinase receptor is detected. Additional molecular abnormalities and even coexistence of other hematological cancers, e.g . acute leukemia, are also observed. Regardless of the form of disease or serum tryptase concentration, patients are exposed to symptoms resulting from the release of mast cell mediators — most often itching, paroxysmal redness and blisters, and general mediator-induced symptoms — such as nausea, vomiting, diarrhea, abdominal pain, hypotensive episodes, fatigue, headache, fever, shortness of breath, osteopenia, osteoporosis and severe anaphylactic reactions. This paper presents current outlook on the diagnostic and treatment process of SM, taking into account the interdisciplinary aspects of the disease.

Background/aim To study the long-term clinical efficacy and tolerability of ibrutinib monotherapy in real-world relapsed and refractory chronic lymphocytic leukemia (RR-CLL) patients outside clinical trials. Patients and methods Clinical data of 171 RR-CLL patients treated with ibrutinib were collected within the observational study of the Polish Adult Leukemia Study Group. Results Median patient age was 64 years. Patients were pretreated with 3 (1-10) median lines of therapy, while 42 (24.6%) had 17p deletion. The median observation time was 40 months (range=1-59 months), while median ibrutinib monotherapy reached 37.5 months (range=0.4-59.2 months). Response was noted in 132 (77.2%) patients. The estimated 5-year progression-free survival (PFS) and overall survival (OS) rates were 61.1% (95%CI=49.3-70.9%) and 56.8% (95%CI=45.6-66.6%), respectively. At the time of analysis 97 (56.7%) remained under ibrutinib monotherapy. Conclusion Ibrutinib is clinically effective and tolerable as a monotherapy in real-world RR-CLL patients.

Metabolic and water-electrolyte disorders occur in hematologic malignancies and arise from the disease itself as well as anti-cancer treatment. The most common metabolic and electrolyte complications include: hyperuricemia and tumor lysis syndrome, hyperammonemia, metabolic acidosis, syndrome of inappropriate antidiuretic hormone, hyponatremia, hypercalcemia, hypokalemia and disorders of carbohydrate metabolism. Co-morbidities, performance status of the patient, type of causative and supportive treatment may contribute to disturbing the metabolic balance of the patient. The article discusses the most common causes of these disorders, their symptoms and treatment.

Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease.

Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4-80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 109/L (23.8-342) with immature progenitors amounting at 27.5% (12-72), haemoglobin 8.6 g/dL (3.9-14.9), and platelet count 66 × 109/L (34-833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia-free survival of 13.3 months (95% CI, 3.6-22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%-29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses.

A dynamic course of hematologic neoplasms as well as intensive chemotherapy are related with development of malnutrition symptoms in a short time. For this reason, it is necessary to perform not only screening procedure but also detailed assessment of nutritional status. The purpose of this research was the assessment of nutritional status and nutritional intervention needs in patients with hematologic neoplasms by PG-SGA score. Most of people (45%) were assigned to category: well malnourished. Next, 43% people were moderately nourished and 11% were severely malnourished. Nutritional intervention was recommended to 83% people, among who 44% indicates a critical need for intervention. The PG-SGA score allows to fully assess actual nutritional status and estimate further changes, what may help to decide on initiation of nutritional therapy.

