ALBERT

Description: Abstract 4504 Patients (pts) with acute leukemias i.e. acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) suffering form primary refractory disease or refractory relapse have a very poor prognosis. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only potential curative treatment option for such pts. However, disease-control prior to HSCT is essential for long term CR. In the present study we have retrospectively analyzed the outcome of pts who received clofarabine (10 mg/m2, d 1–4) and cyclophosphamide (200 mg/m2, d 1–4; ClofCy) to reduce the burden of leukemic cells prior to alloHSCT. A total number of 18 pts (females, n= 11; males, n= 7; median age; 37.5 years, range 21–64 years) with refractory leukaemias (AML, n=14; ALL, n=4) received ClofCy between December 2008 and January 2012 (1 cycle: 7 pts; 2 cycles: 3 pts; 3 cycles: 7 pts; 4 cycles: 1 patient). In all pts a marked decrease in leukemic cells was observed after a median of 2 cycles (range 1–4 cycles). Side effects included infections (n=7), moderate skin rush (n=4), transient increase in ALT and AST (n=2) and diarrhoea (n=1). AlloHSCT was performed in 13/18 pts. Five pts were not eligible for alloHSCT because of severe systemic fungal infections in 3 pts, clinical deterioration in 1 patient, or CNS relapse of leukemia in 1 patient. Myeloablative conditioning (cyclophosphamide/TBI) was administered in 9 pts, and dose-reduced conditioning (FLAMSA n=2; Fludarabin/Melphalan/Carmustin/ATG n=2) in 4 pts. Following stem cell infusion (median number of CD34+ cells/kg: 7.22×106) from a related (n=4) or unrelated (n=9) donor all pts showed rapid haematologic engraftment and full donor chimerism (median time to ANC 〉 0.5 G/l: 16 days; range: 12–25 days; median time to platelet 〉20G/l without substitution: 17 days; range: 13–32 days). As evidenced by bone marrow biopsy on day +28, all pts achieved CR following alloHSCT. After a median observation time of 262 days (range: 33–1496 days) 7 pts are alive. One patient died because of acute steroid-refractory graft-versus-host disease (day +48) and one from a systemic fungal infection (day +56). Four pts died after following reoccurrence of leukemia. Three pts had a hematologic relapse (days +383, +275, +141, respectively) and 1 patient developed a myelosarcoma on day +934. Of the 7 patients alive 5 are in continuous CR (691, 673, 555, 533 and 170 days post TX), two patients had a relapse and achieved a CR after DLI or a second HSCT, respectively. Together, we demonstrate that cytoreduction with ClofCy is a novel reasonable treatment approach for pts with refractory acute leukemias prior to alloHSCT. The regimen is relatively well-tolerated and resulted in a high response rate. Whether this novel debulking protocol will lead to improved long term outcome in pts with refractory leukemias remains to be determined in forthcoming studies with larger patient samples and longer observation periods. Disclosures: Valent: Phadia: Research Funding. Sperr:Genzyme: Speakers Bureau.

Description: In patients (pts) with mast cell (MC) proliferative disorders, the clinical course, prognosis, and outcome vary depending on age, organ-involvement, and the disease-variant. We have retrospectively analyzed the clinical course and outcome in 56 pts with MC disorders refered to the University of Vienna between 1987 and 2004. Using WHO criteria, pts were found to have cutaneous mastocytosis (CM, n=6), indolent systemic mastocytosis (ISM, n=35), aggressive SM (ASM, n=3), mast cell leukaemia (MCL, n=1), SM with associated clonal hematologic non-MC-lineage disease (SM-AHNMD, n=6), and myelomastocytic leukemia (MML, n=5). These groups differed from each other in serum tryptase levels, hemoglobin, platelet counts, and lactate dehydrogenase (p

