ALBERT

Description: Key Points Alternatively polarized macrophages are abundant constituents of the tumor microenvironment in T-cell lymphoproliferative disorders. GATA-3 expression identifies a subset of PTCL, NOS with a distinct cytokine profile and inferior survival.

Description: Background IL-10 polarized macrophages promote tumor growth and survival. The T-cell transcription factor GATA binding protein-3 (GATA3) epigenetically regulates IL10 expression. Therefore, we investigated the extent to which GATA-3 regulates IL-10 production and macrophage polarization in T-cell lymphomas. Methods Monocyte-derived macrophages were generated and polarized with T-cell lymphoma conditioned media ((TCL-CM). Immunophenotypic and functional characteristics associated with IL10-polarized macrophages were examined. GATA3-dependent cytokine production was evaluated in T-cell lymphoma lines by shRNA knockdown. Alternatively polarized macrophages and GATA3 expression were examined in a cohort of patients with peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) (n=76). Comparisons among groups were evaluated using a Student's t test. Progression-free and overall survival (PFS & OS) was estimated using the Kaplan-Meier method and two-tailed log-rank test based on Cox proportional hazards model. Results To investigate the ability of T-cell lymphomas to alternatively polarize macrophages, monocytes from healthy donors were cocultured with TCL-CM. Macrophages were shown to have immunophenotypic characteristics of IL10-polarized macrophages (pSTAT3+/CD16hi/CD163hi/HLA-DR-/lo) by flow cytometry, which was abrogated by IL10, but not IL6, neutralization. TCL-CM polarized macrophages produced abundant IL-10 and were impaired in their ability to stimulate T-cell proliferation. Collectively, these results demonstrate that T-cell lymphomas promote alternative macrophage polarization in an IL-10 dependent manner, and both CD163 and pSTAT3 may aid in their identification in clinical T-cell lymphoma specimens. Therefore, CD163+/pSTAT3+ macrophages were visualized by immunofluorescence in PTCL, NOS specimens. IL-10 polarized macrophages were not identified in normal tissues, but were abundant constituents of the tumor microenvironment in 68% of the PTCL, NOS specimens examined (n=31). STAT3 phosphorylation in response to IL-10 is dependent upon the Janus kinases (JAK) JAK1 and TYK2, both of which are inhibited at nanomolar (and clinically achievable) concentrations by the “JAK2” inhibitor ruxolitinib. Therefore, we sought to determine whether ruxolitinib may prevent IL-10-induced macrophage polarization. As expected, ruxolitinib inhibited IL-10-induced STAT3 phosphorylation. More importantly, macrophages polarized in the presence of ruxolitinib lost the immunophenotype characteristics of IL-10 polarized macrophages, and were CD16-/loCD163-/loHLA-DRhi. Furthermore, IL-10 production was significantly impaired in macrophages polarized in the presence of ruxolitinib, while their ability to stimulate T-cell proliferation was significantly increased. In a separate initiative, we identified GATA3 as the key regulator of IL-10 and Th2 cytokine (IL-4, IL-13 and IL-5) expression in T-cell lymphoma lines by shRNA knockdown assays. Therefore, we examined GATA3 expression by immunohistochemistry in PTCL, NOS specimens. GATA-3 expression was observed in most of the T-cell lymphoma lines and in 47% of PTCL, NOS specimens (n=76). In the cohort of the 76 PTCL, NOS patients, the median PFS and OS observed in GATA3+ PTCL, NOS was 5 months (4-8 months, 95% CI) and 8 months (5-14 months, 95% CI), respectively. In contrast, the median PFS and OS in GATA3- PTCL, NOS was 1.3 years (0.6-1.6, 95% CI) and 1.6 years (0.7-6.9 95% CI), respectively. Conclusions Alternatively polarized macrophages are abundant in T-cell lymphomas and are generated in an IL-10- and STAT3-dependent manner. GATA-3 regulates IL-10 production in these lymphomas, and its expression identified a high-risk subset of PTCL, NOS with distinct clinicopathological features. As IL-10-dependent STAT3 phosphorylation and macrophage polarization were impaired by ruxolitinib, the JAK2 inhibitors may warrant closer scrutiny as immunomodulatory agents. Disclosures: Off Label Use: Ruxolitinib, a JAK2 inhibitor, may warrant closer scrutiny as an immunomodulatory agent in TCL therapeutics.