In Poland, there is a shortage of statistical data regarding neoplasia of hematopoietic system. There is an unmet demand for epidemiological data concerning such cancers stemming from both scientific and health care management reasons. As all medical services for patients with these disorders are reported to the National Health Fund (NFZ) the aim of this study was to use NFZ data for determining incidence and prevalence of neoplasia of myelopoietic part of hematopoietic system in Poland, as well as defining the overall survival (OS) in affected patients. This work was performed under the project ‘Map of healthcare needs — database of systemic and implementation analyses’ co-funded by the European Union Social Fund from the Operational Programme for the Development of Knowledge and Education. The incidence rate in 2014 for acute myeloid leukaemia (AML) was 4.1/100,000 whilst the registered disease prevalence rate was 10.9/100,000. The median OS during 2009–2015 for AML — reported patients was 6 months and the 3- and 5-year OS was estimated as respectively being 26.5% and 23.4%. For chronic myelogenous leukemia (CML) the incidence and disease prevalence rates were 1.0/100,000 and 7.2/100,000 respectively, and those for Philadelphia-negative myeloproliferative neoplasms (MPN Ph–) were 8.9/100,000 and 55.9/100,000 respectively, whilst those for myelodysplastic syndromes (MDS) were 3.8/100,000 and 11.5/100,000 respectively. In patients reported as having CML, the 3- and 5-year OS was 76.2% and 68.1% respectively. In patients reported as having MPN Ph(–), the 3- and 5-year OS was 86.6% and 78.6% respectively. The median OS for patients reported as having MDS was 30 months and the probability of patients achieving 3- and 5-year OS was 45.8% and 36.1% respectively. Data reported to the NFZ for reimbursement of medical services provided seem to be the most reliable concerning such large patient population. Yet, there are still prone to errors arising from the mis-coding of cancers and to limited compatibility of the ICD-10th Revision (International Classification of Diseases) to current World Health Organization classification, Nevertheless, our data are similar to the European and USA registers regarding AML and MDS. However, in the case of MPNs (CML excluding) they require further verification.

Hemophagocytic lymphohistiocytosis (HLH) is a rare condition having a severe clinical course and 50% mortality. Two subgroups of HLH may be distinguished: familial HLH or HLH due to genetic defects and secondary HLH linked to neoplasms, autoimmunological diseases and infections. The case presented is of secondary HLH apparently resulting from bacterial infection. Diagnos­ing HLH is a clinical challenge due to unclear clinical presentation and diagnostic difficulties in histopathogical evaluation. Patients with HLH have non-specific symptoms that may overlap with symptoms of an underlying condition like infections or lymphoma. In the presented case, diagnosis of HLH was delayed due to suspected lymphoma, that was subsequently ruled out. The Histiocyte Society HLH-1994 protocol of treatment was initiated based on dexamethasone, etoposide and cy­closporine A (CsA). A normalization of laboratory markers for HLH was achieved and cytopenia was resolved. Maintenance treatment with CsA was administered, but a recurrence of HLH was noted. The patient was referred to allogeneic hematopoietic stem cells transplantation (allo-HSCT) from the bone marrow of an unrelated donor. The follow up at the +100 day and then subsequently every 3 months after allo-HSCT showed a full hematological recovery and 100% donor chimerism. At present, 20 months after transplantation, total remission of HLH is noted. The patient does not present any adverse events linked to transplantation and is pursuing his professional career.

High-dose methylprednisolone (HDMP) with or without anti-CD20 antibody treatment in the pre B-cell receptor inhibitor (BCRi) era was used as potential salvage therapy for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) patients bearing the 17p deletion.Outcomes were compared in retrospect between r/r patients treated with HDMP (n = 20), ibrutinib (n = 39) and idelalisib with rituximab (n = 14).Higher overall response rates were found in those patients undergoing BCRi therapy compared to HDMP (79.2% vs. 0%; p 0.0001), along with longer median progression-free survival (not reached vs. 24.1 months; p 0.01). Nevertheless, there were no differences in the overall survival (HDMP 35.87 months vs. not reached; p = 0.58).HDMP treatment was significantly inferior in terms of response rate and progression-free survival in r/r CLL/SLL patients with the 17p deletion, and may only be used whenever novel compounds are unavailable.

Bialaczki z duzych ziarnistych limfocytow (LGL) obejmują biologicznie heterogenną grupe rzadkich nowotworow ukladu chlonnego wywodzących sie z limfocytow T (T-LGL) lub z komorek naturalnej cytotoksyczności (NK-LGL). Wydaje sie, ze bialaczka T-LGL powstaje w wyniku dlugotrwalej stymulacji antygenowej, a przezycie komorek LGL jest związane ze stalą aktywacją antyapoptotycznych szlakow wewnątrzkomorkowych JAK/STAT, RAS/RAF/MEK/ERK, sfingolipidow i szlakow zewnątrzkomorkowych, takich jak FAS/FASL. Przebieg kliniczny moze byc rozny — indolentny lub agresywny. U wiekszości pacjentow wystepują objawy kliniczne pod postacią cytopenii, organomegalii o roznym nasileniu, czesto ze wspolistniejącymi chorobami autoimmunizacyjnymi, zwlaszcza reumatoidalnym zapaleniem stawow. Podstawą wspolczesnej diagnostyki bialaczek LGL są cytometria przeplywowa oraz badanie rearanzacji genow kodujących receptor T-komorkowy. Wiekszośc pacjentow wymaga leczenia ze wzgledu na ciezką powiklaną zakazeniami neutropenie. Terapia jest oparta na leczeniu immunosupresyjnym; lekiem z wyboru w I linii jest metotreksat lub cyklofosfamid. Dotychczas nie opracowano standardow postepowania w bialaczce T-LGL. Przewlekle bialaczki T/NK-LGL mają charakter indolentny o korzystnym rokowaniu, natomiast bialaczki agresywne T/NK-LGL są gwaltownie przebiegającymi chorobami o zlym rokowaniu.