Description: The mammalian target of rapamycin (mTOR), a key-regulator of cell cycle progression, has recently been implicated in growth of neoplastic cells and tumor- and leukemia-associated angiogenesis. In addition, mTOR has been described as a regulator of expression of vascular endothelial growth factor (VEGF), a cytokine involved in tumor-related angiogenesis, in various neoplasms. We asked whether mTOR can be employed as a new therapeutic target in acute myeloid leukemia (AML) using the mTOR-targeting drug rapamycin and its derivatives RAD001 (everolimus) and CCI-779. As assessed by 3H-thymidine incorporation, rapamycin was found to counteract growth of AML cells in vitro in 9/11 patients examined as well as in the AML-derived cell lines U937, HL60, and KG1a. The effects of rapamycin on growth of AML cells were dose-dependent (primary AML cells: IC50: 10 pM - 1 nM; inhibition of 3H-thymidine uptake at 1 nM of rapamycin: 43±15 % of control; p

Description: Heme oxygenase 1 (HO-1), also known as heat shock protein 32 (Hsp32), has recently been identified as a stress-related survival molecule that acts anti-apoptotic and cytoprotective in inflammatory reactions. Recent data suggest that HO-1/Hsp32 is also expressed in neoplastic cells in various malignancies. In the present study, we provide evidence that HO-1 is constitutively expressed in primary leukemic cells in patients with acute myeloid leukemia (AML, n=17) and in various AML cell lines such as HL60, KG1, KG1a, and U937. Expression of HO-1 mRNA was demonstrable by RT-PCR, and the HO-1 protein by immunocytochemistry and Western blotting. In addition, we were able to demonstrate expression of HO-1 mRNA and of HO-1 protein in the CD34+/CD38− progenitor/stem cell fraction in the leukemic clone in patients with AML. The HO-1 inductor hemin (10 μM) was found to promote expression of HO-1 in AML cells. Incubation with the HO-1-targeting drugs pegylated zink protoporphyrin (PEG-ZnPP) or styrene maleic acid-conjugated ZnPP (SMA-ZnPP), resulted in a dose-dependent inhibition of growth of leukemic cells at pharmacologic concentrations (IC50: 5–20 μM for cell lines and primary AML cells). The SMA-ZnPP-induced growth-inhibition of AML cells were found to be associated with induction of apoptosis as evidenced by light microscopy, electron microscopy, and by a Tunel assay. In consecutive experiments, combination experiments were performed using SMA-ZnPP and AML cell lines. In these experiments, SMA-ZnPP was found to synergize with cytarabine in producing growth inhibition in all AML cell lines tested. In summary, these data show that HO-1/Hsp32 is a novel survival factor and interesting target in AML. The clinical significance of this observation remains to be determined in forthcoming trials.

Description: CD44, also known as Hermes antigen, is a multifunctional invasion receptor that mediates homing and expansion of normal and neoplastic stem- and progenitor cells in various organs including the bone marrow (BM). Mast cells (MC) and their progenitors also express CD44. However, little is known about the impact and regulation of CD44 in neoplastic cells in systemic mastocytosis (SM). We examined the expression, regulation, and functional role of CD44 in neoplastic cells in SM. As assessed by multi-color flow cytometry, CD34+/CD38- stem cells (SC), CD34+/CD38+ progenitor cells (PC), and KIT+/CD34- MC invariably expressed CD44 in all SM variants, including patients with indolent SM (ISM, 11/11), SM with associated hematologic neoplasm (SM-AHN, 7/7), aggressive SM (ASM, 3/3), and MC leukemia (MCL, 8/8). Expression of CD44 on SC, PC, and MC increased significantly with the aggressiveness of SM. Moreover, soluble CD44 levels measured in the sera of patients with SM by ELISA were found to correlate with the WHO type of SM. In particular, significantly higher levels of soluble CD44 were measured in advanced SM compared to ISM, cutaneous mastocytosis (CM), or healthy controls (p