Description: Abstract 5178 Background: Natural Killer cells (NK cells) are part of the innate immune system. These cells have the ability to recognise and kill malignant cells, like myeloma cells. NK cell activation is tightly regulated by different activating or inhibiting receptors. Killer immunoglobulin like receptors (KIR, CD158) are a family of receptors which have activating as well as inhibitory function. KIR molecules are thought to recognize the HLA-C molecules, which then lead to NK cell signal transduction. Our knowledge about KIR expression and impact on tumor cell control has developed over the last years, but still our understanding of how the receptors are activated in multiple myeloma is limited. We therefore, investigated three different model systems for NK cell alloreactivity: 1) HLA-C/ HLA-C interaction model (KIR-Ligand model), 2) HLA-C/ KIR receptor interaction model, and 3) impact of donor KIR haplotype. Material and Methods: Three different myeloma cell lines (KMS12BM [C1/C1], MOLP8 [C1/C2] and RPMI8266 [C2/C1]) and a NK cell line (NKL) were cultured under standard conditions. NKL cells were transfected with human KIR2DL1 and KIR2DL3 alleles, respectively. For RNAi experiments two siRNA and two control siRNA were used. NK cells from healthy donors were isolated by magnetic end labeling. Enriched NK cells were HLA-typed for expression of HLA-C molecules, KIR receptor expression or KIR haplotype. Thereafter, NK cells were transiently transfected with the siRNA or control siRNA against the KIR2DL1 or KIR2DL3 receptors for up to 48 h. Functional analysis of the NK cell cytotoxicity was measured using a LDH release assay, based on their killing ability against the three fore mentioned myeloma cell lines. Results: Using NK cells that have been HLA-C genotyped as HLA-C1/C1, we observed a rescue of C1/C1 positive meyeloma cell lines in contrast to the C2/C1 myeloma cell line (12% cytotoxicity vs. 38% and 45% cytotoxicity, respectively, p

Description: The natural killer (NK) type of aggressive large granular lymphocytic (LGL) leukemia is a fatal illness that pursues a rapid clinical course. There are no effective therapies for this illness, and pathogenetic mechanisms remain undefined. Here we report that the survivin was highly expressed in both aggressive and chronic leukemic NK cells but not in normal NK cells. In vitro treatment of human and rat NK-LGL leukemia cells with cell-permeable, short-chain C6-ceramide (C6) in nanoliposomal formulation led to caspase-dependent apoptosis and diminished survivin protein expression, in a time- and dose-dependent manner. Importantly, systemic intravenous delivery of nanoliposomal ceramide induced complete remission in the syngeneic Fischer F344 rat model of aggressive NK-LGL leukemia. Therapeutic efficacy was associated with decreased expression of survivin in vivo. These data suggest that in vivo targeting of survivin through delivery of nanoliposomal C6-ceramide may be a promising therapeutic approach for a fatal leukemia.