OBJECTIVES PALG CLL4 is the first, randomized, phase IIIb study with rituximab, cladribine, and cyclophosphamide (RCC) induction and subsequent maintenance with rituximab in previously untreated chronic lymphocytic leukemia (CLL) patients. METHODS The induction treatment consisted of 6 RCC cycles regimen. Patients with complete response (CR) or partial response (PR) after an induction phase were randomized into a maintenance arm with rituximab or an observational arm. RESULTS In the intention-to-treat population, 97 patients completed the induction phase with an overall response rate (ORR) of 73.2% (CR 22.7%, PR 50.5%). Subsequently, 66 patients were randomized into the rituximab maintenance arm (n = 33) or the observational arm (n = 33). CR rates were 57.1% in the maintenance group vs 50% in the observational group. PFS was significantly longer in the rituximab maintenance vs the observational arm (P = .028). The multivariate Cox model indicated that del17p (P = .006) and elevated beta-2-microglobulin (P = .015) significantly increased the hazard ratio (HR) of progression, whereas the presence of CD38 (P = .013) significantly decreased it; maintenance therapy with rituximab (P

Background/aim There is limited amount of data available on the comparative efficacy of ibrutinib and idelalisib, the B-cell receptor inhibitors (BCRi) newly approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) treatment. The aim of our study was to analyze and compare the outcomes of real-world r/r CLL/SLL patients treated with these two BCRi in outside clinical trials. Patients and methods A comparative case matched 1:2 analysis was performed on idelalisib combined with rituximab and ibrutinib efficacy in 102 patients with r/r CLL/SLL from two observational studies of the Polish Adult Leukemia Group (PALG). Results Both therapies produced similar overall response rates (idelalisib plus rituximab 76.4% and ibrutinib 72.1%). Median progression-free survival (PFS) and overall survival (OS) in both groups were not reached. Furthermore, no significant difference was observed between both BCRi regimens in regard to PFS (HR=0.75, 95% CI=0.30-1.86, p=0.55) and OS (HR=0.65, 95%CI=0.26-1.68, p=0.39). Conclusion In summary, the results of this retrospective analysis suggest that idelalisib combined with rituximab and ibrutinib therapies have comparable activity in r/r CLL/SLL in daily clinical practice.

This prospective study estimated outcomes in 509 elderly patients with acute myeloid leukemia (AML) with different treatment approaches depending on Eastern Cooperative Oncology Group (ECOG) performance status and Charlson Comorbidity Index (CCI). Patients were stratified into fit (ECOG 0–2 and CCI 0–2) or frail (ECOG > 2 and/or CCI > 2) groups. Fit patients with CCI 0 received intensive chemotherapy whilst reduced-intensive chemotherapy (R-IC) was given to those with CCI 1–2. Frail patients received best supportive therapy. Fit patients presented a longer overall survival (OS) than frail subjects, but 8-week mortality rates were similar. The complete response (CR) rate between fit CCI 0 and CCI 1–2 subgroups was significantly different. Both of the fit subgroups showed similar 8-week mortality rates and OS probabilities. Allocating fit patients with CCI 1–2 to R-IC enabled an increase in the group of elderly patients who could be treated with the intention of inducing remission.

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients, the present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend towards higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs 34%; p=0.19), which did not lead to improved median overall survival (OS), which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (p=0.64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; p=0.02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (p=0.02). No differences in hematological and non-hematological toxicity between the DA and DAC regimens were observed. This article is protected by copyright. All rights reserved.