Description: Systemic mastocytosis (SM) is a rare hematologic neoplasm characterized by abnormal growth and accumulation of tissue mast cells (MC) in various organ systems, including bone marrow (BM). Indolent and advanced forms of SM have been described. Whereas patients with ISM have a normal or near normal life-expectancy, patients with advanced SM, including those suffering from mast cell leukemia (MCL) have a poor prognosis. In these patients, neoplastic MC are usually resistant against conventional drugs and various targeted drugs. In rapidly progressive aggressive SM (ASM) and MCL, polychemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHCT) has been proposed. However, outcome of alloHCT in advanced SM is unknown, and it also remains uncertain whether clinically relevant graft-versus-SM (GVSM) effects may occur in these patients, as only sporadic case reports have been published. We performed a retrospective multi-center analysis to evaluate the outcome of alloHCT in patients with advanced SM. Fifty-four advanced SM patients receiving SCT in 32 transplantation centers in Europe and America were identified between 1990 and 2013. The median patient age was 45 years. Donors were: HLA identical siblings (31), unrelated donors (URD) (15), umbilical cord blood donors (UCB) (2), and haploidentical donors (1). In 5 patients, stem cell source was not defined (5). Thirty-four patients received myeloablative conditioning (MAC) and 18 received reduced intensity conditioning regimens (RIC). In 2 patients, conditioning regimen was not specified. Indications for alloHCT were SM with an associated clonal hematologic non-mast cell lineage disease (SM-AHNMD) (n=32), MCL (n=13, including one with MCL-AHNMD), 8 with ASM and 1 with myelomastocytic leukemia (MML). The most prevalent AHNMD was acute myeloid leukemia (AML, n=16). With follow-up of 35-6180 (median 365) days, SM responses (defined as ≥50% decrease in BM mast cells ± decrease in serum tryptase ± regression of other organ manifestations) were observed in 39 patients (72%), including complete responses (CR) documented in 12 patients (22%). Eleven patients had stable disease, whereas 4 patients (7%) progressed immediately after alloHCT (primary resistance). In addition, 10 patients progressed (5 of them within 100 days) after an initial response. Progression was most frequently seen in MCL patients (n=6, 50%). In the AHNMD group, only 8 patients relapsed/progressed (25%). The overall survival (OS) and SM progression-free survival (PFS) at 1 year were 63% and 50% for all patients, 77% and 68% for SM-AHNMD, 63% and 50% for ASM, and 25% and 17% for MCL, respectively. The strongest predictive variable associated with inferior survival was a diagnosis of MCL. Other factors associated with poor outcome were: Karnofsky performance status ≤70%, ≥2 SM regimens given before alloHCT (e.g., steroids, cladribine, chemotherapy, tyrosine kinase inhibitor), donor source (alternative donors-UCB and haploidentical compared to sibling or URD), SM progression within the first 100 days, normal cytogenetics (compared to t(8;21) (q22;q22), and RIC (compared to MAC). The following variables were not associated with poor outcome: patient and donor age, recipient-donor sex match status, graft source (BM vs. peripheral stem cells), BM mast cell percentage at time of alloHCT, and CR status of AML or SM response at time of alloHCT. This largest multi-center analysis of results in advanced SM provides evidence for clinical efficacy of alloHCT, presumably because of a GVSM effect of alloHCT (achieving CR, and response to donor-lymphocyte infusions and RIC alloHCT). However, responses varied among different SM categories: while patients with SM-AHNMD enjoyed excellent outcomes, the OS for MCL patients in general, was poor. Nevertheless it is remarkable that 3 of 13 patients with MCL – an otherwise fatal disease with a median survival of