Description: Introduction: Bendamustine is a bifunctional alkylating agent with low toxicity that produces both single- and double-strand breaks in DNA, and shows only partial cross resistance with other alkylating drugs. Treatment of patients with newly diagnosed multiple myeloma using Bendamustine and Prednisone in comparison to Melphalan and Prednisone results in superior complete response rate and prolonged time to treatment failure (Poenisch et al, Res Clin Oncol 132: 205-212;2006). So far, however, reliable information on stem cell toxicity and mobilization of stem cells for autologous stem cell transplantation (SCT) after induction treatment with a combination of bendamustine, prednisone and bortezomib (BPV) is missing. Material and Methods: A retrospective analysis of peripheral blood stem cell mobilization and autologous SCT was performed in 35 patients with multiple myeloma who had received at least two cycles of a BPV induction therapy consisting of bendamustine 60 mg/m2 on days 1 and 2, bortezomib 1.3 mg/m² on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 between October 2008 and May 2014. The mobilization regimen consisted of cyclophosphamide 4 g/m2 and G-CSF (2x5µg/kg). Apheresis was started as soon as peripheral blood CD34+ counts exceeded 20x106/l with a harvest target of 8x106 CD34+/kg. The minimal accepted target was 2x106 CD34+/kg. Results: A median number of two (range 1–5) BPV treatment cycles were given to the patients. The majority of the patients (n = 31, 89 %) responded including 2 sCR, 5 nCR, 11 VGPR, and 13 PR. Three patients had MR, and 1 SD. Stem cell mobilization and harvest was successful in all patients. In 19 of 35 patients (54 %) a single apheresis was sufficient to reach the target. The median number of aphereses was one (range 1-4) and the median CD34+ cell-count/kg was 13.5 (range 3.2-33.1) x106. All patients received an autologous SCT. The pre-transplantation conditioning therapy consisted of melphalan 200 mg/m2. In 8 patients with concomitant heart amyloidosis or severe renal insufficiency melphalan dose was reduced to 100 or 140 mg/m2. Engraftment was successful in 34 of 35 patients. The median time to leucocytes count 〉l×109/l was reached after 11 (range 9–18) days and the time to untransfused platelet count of 〉50×109/l was 13 (range 10–55) days. 34 patients (97%) responded after the autologous SCT with 11 sCR, 2 CR, 7 nCR, 7 VGPR, and 7 PR. The progression free survival at 18 months was 87 % and overall survival was 92 %. Conclusion: Stem cell mobilization and autologous SCT is feasible in multiple myeloma patients who have received BPV induction therapy. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Lange:Novartis: Consultancy, Honoraria, Research Funding.

Description: Abstract 893 Introduction: A European collaborative harmonization study involving 61 laboratories is being conducted under the auspices of the European Treatment and Outcome Study (EUTOS) for CML that aims to facilitate reporting of molecular BCR-ABL quantification results according to the International Scale (IS). The aim of this analysis was to investigate the effectiveness of this process and specifically the stability of conversion factors (CF) over time. Methods: The currently accepted way of adopting the IS is to establish and validate a laboratory-specific CF which is then used to convert local results to the IS. For round 1, preliminary CFs were calculated by centrally distributing standard samples containing 10–20 million WBC approximating to 10%, 1%, 0.1%, and 0.01% BCR-ABL IS. Rounds 2 and 3 were employed to refine the CF calculations using 25–30 CML patient samples from each participating laboratories covering a range of BCR-ABL levels between 0.01% and 10%. Log BCR-ABL values for the same samples were compared between reference and local laboratories applying the Bland-Altman bias plot. In order to judge the stability of each laboratory`s methodology, a CF index (ratio of round 3 CF divided by round 2 CF) was calculated and evaluated according to its capability to achieve optimum concordance of results. Results: Of the 61 laboratories participating in round 1, evaluable patient samples have been provided to date by 56 and 30 laboratories in rounds 2 and 3, respectively. Of the 30 laboratories with complete data, 12 had stable CFs (defined as a CF index within 0.75–1.33) whereas 18 laboratories were outside this range. Comparison of the CFs derived from round 2 with those derived from round 3 revealed better and more consistent concordance between laboratories with stable CFs compared to those with unstable CFs. For the 12 stable laboratories, 79% (round 3 CF) vs 79% (round 2 CF) of the samples were within a 2-fold range (0.5–2.0) and 93% vs 89% were within a 3-fold range (0.33–3.0). For the 18 unstable laboratories, 74% vs 55% of the samples were within a 2-fold range (0.5–2.0), p=0.0005 and 92% vs 77% were within a 3-fold range (0.33–3.0), p=0.0005. 2 of 12 laboratories with stable CFs and 8 of 18 laboratories with unstable CFs indicated changes in either one or more components of their procedures (cDNA synthesis, PCR platform, RQ-PCR protocol) that may have impacted on their CFs. Conclusion: These data indicate that CFs may be unstable in some laboratories even in the absence of significant changes to laboratory protocols. Further, it supports the need for continuous revalidation of CFs. In laboratories with unstable CFs we suggest revalidation within 3 to 6 months whereas those with stable CFs should be assessed on a yearly basis. We also suggest that laboratories with unstable CFs need to rigorously examine their internal processes to identify potential sources of variation. Disclosures: Müller: Novartis: Honoraria, Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.