We report three cases of light chain escape (LCE) at a single institution in Poland, including an interesting case of biclonal monoclonal gammopathy of undetermined significance (MGUS) that satisfied the criteria for progression to light chain multiple myeloma (LCMM) with a rapid rise in serum free light chain (FLC) levels, following steroidal treatment for simultaneous temporal artery inflammation and polymyalgia rheumatica (PMR). In the three cases discussed, progression of the disease by light chain escape was associated with rapid and severe renal impairment, highlighting the necessity for prompt detection of such free light chain-only producing clones in order to prevent the possible development of irreversible end-organ damage. Interestingly, monitoring of these three patients by serum free light chain assay (sFLC) and retrospective heavy/light chain analysis (HLC) detected this clonal evolution prior to clinical relapse and suggests that these assays represent important additional tools for more accurate monitoring of multiple myeloma patients.

PIM kinases represent an emerging therapeutic target in multiple hematological malignancies, as exemplified by currently ongoing phase I clinical trials by Astra Zeneca (AZD1208) and Novartis (LGH447) in acute myeloid leukemia and multiple myeloma. Selvita has developed a potent and selective dual PIM/FLT3 mutant kinase inhibitor - SEL24-B489 showing high inhibitory activity on all three PIM kinase isoforms and FLT3 kinase mutants. We have previously reported that PIM kinases are important downstream effectors of FLT3 signaling and play a crucial role in cell survival and inhibition of apoptosis upon expression. Due to heterogeneous nature of AML, dual inhibition of FLT3 mutant kinase and PIM kinases led to improved efficacy of our compound in comparison to selective inhibitors of either PIM of FLT3 kinases. Herewith, we would like to report further progress of characterizing the B489 inhibitor beyond AML. We assessed PIM kinase expression levels in a panel of lymphoid malignancies and found that PIM1 and PIM2 exhibit high expression levels in a fraction of mantle cell lymphoma (MCL), diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma (FL), Hodgkin's lymphoma (HL), chronic lymphocytic leukemia (CLL) and mucosa associated lymphoid tissue-type (MALT) lymphoma cell lines and primary tumors . High levels of PIM kinases were associated with certain established adverse prognostic factors and clinical outcome of the patients and correlated with aggressiveness of the disease in some of these tumors. Inhibition of PIM kinases with tool inhibitors was shown to influence cellular proliferation and, translational inhibition of 4EBP1 as reported in the literature. In addition, SEL24-B489 inhibited NFκB activity and decreased CXCR4 expression. Comparison of SEL24-B489 to competitive PIM inhibitors revealed higher cellular activity and biomarker response, as shown by inhibition of phospho-S6 phosphorylation in sub-microM concentrations. The presented data will further validate SEL24-B489 as a successful example of rational drug design and present a promising therapeutic approach in multiple hematological malignancies, both stand alone and in combination with standard of care and targeted therapies in clinical development. Citation Format: Wojciech Czardybon, Renata Windak, Izabela Dolata, Magdalena Salwińska, Maciej Szydlowski, Tomasz Sewastianik, Emilia Białopiotrowicz, Elżbieta Mądro, Ewa Lech-Marańda, Bożena K. Budziszewska, Katarzyna Borg, Przemysław Juszczynski, Krzysztof D. Brzózka. Preclinical characterization of SEL24-B489, a dual PIM/FLT3 inhibitor for the treatment of hematological malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1749. doi:10.1158/1538-7445.AM2014-1749