Description: Introduction: Most patients with FLT3-ITD-positive AML, who relapse after allogenic stem cell transplantation (allo-SCT) die from their disease. Whether prophylactic FLT3-ITD inhibition with sorafenib can prevent AML relapse and improve outcome of patients in complete hematological remission (CHR) after allo-SCT is unknown and was tested in the SORMAIN trial. Methods: This randomized, double blind, placebo-controlled study was done at 14 centers in Germany and Austria. Patients with FLT3-ITD+ AML, aged 18 years or older, who had undergone allogenic stem cell transplantation from a HLA-matched sibling donor, 10/10 or 9/10 HLA-matched unrelated donor, and who were in confirmed CHR at the time of screening between day +30 and day +100 post allo-SCT, were included. Patients were randomly assigned (1:1) to receive either sorafenib (starting dose: 2 x 1 tbl. [2 x 200mg] qd, increasing every 14d to up to 2 x 2 tbl. [2 x 400mg] qd according to tolerability) or placebo (2 x 1 or 2 tbl. qd) for up to 24 months. Randomization was done centrally. In case of drug related adverse events, study medication could be interrupted, stepwise reduced to a minimum of 2 x 1 tbl. qd, temporarily withheld and recommenced at a lower dose level. FLT3-ITD diagnostics was done centrally at baseline and at time of relapse. In relapsing patients, off-label compassionate use of sorafenib was possible. The primary endpoint was relapse-free survival (RFS) as defined by either hematological relapse or death from any cause. The secondary endpoint was overall survival (OS). We here report the final RFS analysis. The OS results will be unblinded only prior to the ASH meeting and will be reported there. The SORMAIN study was terminated prior to full recruitment because of slow accrual. SORMAIN was registered with the European Clinical Trials Database (EudraCT 2010-018539-16) and the German Clinical Trials Register (DRKS00000591). Results: Between October 29, 2010, and May 17, 2016, 83 patients (41 males, 42 females) were randomized and included in the primary analysis (placebo, n=40; sorafenib, n=43). Median age was 54 years (IQR 47.75 - 61.33) for the entire study population and not significantly different between sorafenib and placebo groups. With a median follow up of 41.8 months after randomization (IQR 24.1 - 42.5), median RFS was 30.9 months (lower bound of 95% CI 5.2 months) in the placebo group versus not reached in the sorafenib group, corresponding to a 2-year RFS of 53,3 % (95% CI 36.5-67.5) in the placebo versus 85.0 % (69.5-93.0) in the sorafenib group (hazard ratio [HR] 0.39, 95% CI; 0.18 -0.85; P=0.0135) (Fig. 1). Overall, sorafenib was well tolerated. The most common grade 3-4 adverse event in both groups was acute GvHD (seven [ 17.5%] in the placebo group vs. nine [20.9%] in the sorafenib group. Conclusion: Sorafenib maintenance therapy after allo-SCT is feasible and significantly reduces the risk of relapse or death in patients with FLT3-ITD positive AML. OS results will be presented at the meeting. Figure 1. Figure 1. Disclosures Burchert: Bristol Myers Squibb: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; AOP Orphan: Honoraria, Research Funding; Novartis: Research Funding. Bug:Amgen: Honoraria; Neovii: Other: Travel Grant; Novartis Pharma: Honoraria, Research Funding; Astellas Pharma: Other: Travel Grant; Jazz Pharmaceuticals: Other: Travel Grant; Celgene: Honoraria; Janssen: Other: Travel Grant. Finke:Riemser: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Other: travel grants, Research Funding; Neovii: Consultancy, Honoraria, Other: travel grants, Research Funding; Medac: Consultancy, Honoraria, Other: travel grants, Research Funding. Stelljes:Pfizer: Consultancy, Honoraria, Research Funding; MSD: Consultancy; JAZZ: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Rollig:Bayer: Research Funding; Janssen: Research Funding. Wäsch:Pfizer: Honoraria. Lang:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; GEMoaB Monoclonals GmbH: Employment, Equity Ownership; Bayer: Research Funding. Serve:Bayer: Research Funding. Kroeger:Neovii: Honoraria, Research Funding; JAZZ: Honoraria; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding. Schmid:Jazz Pharma: Honoraria, Other: Travel grant, Speakers Bureau. Wolf:BMS: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; AOP Orphan: Honoraria, Research Funding. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bethge:Miltenyi Biotec GmbH: Consultancy, Honoraria, Research Funding; Neovii GmbH: Honoraria, Research Funding.

Description: Key Points CD44 is a RAS/STAT5-dependent target in neoplastic mast cells and correlates with aggressiveness of mastocytosis. Depletion of CD44 in neoplastic mast cells is associated with reduced invasion and prolonged survival in SCID mice.