Description: Key Points GO before transplant improves outcome of CBF-AML patients in first relapse.

Description: Background Idelalisib (IDELA) is a first-in-class, selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues. Phase 1 trials demonstrated that IDELA is highly active as a single agent or in combination with rituximab (R) in heavily pretreated patients (pts) with CLL. Pts in these trials experienced reductions in disease-associated chemokines, improvement of organomegaly and cytopenias, profound reductions in lymphadenopathy, and durable clinical benefit with an acceptable safety profile (Brown 2013; Barrientos 2013). Patients with early progression and significant co-morbidities have limited treatment options; single-agent rituximab is an option in these pts (NCCN 2013; Zelenetz 2013). Methods This Phase 3 study evaluated the efficacy and safety of IDELA + R vs placebo + R in pts with previously treated CLL. Eligibility criteria included the need for treatment per IWCLL guidelines, measurable lymphadenopathy, and CLL progression 6), renal dysfunction, or cytopenias due to poor marrow reserve. All pts received R at 375 mg/m2 [1st dose] and then 500 mg/m2q2 wks x 4, followed by q4 wks x 3 [8 doses total]) and were randomized to Arm A (n=110; IDELA 150 mg BID continuously) or Arm B (n=110; placebo BID continuously). Primary endpoint was progression-free survival (PFS). Response and progression in both arms were assessed by an independent review committee using standard criteria (Hallek 2008; Cheson 2012). Results were reviewed by an external Data Monitoring Committee (DMC). Results Results are from a pre-specified interim analysis after ∼50% of the total number of 119 planned events of CLL progression or death from any cause. Data cutoff was 30 Aug 2013. Pt characteristics (n=220) included a median age of 71 yrs (78% ≥ 65 yrs); CIRS 〉 6 in 85%; median creatinine clearance of 63.6 mL/min; and presence of anemia (73%), thrombocytopenia (61%), neutropenia (34%). Median time since diagnosis was 8.5 yrs, median number of prior therapies was 3 (range: 1-12), 44% had del(17p)/TP53 mutation, and 84% had unmutated IGHV. PFS in the IDELA + R arm was superior to placebo +R (HR [95% CI] = 0.15 [0.08, 0.28]; p = 3.0 x 1011). Median PFS of pts treated with IDELA + R was not reached and for placebo + R was 5.5 mos. At 24 wks, the PFS rate for IDELA +R was 93% compared to 46% for placebo + R. PFS strongly favored IDELA + R in all subgroups, including those with del(17p)/TP53 or unmutated IGHV. Pts treated with IDELA + R and with ≥1 post-baseline assessment also had a superior overall response rate (ORR) relative to those in the control arm (81% vs. 13%; odds ratio 29.9; p = 3.0 x 1019) and a higher lymph node response (LNR) rate (93% vs. 4%; odds ratio 264.5; p = 1.3 x 10-30). Relative to the control group, pts treated with IDELA +R also had a significant improvement in overall survival (OS): HR (95% CI) = 0.28 (0.09, 0.86), p = 0.018. Adverse events (AEs) occurring in ≥20% of pts (any Gr/Gr ≥3) by arm were: pyrexia (IDELA + R 29%/3%; placebo + R 16%/1%), fatigue (IDELA + R 24%/3%; placebo + R 27%/2%), nausea (IDELA + R 24%/0%; placebo + R 22%/0%), chills (IDELA + R 22%/2%; placebo + R 16%/0%), infusion-related reactions (IDELA + R 16%/0%; placebo + R 28%/4%), and cough (IDELA + R 15%/0%; placebo + R 25%/2%). Other selected AEs (any Gr/Gr ≥3) included diarrhea (IDELA + R 19%/4%; placebo + R 14%/0%) and rash (IDELA + R 10%/2%; placebo + R 6%/0%). Select lab abnormalities (any Gr/Gr ≥3) included ALT elevation (IDELA + R 31%/6%; placebo + R 9%/1%), anemia (IDELA + R 26%/6%; placebo + R 30%/14%), neutropenia (IDELA + R 55%/34%; placebo + R 49%/22%), and thrombocytopenia (IDELA + R 17%/10%; placebo + R 26%/16%). The most common SAEs were pneumonia (6.4%), pyrexia (6.4%), and febrile neutropenia (4.5%) in IDELA + R, and pneumonia (8.4%), febrile neutropenia (5.6%), and dyspnea (3.7%) in placebo + R. AEs led to study drug discontinuation in 9 pts (8.2%) in IDELA + R and 11 pts (10.3%) in placebo + R. Based on a review of efficacy and safety, the DMC recommended stopping the study early. Conclusions IDELA + R demonstrated statistically significant improvement with acceptable safety over placebo + R in PFS, ORR, LNR and OS in heavily pretreated pts with relapsed CLL, including those with adverse genetic features. Disclosures: Furman: Gilead Sciences: Research Funding. Sharman:Gilead Sciences: Consultancy, Research Funding. Coutre:Gilead Sciences: Research Funding. Cheson:Gilead Sciences: Research Funding. Pagel:Gilead Sciences: Research Funding. Hillmen:Gilead Sciences: Research Funding. Barrientos:Gilead Sciences: Research Funding. Zelenetz:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Kipps:Gilead Sciences: Research Funding. Flinn:Gilead Sciences: Research Funding. Ghia:Gilead Sciences: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Eradat:Gilead Sciences: Research Funding. Ervin:Gilead Sciences: Research Funding. Lamanna:Gilead Sciences: Research Funding. Hallek:Gilead Sciences: Research Funding. Coiffier:Gilead Sciences: Research Funding. Pettitt:Gilead Sciences: Research Funding. Ma:Gilead Sciences: Research Funding. Stilgenbauer:Gilead Sciences: Honoraria, Research Funding. Aiello:Gilead Sciences: Employment. Johnson:Gilead Sciences: Employment, Equity Ownership. Miller:Gilead Sciences: Employment, Equity Ownership. Li:Gilead Sciences: Employment. Jahn:Gilead Sciences: Employment. Dansey:Gilead Sciences: Employment, Equity Ownership. O'Brien:Gilead Sciences: Research Funding.

Description: Abstract 2373 NK-cell alloreactivity determined by donor killer-cell immunoglobulin-like receptors (KIRs) has been shown to be predictive for relapse-free survival in myeloid leukemia after allogeneic stem cell transplantation. The role role of NK-cell allo reactivity in patients with multiple myeloma is unclear. Although the ligands for activating KIRs remain elusive, inhibitory KIRs on donor derived NK-cells and HLA class I molecules on the recipient cell determine NK cell alloreactivity. KIR genes on chromosome 19 segregate independently from HLA genes KIR haplotypes can be distinguished in two groups: group A has a fixed number of inhibitory receptors and only one activating receptor (KIR2DS4), while group B haplotype includes more activating receptor genes. Therefore individuals can be categorised as having A-KIR haplotype (A/A), or B-KIR haplotype which contains either A/B heterocygotes or B/B homocygotes KIRs. To analyse the effect of donor KIR-haplotype on outcome in multiple myeloma, we analysed 118 patients with a median age of 51 years (r: 29 – 68) who underwent allogeneic stem cell transplantation. Gender of the study population was predominantly male (n = 75, female: n = 33). Stem cell source was mainly peripheral blood stem cells (n = 105) and derived from unrelated donors (n = 81) or HLA-identical sibling (n = 37). 46 patients received graft from HLA-mismatched donor. The majority of the patients received a melphalan (100 – 140 mg/m2)/fludarabine-based reduced conditioning regimen (N = 106), either as part of an auto-allo-tandem protocol or as an allogeneic salvage protocol after relapse to an autograft. 46 patients had experienced relapse to an autograft prior to allogeneic stem cell transplantation. 79 patients were transplanted from KIR haplotype Bx and 39 from KIR haplotype A. Both groups were well balanced regarding age, HLA match, stem cell source, CMV seropositivity, remission status prior to transplantation, del 13q14, and relapse to prior autograft. After a median follow-up of 5 years the 5-year estimated disease-free and overall survival was better for KIR haplotype B donors in comparison to KIR haplotype A donors (30 % vs. 14 %, p = 0.008, and 49 % vs. 36 %, p = 0.07). The disease-free survival benefit for KIR haplotype B was mainly seen in HLA-matched patients (4y DFS: 39 % vs. 18 %, p = 0.005), while in HLA mismatch transplantation no difference according to KIR haplotype could be detected (26 % vs. 18 %, p = 0.5).The difference in survival in