RFC (rituximab, fludarabine, cyclophosphamide) regimen showed extraordinary clinical activity in untreated CLL patients, with high rates of overall response (ORR), complete remission (CR), progression-free survival (PFS) and prolonged overall survival (OS). Recent reports suggest also high activity of rituximab combination with cladribine, and cyclophosphamide (RCC regimen) in previously treated CLL patients. The use of rituximab maintenance after induction treatment may prolong response duration in patients with CLL. The aim of current multicenter, open-label, randomized, two arm phase III b PALG CLL4/ ML 21283 study was to assess the effect of maintenance treatment with rituximab vs. no further treatment, after induction therapy with RCC regimen in previously untreated patients with progressive CLL. The initial induction treatment included rituximab 500mg/m2 on day 1 (375 mg/m2 the first cycle), cladribine (2-CdA) 0,12 mg/kg/day i.v.- days 2-4, cyclophosphamide 250mg/m2 on days 2 to 4, for six cycles. After response assessment was performed 8 weeks after last induction cycle, patients who obtained a CR or a PR were randomized 1:1 to either rituximab maintenance or observation. Rituximab maintenance was started 12 weeks after the last induction cycle and included 8 doses of rituximab at 375 mg/m2 i.v., given in 12 weeks intervals. Six centers entered a total of 128 patients to the study. Baseline demographics, disease characteristics, and prognostic factors were balanced between the two arms. Median patient age was 58 (range 31-74) years, and 37% of patients had advanced CLL stage (3 or 4 according to Rai classification). Following induction phase 22.6% of patients obtained CR, 51.6% of patients had PR while the remainder did not respond to RCC therapy rates. Median PFS in the total study population reached 36 months. In terms of safety and tolerability during induction with RCC regimen grade 3-4 neutropenia developed in 64.8% of patients and major infections were reported in 7.8%. Grade 3-4 thrombocytopenia in 10.94% and anemia 10.16% of patients were noted. During second maintenance/observation phase of the study in grade 3-4 adverse events were observed in 16 (48.5%) patients receiving maintenance with rituximab and in 9 (27.3%) patients in observation arm, p= 0.076. Grade 3-4 neutropenia and febrile neutropenia was significantly more common in maintenance arm (36%) than in observation arm (9%) (p=0.017). However, there was no significant difference regarding the rate of major grade 3-4 infections that were reported in 3% of patients in the maintenance arm as compared to 12% of patients in observation arm (p=0.36). Grade 3-4 thrombocytopenia or anemia were observed in 6% vs 0% (p=0.49) and 0% vs 3% (p=1.0) of patients, in maintenance and observation arm, respectively. In conclusion, early analysis of this study shows moderate toxicity of maintenance with rituximab in patients who achieved response after rituximab-based immunochemotherapy. Although severe neutropenia is more common in patients receiving rituximab immunotherapy as maintenance treatment in CLL this seems not to be followed by increased rate of major infections. Disclosures: Robak: ROCHE: Consultancy, Honoraria, Research Funding. Off Label Use: Cladribine is not registersed by FDA and EMA for the treatment of CLL, but is approved for the treatment of this disease in Poland. Rituximab is not approved for maintenance treatment in CLL but is approved in follicular lymphoma. Fidecka:Roche: Employment.