Description: Background: Patients suffering from chronic lymphocytic leukemia (CLL) are observed and treated intra- as well as extramural during the course of their disease. Generally, hematological centers only see patients who are eligible for active treatment and/or candidates for clinical trials. Thus, a bias between published and real-life patients' data is likely. In our "Hämatologieverbund der WGKK" we take care of CLL patients who are under observation as well as of patients who are in need of treatment. This allows representative analyses of comorbidities and treatment periods during the course of the disease in an in- and outpatient setting. Therefore, a bias in the analyzed population can be excluded. Although new potent oral drugs are now available for the treatment of CLL, still some toxicities are of concern. Disease-related factors as IGHV-mutation and/or TP53-mutation/17p deletion guide specific treatment decisions, but patient-related factors such as age and comorbidities become more and more important. Especially the comorbidities in the usually elderly CLL-population might influence the choice of treatment. Depending on the side effects, caution has to be taken to decide the appropriate individual drug for the patients. Real world data concerning functional status and comorbidities of CLL patients may help to improve treatment results. In a retrospective study 888 patients diagnosed with CLL, having been observed and cared for within the "Hämatologieverbund der WGKK" between 2012 and 2018, were identified and analyzed according to their whole history of disease. Comorbidities were assessed in detail during the whole course of the disease. Results: At time of diagnosis, the median age was 67.5 years. 96.6% of patients presented with an ECOG-status of 0-1. 89.1% of patients had Binet-stadium A, 8.6% had Binet-stadium B and 2.3% had Binet-stadium C. In 43.2% of patients pathological lymph nodes had been observed and 7.7% of patients reported suffering from constitutional symptoms. 7.5% of patients presented with a del(17p)/TP53 mutation status of ≥10%, while 57.0% of patients were IGHV-mutated. 258 of 888 (29.1%) patients received at least one line of treatment (median 1.7, range 1-6), whereas 71% of patients did not require therapy in the observation period. The most common treatment regimens were: rituximab-bendamustine (BR) (N=135), ibrutinib (N=48), FCR (N=58), chlorambucil combinations (N=39) and venetoclax (N=10). Patients treated with ibrutinib had a comorbidity rate of 41.7% and patients who received BR had a comorbidity rate of 31.9% at time of diagnosis. The mean time from diagnosis to first treatment was 4.0 years (range: 0.0-31.8 years). The median observation time was 6.4 years in both treated and untreated patients (SD 5.6 years, max. 37.0 years). Between the observation period from 2012 to 2018, 17.3% of patients died. Comorbidities were assessed using the Charlson Comorbidity Index (CCI). 40.0% of patients had at least one comorbidity according to the CCI. Interestingly, patients who received treatment showed the higher percentage of comorbidities (50%) documented during the whole observation period, than patients who never received any treatment (36%). Treated patients showed a rate of comorbidities at time of diagnosis of 30.6%, which increased to 50% during the observation period. Besides the established CCI, we investigated details of cardiovascular comorbidities, including arterial hypertension, in patients who received treatment at time of diagnosis and during the whole observation period (details are shown in Fig. 1). Patients who received ibrutinib in general had more comorbidities compared to all treated patients. Conclusion: We think that our patient population is representative and the number of patients with p53- and/or IGHV-mutation is similar to previously reported data. It is interesting that the rate of comorbidities in our population group was higher than expected. Especially the rate of cardiovascular comorbidities including arterial hypertension was impressive. Also, patients requiring treatment had more comorbidities than those under surveillance during the observation period. We conclude, that in the era of new drugs with specific toxicities (cardiovascular, renal, pulmonary), awareness, diagnosis and consequent treatment of possibly co-existing comorbidities should be in the central focus in patients suffering from CLL. Disclosures Keil: Pfizer: Honoraria; Roche: Honoraria; Takeda: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; AbbVie: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Novartis: Honoraria; Bionorica: Honoraria, Research Funding; Celgene: Honoraria; Janssen: Honoraria, Research Funding. Noesslinger:Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria.

Description: An increased lactate dehydrogenase (LDH) level at diagnosis is associated with a reduced probability of survival and an enhanced risk of AML development in primary (de novo) myelodysplastic syndromes (MDS). However, so far, little is known about the prognostic value of an increase in LDH levels during the follow up in these patients. We have serially determined LDH levels in 221 patients (102 males, 119 females) with de novo MDS (median age 70 years; FAB-types: RA, n=62; RARS, n=46; RAEB, n=48; RAEBT, n=36; CMML, n=29), and examined the prognostic value of LDH as a follow-up parameter. Confirming previous data, an elevated LDH level at diagnosis was found to be associated with a significantly increased probability of AML evolution and a significantly decreased probability of survival (p