the HLA-matched group was due to higher risk of relapse for KIR haplotype A in the HLA-matched group (cumulative incidence at 1 year 46 % vs. 17 %, p = 0.005). In a multivariate Cox model KIR haplotype A remained a significant factor for worse disease-free (HR: 1.82, p = 0.008) and overall survival (HR: 1.69, p = 0.042). Other significant factors in the multivariate analysis were female donor sex (HR: 1.67, p = 0.04) and chemo-refractory disease at transplantation (HR: 1.76, p = 0.03) for OS and factors for DFS were unrelated donor (HR: 1.83, p = 0.02) and patient's age as continous variable (HR: 1.03, p =0.008) and donor female sex (HR: 1.62, p = 0.03). We conclude that female donor sex and KIR haplotype A are important risk factors for outcome of allogeneic SCT in multiple myeloma and should be considered for donor selection. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1709 Introduction: Currently, small molecule FLT3 tyrosine kinase inhibitors (TKIs) are promising therapeutic approaches to overcome the dismal prognosis of AML patients harbouring FLT3-ITD mutations. However, up to 30% of these patients show primary resistance to FLT3-TKIs. Recently, we uncovered a novel mechanism of primary resistance to FLT3 TKIs in a patient displaying an atypical integration site of ITD within the beta2-sheet (ITD_A627E). The data suggested that atypical integration sites of ITDs within the tyrosine kinase domain-1 (TKD1) of FLT3 (beta1-sheet, nucleotide binding loop and beta2-sheet) are associated with rewired signaling and differential responsiveness to TKIs. Here, we characterized response to FLT3-TKIs employing various TKD1-ITDs of the beta1-sheet and nucleotide binding loop, respectively in a cellular reconstitution model. Methods: FLT3 TKD1-ITDs isolated from patient material, were sequenced, subcloned and stably transfected into growth-factor dependent hematopoietic Ba/F3 cells. Constitutive FLT3 phosphorylation and activation of downstream signaling was analyzed by Western-blotting. Transformation potential was analyzed by colony formation in methylcellulose medium and by withdrawal of IL-3. Induction of apoptosis in response to TKI (midostaurin/sorafenib) was measured by FACS analysis. Results: Biological characteristics of FLT3-ITDs from two structural domains of FLT3-TKD1 were characterized: (1) beta1-sheet-ITDs E611V (96nt) and Q613E (99nt) and (2) nucleotide binding loop-ITD A620V (84nt). Ba/F3 cells expressing these ITDs showed colony formation in methylcellulose assays and growth-factor independent proliferation upon IL-3 withdrawal indicating transformation. Western-blotting revealed constitutive phosphorylation of FLT3 and of downstream signaling nodes (STAT5/AKT/ERK). As compared to a typical juxtamembrane domain (JMD) ITD (ITD598, 36nt), we observed significantly less induction of apoptosis in TKD1-ITDs investigated at 24h of incubation across all concentrations of midostaurin used. Similar results were observed when TKD1-ITDs were treated with different concentrations of sorafenib for 24h. However, this difference in sensitivity gradually decreased when incubating with midostaurin or sorafenib for longer periods of time as 36h and 48h. Currently, additional FLT3-TKIs are being investigated and results will be presented. Conclusion: Our results employing representative TKD1-ITDs from beta1-sheet and nucleotide binding loop revealed that TKD1-ITDs mediate constitutive activation of FLT3 receptors leading to transformation of hematopoietic cells. In comparison to a typical JMD-ITD, TKD1-ITDs analyzed revealed differential responsiveness in induction of apoptosis to midostaurin and sorafenib. Thus, our in vitro data suggest that different ITD integration sites may be associated with differential sensitivity to midostaurin and sorafenib in vivo and provides a rationale to prospectively analyze not only the FLT3-ITD mutation status but also the ITD integration site in ongoing/future clinical trials using FLT3-TKIs. Disclosures: No relevant conflicts of interest to declare.