Abstract 3602 Background: AML in elderly patients is associated with very poor prognosis. The best treatment option for this group of patients is not established, yet. The intensity of treatment depends on performance status and comorbidities. The previous PALG AML study showed that addition of cladribine (2CdA) to conventional induction therapy; especially in patients above 40 yrs, is associated with better outcome (Ho3owiecki 2004). Based on this observation we designed a study addressed to newly diagnosed AML patients above 60 yrs old, who were fit enough to intensive treatment. Aim: To verify whether addition of 2CdA has an impact to clinical outcome in newly diagnosed AML patients older than 60 years old. Methods: From October 2004 to November 2011, 178 patients from 16 hematological PALG centers were randomly assigned to DA induction therapy consisting of daunorubicine (DNR) 45mg/m2, intravenously (iv), day 1–3 and cytarabine (AraC) 100 mg/m2, iv, day 1–7 (DA) or DA with addition of 2CdA 5mg/m2, iv, day 1–5 (DAC). Patients, who achieved complete remission (CR), received one course of consolidation with mitoxantron 6mg/m2 iv day1–2 and AraC 100mg/m2 iv day 1–5, followed by six cycles of maintenance consisting of (DNR 30mg/m2 iv day 1–2 with AraC 100mg/m2 sc day 1–5 and tioguanine 100mg/m2, p.o., twice day, day 1–5 with AraC 100mg/m2 s.c. day 1–5, alternately). Response criteria were determined according to revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia (Chesson 2003). Statistical analysis: Pairwise comparisons between patient characteristics were performed by the Mann-Whitney U-test for continuous variables and by χ2-statistics or Fisher's exact test for categorical variable. The Kaplan-Meier estimates of survival were calculated and compared using the log-rank test. For multivariate analysis, the Cox proportional hazard regression model was applied. P values < 0.05 were considered significant. Results: 88 pts with median age 66 yrs (range 60–79 yrs) were randomized to DA and 90 pts with median age 64 yrs (range 60–79 yrs) was enrolled to DAC schema. The both groups were comparable in terms of age, sex, performance status, white blood cell count, hemoglobin level, platelets count, tumor burden parameters, cytogenetic, between the both groups. The overall CR rate was 38%. In DA and DAC groups CR was achieved in 33% and 43% pts, respectively (p=0.12). However, in patients under 65 yrs the trend towards higher CR rate in DAC arm than DA group was observed (47% vs. 29%, p=0.09). In pts above 65 yrs the CR rate was comparable (39% vs. 38%, p=0.8). The efficacy and hematological toxicity in DA and DAC groups was similar (Table 1). Also no statistical significant differences in non-hematological toxicity were observed (data not shown). Early deaths in DA and DAC did not differ significantly. Median overall survival (OS) in DA and DAC arm was also similar in both groups (Table 1). In proportional hazard Cox analysis only age under 65yo, CR achievement and WBC above 100G/L were important for better OS (p=0.02, p Conclusions: Our data suggest that prolonged overall survival can be achieved in elderly AML patients mainly till 65yrs. Intensive therapy, especially in patients older than 65yrs, may be associated with high number of complications what results withdrawing from intensive treatment protocol. Hematological and non-hematological toxicity of DA and DAC schema is comparable, however higher CR rate in DAC group in patient till 65yrs may suggest, that addition of 2CdA to DA does not increase toxicity and may be a treatment option in this patient population. Disclosures: Wiktor-Jedrzejczak: Janssen-Cilag: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Speakers Bureau; Pfizer: Consultancy; Bayer: Consultancy; Genopharm: Speakers Bureau; Celgene: Speakers Bureau; Genzyme: Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract 1067 Elderly patients with acute myeloid leukemia are heterogenous group with poor outcome. All age, biological status and co-morbidities limit applicability of intensive chemotherapy. The PALG elaborated original system allowing stratification of patients aged >60 years to three groups with different therapeutic approach. Altogether 537 patients with newly diagnosed AML and median age 70 years (range 60–93) were classified as 1) ‘fit’ (n=163): age 60–79y, ECOG 0–2, proper liver and kidney function, without comorbidities, 2) ‘unfit’ (n=210): age >60 years, ECOG 0–2, normal liver and kidney function, comorbidities allowed, 3) ‘frail’ (n=164): ECOG 3–4. According to PALG 1/2005 protocol ‘fit’ patients were treated similarly as younger adults with daunorubicin (DNR, 3 days) + cytarabine (AraC, 7 days) +/− cladribine, followed by DNR + AraC consolidation and maintenance. ‘Unfit’ patients received either two courses of AraC+DNR (2+5) or AraC (5 days) + thioguanine + methotrexate, followed by manitenance. ‘Frail’ patients were considered for palliative cytoreduction and supportive care. Results: Complete remission (CR) rate was 35% for ‘fit’, 22% for ‘unfit’ and 0% for ‘frail’ patients. Median survival in the respective groups equaled 39 weeks, 26 w., and 14 w., while the probability of survival at 1 year was 39%, 27% and 10%. The rate of early (up to 8 weeks) mortality was 31%, 24% and 31%, respectively. In the Cox model the only factor independently affecting the risk of overall mortality in both ‘fit’ and x‘unfit’ group was serum LDH above upper quartile (HR=2, p=0.005 for ‘fit’, HR=1.65, p=0.006 for ‘unfit’). Among ‘frail’ patients the risk of mortality was increased in patients with performance status ECOG>2 (HR=1.85, p=0.0008), initial WBC >8.5×10e9/L (HR=1.65, p=0.006), and bone marrow blasts >58% (HR=1.8, p=0.001). We conclude that the proposed stratification system is feasible for elderly AML patients and represets a model for further developments of individualized therapeutic approaches. Survival of patients in whom remission induction therapy may be applied depends on initial tumor burden as reflected by high serum LDH level. The outcome of patients referred for palliative treatment depends additionally on initial performance status. In contrast, neither age nor karyotype were found to independently affect outcome in this study. Disclosures: No relevant conflicts of interest to declare.

The purpose of the study was to evaluate response, duration of response, and toxicity of fludarabine (F), mitoxantrone (M), and dexamethason (D) (FMD) in patients (pts) with relapsed or refractory low-grade non-Hodgkin lymphoma (LGNHL). 26 pts with advanced relapsed/refractory LGNHL exposed to previous chemotherapy (CHT) received 3–6 monthly cycles of FMD. The median age was 60 years (range 34–73), included 13 male (50%) and 13 female (50 %). The regimen consisted of F (25 mg/m2 i.v., day 1–3), M (10 mg/m2 i.v., day 1) and D (20 mg p.o., day 1–5). Parameters analyzed included response, toxicity and infection rates, number of previous CHT lines, performance status (ECOG), Ann Arbor scale, LDH, International Prognostic Index score, freedom from progression (FFP) and overall survival (OS). In total 78 cycles of FMD was administered. This induced 25% complete and 37,5% partial response, with a total response rate of 62,5%. After 14 months of the median follow-up of the pts remaining alive, median FFP was 11 months and median OS has not been achieved yet. Out of 78 administered cycles 16 (20%) were associated with toxicity, including 8 (10%) severe infections despite prophylaxis and 6 (8%) grade III/IV neutropenias. In addition, one case of grade III/IV thrombocytopenia and acute noninflammatory renal dysfunction were observed. Toxicity rate was not correlated with the number of previous CHT lines or ECOG, but IPI >2 was significant factor predictive for FMD-related toxicity (p=.037). Shorter OS was observed for the pts with ECOG>1 (p=.049), IPI>2 (p=.005) and FMD-related toxicity (p=.036). FMD is an active regimen for relapsed and refractory LGNHL. Toxicity rate is substantial and seems to predict survival.

Lymph node microenvironment provides chronic lymphocytic leukemia (CLL) cells with pro-survival and protective signals, fostering resistance to conventional chemotherapeutics. CLL cells overexpress oncogenic PIM kinases, which modulate proteins engaged in transcription, translation, apoptosis, cell cycle and adhesion/motility (Mol Cancer Ther 2014, 13: 1231-45). Herein, we searched for the link between tumor microenvironment and PIMs expression, compared the clinical characteristics of CLL patients with high versus low expression of PIM kinases, and investigated the consequences of their inhibition with newly developed pan-PIM inhibitor, SEL24-B489 in primary CLL cells. We first evaluated the expression of PIM kinases in CD19+ cells derived from 88 newly diagnosed CLL cases. Patients with unmutated IGHV status exhibited significantly higher PIM1 transcript levels than patients with mutated IGHV genes. Subjects with advanced CLL (Binet C) exhibited higher PIM2 expression than patients in Binet A/B stage. Significantly higher PIM2 transcript abundance at the time of diagnosis was also observed in patients who relapsed after first line treatment (p=0.005). Expression of PIM2 and PIM3 kinases in lymph nodes was significantly higher than in peripheral blood, suggesting a relationship between PIM kinase expression/activity and CLL cell microenvironment. To further explore the role of microenvironment in the control of PIM expression, peripheral blood CLL cells were incubated with anti-IgM or CD40 ligand. Both stimuli induced PIM1 and PIM3 expression. Co-culture of CLL cells with stromal cell (HS5) monolayers promoted the expression of PIM3 isoform. We next assessed the consequences of PIM inhibition in CLL cells using novel pan-PIM inhibitor, SEL24-B489. Incubation with SEL24-B489 decreased phosphorylation of PIM substrates, p-FOXO1/3a(T24/T32) and p-4EBP1(S65), and induced dose-dependent apoptosis in 27 out of 28 analyzed cases, regardless of the IGHV mutation status and including relapsed patients. Of note, SEL24-B489 induced higher apoptotic response in primary CLL cells than referential pan-PIM inhibitor AZD1208. CLL cells with 17p13 deletion and obtained from chemo-refractory patients were also vulnerable to SEL24-B489, suggesting that functional p53 is not required for execution of SEL24-B489-mediated apoptosis. Importantly, SEL24-B489 was not toxic for cells derived from healthy donors. Since microenvironmental cues increase expression of PIM kinases, we hypothesized that interactions with stromal cells might hinder the in vitro activity of the PIM inhibitor. To explore this possibility, we compared apoptotic response to SEL24-B489 in CLL cells co-cultured on HS5 monolayers and CLL cells grown without the stromal support. In 6 out of 7 tested cases, SEL24-B489 overrode the protective signals from HS5 cells and induced apoptosis, although the cytotoxic effect of PIM inhibitor was stronger in the absence of stromal cells. PIM1 was shown to regulate CLL cells migration through CXCR4(S339) phosphorylation (Mol Cancer Ther 2014, 13: 1231-45). Accordingly, SEL24-B489 decreased phospho-CXCR4(S339), CXCR4 surface expression, and impaired CLL cells migration in the CXCL12 gradient. Surprisingly, decrease in the CXCR4 surface expression after SEL24-B489 was relatively modest when compared to the effect of this inhibitor on CXCL12-directed migration. We found that incubation of CLL cells with CXCL12 led to increase in the phosphorylation of mTOR(S2448) and Akt(S473). SEL24-B489 reduced the levels of p-mTOR(S2448), p-Akt(S473), p-4EBP1(T37/T46) and p-TSC2(S1798), revealing inhibitory effect on mTOR pathway. Pre-incubation of CLL cells with an mTOR inhibitor similarly restrained CXCL12-mediated mTOR activity and led to impaired CLL cells migration, uncovering the key role of mTOR axis in CXCR4-dependent migration. Thus, SEL24-B489 impairs the CLL cell migration by inhibiting CXCR4 surface expression and the CXCR4-triggered mTOR pathway. Taken together, we show that microenvironment signals increase expression of PIM kinases, supporting CLL cell survival and migration. Inhibition of PIM kinases impairs CXCR4-dependent migration and leads to CLL cells death, regardless of the p53 status. Targeting PIM kinases in CLL patients will likely release the cells from microenvironmental niches and might be a rational therapeutic strategy. Disclosures Warzocha: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Czardybon:Selvita S.A.: Employment. Galezowski:Selvita S.A.: Employment. Windak:Selvita S.A.: Employment. Brzozka:Selvita S.A.: Employment. Juszczynski:Selvita S.A.: Consultancy, Membership on an entity's Board of Directors or advisory committees.

The survival of chronic lymphocytic leukemia (CLL) cells depends on their interactions with microenvironment components, such as stromal and T cells. Lymph node microenvironment provides protective signals that enable the formation of proliferation centers and favor resistance to conventional chemotherapeutics. One of the key molecules engaged in the communication of CLL cells with their microenvironment is C-X-C chemokine receptor type 4 (CXCR4). The surface expression of CXCR4 is regulated by PIM1 (provirus integration site for Moloney murine leukemia virus) kinase. PIM 1-3 kinases are overexpressed in CLL cells and recent data suggest that targeting PIMs might be a rational therapeutic approach in this type of leukemia. Herein, we assessed associations of PIM kinase expression with clinical characteristics of CLL patients and investigated the consequences of PIM kinase inhibition for cell survival and CXCR4 - dependent signal transduction and migration of primary CLL cells. In primary CLL cells from peripheral blood, PIM2 transcript abundance was higher than PIM1 and PIM3 (p Taken together, our data demonstrate that CXCR4/SDF1 signal in chronic lymphocytic leukemia cells is transduced through mTOR pathway and that CXCR4 - triggered mTOR activity is modulated by PIM kinases. Pan-PIM inhibitor SEL24-B489 decreased CXCR4 surface expression and SDF-1 - triggered mTOR activity. Finally, SEL24-B489 decreased protective effects of tumor microenvironment and induced CLL cells apoptosis even in the presence of stromal cells. Since overexpression of PIM kinases might be associated with adverse clinical characteristics at diagnosis, PIM inhibition might be a rational therapeutic strategy in CLL. Disclosures Czardybon: Selvita S.A.: Employment. Galezowski:Selvita S.A.: Employment. Windak:Selvita S.A.: Employment. Brzozka:Selvita S.A.: Employment. Juszczynski:Selvita S.A.: Other: member of Selvita Scientific Advisory Board.