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PURPOSE Colony-stimulating factor-3 receptor ( CSF3R)-T618I is a recurrent activating mutation in chronic neutrophilic leukemia (CNL) and to a lesser extent in atypical chronic myeloid leukemia (aCML) resulting in constitutive JAK-STAT signaling. We sought to evaluate safety and efficacy of the JAK1/2 inhibitor ruxolitinib in patients with CNL and aCML, irrespective of CSF3R mutation status. METHODS We conducted a phase II study of ruxolitinib in 44 patients (21 CNL and 23 aCML). The primary end point was overall hematologic response rate (ORR) by the end of 6 continuous 28-day cycles for the first 25 patients enrolled. We considered a response as either partial (PR) or complete response (CR). We expanded accrual to 44 patients to increase our ability to evaluate secondary end points, including grade ≥ 3 adverse events, spleen volume, symptom assessment, genetic correlates of response, and 2-year survival. RESULTS ORR was 32% for the first 25 enrolled patients (8 PR [7 CNL and 1 aCML]). In the larger cohort of 44 patients, 35% had a response (11 PR [9 CNL and 2 aCML] and 4 CR [CNL]), and 50% had oncogenic CSF3R mutations. The mean absolute allele burden reduction of CSF3R-T618I after 6 cycles was greatest in the CR group, compared with the PR and no response groups. The most common cause of death is due to disease progression. Grade ≥ 3 anemia and thrombocytopenia were observed in 34% and 14% of patients, respectively. No serious adverse events attributed to ruxolitinib were observed. CONCLUSION Ruxolitinib was well tolerated and demonstrated an estimated response rate of 32%. Patients with a diagnosis of CNL and/or harboring CSF3R-T618I were most likely to respond.

7027 Background: TP-0903 is a multi-kinase inhibitor designed to target AXL, a receptor tyrosine kinase, and also inhibits cell cycle regulators such as Chk1/2 and other AML associated kinases. TP-0903 has shown prior anti-tumor activity at a safe dose in solid tumors. In pre-clinical AML studies, TP-0903 shows potent cytotoxicity in TP53 mutant ( TP53m) AML cell lines, an adverse prognostic genomic sub-group of AML. TP-0903 also had synergistic activity with decitabine (dec) in TP53m AML and prolonged survival in xenograft and genetically engineered mouse models. We report here on the initial safety and clinical results from the Leukemia and Lymphoma Society’s ongoing Beat AML phase 1b/2 (Ph1b/2) trial of TP-0903 in combination with dec (ClinicalTrials.gov NCT03013998). Methods: Newly diagnosed AML pts ≥60 years with TP53m and/or complex karyotype (≥3 abnormalities) were selected for a Ph1b/2 dose escalation study of TP-0903 combined with dec. Seven Ph1b pts were given TP-0903 every 28-day cycle from days 1-21 (Dose level (DL) 1 = 37 mg/day) and dec IV days 1-10 (20 mg/m2). A standard 3+3 design was used to evaluate the safety and tolerability. Nine additional patients enrolled onto Ph2 at DL1, but further assessments of safety, pharmacokinetics (PK) and correlative data was used to update the final recommended Ph2 dose (RP2D) of TP-0903 to DL-1 (25 mg/day) with dec. Results: At data cutoff (10Jan2022), 16 total pts were accrued. Ph1b treated 7 pts at DL1, 6 were DLT evaluable, and no DLTs were observed. Ph2 enrolled and treated 9 pts at DL1 before concerns of delayed count recovery led to the reduction of the Ph2 dose of TP-0903 to DL-1 (25 mg/day). For all 16 pts treated at DL1, 1 pt achieved CR, 4 pts CRh, and 1 pt CRi, for a composite CR (CR/CRh/CRi) rate of 37.5% (95% CI, 15.2-64.6), with 4 pts achieving MRD negativity by central flow cytometry. For the remaining 10 pts, 1 pt achieved MLFS (6%), 6 pts had stable disease (37.5%), 1 pt had treatment failure (6%), and 2 pts were not evaluable (12.5%) due to withdrawal of consent and death from early disease progression. Two pts (1 CR and 1 CRh) proceeded to stem cell transplantation. The most common grade 3 and above treatment-related AEs include decreased neutrophil counts (37.5%), platelet counts (31.3%), and anemia (18.8%). Finally, PK and correlative data analysis looking at soluble Axl and Gas6 also supported reduction to DL-1. Conclusions: Initial results with DL1 suggest that TP-0903/dec shows preliminary clinical activity in the prognostically poor TP53m/complex karyotype AML sub-group, with 4 pts achieving MRD negative status out of 6 patients who achieved a CR/CRh/CRi (66%). After further patients were treated on DL1, the toxicity profile and correlative data supported the de-escalation to DL-1 as the RP2D. The Ph2 study is ongoing to determine the clinical activity of this new RP2D (DL-1). Clinical trial information: NCT03013998.

7020 Background: The advent of genomic sequencing technologies has revealed underlying genetic alterations, such as FLT3 mutations, that can be targeted in acute myeloid leukemia (AML). However, development of resistance limits the durability of response. Recent data has implicated that factors from the bone marrow microenvironment mediate initial resistance to FLT3 inhibitors (FLT3i) in AML. We combined high dimensional characterization techniques, time-of-flight mass cytometry (CyTOF) and RNA sequencing, to examine sequential marrow stromal samples from a subset of patients with FLT3 mutated AML treated with the FLT3i gilteritinib. Here, we report on the heterogeneity and evolution of cell surface and secreted factors over time. Methods: RNA sequencing of primary FLT3-ITD stromal samples (N = 29) from pre-study and on-treatment patients enabled prioritization of candidate targets for CyTOF. Target-specific purified antibodies were purchased pre-conjugated to metal lanthanides or conjugated in house according to manufacturer protocols (after validation via traditional flow cytometry). Primary stromal cells were cultured ex vivo until confluent and were harvested and stained according to a standardized protocol, and subsequently run on a Helios (Fluidigm) mass cytometer. A computational approach was employed to compensate and visualize data via the CATALYST R package. A total of four pre-treatment and four post-gilteritinib timepoint isolates (N = 8) were analyzed. Results: A 36-target mass cytometry panel revealed protein level differences in patients before and after gilteritinib therapy. Dimensional reduction techniques such as MDS and UMAP showed that samples taken from later timepoints clustered together compared to their earlier counterparts with respect to global protein expression. Inflammatory mediators such as IL1-beta and MCP-1 were upregulated in patient stroma soon after gilteritinib treatment and therefore potentially contribute to early resistance. Novel markers previously implicated in early resistance to targeted therapies in AML such as FGF2 and FGFR1 similarly peaked earlier in treatment, mimicking the clinical course of expression observed in marrow stroma of patients treated with another FLT3 inhibitor quizartinib (Traer et al. Cancer Res. 2016). Conclusions: Our findings show that primary marrow stroma evolves during gilteritinib treatment, and that stromal proteins previously reported to promote early resistance to FLT3i are also upregulated during gilteritinib resistance. The heterogeneity of stromal cell isolates detected by mass cytometry highlights the utility of high dimensional tracking of disease course in patients, and may enable a better understanding of how the temporal evolution of the marrow microenvironment contributes to development of resistance to targeted therapies such as gilteritinib and other FLT3i over time.

7025Background: AML has high molecular complexity and certain markers are predictors of overall survival. Mutations in FLT3-ITD, for example, lead to a poor prognosis with outcomes further worsened...

The introduction of imatinib, a specific inhibitor of the Bcr-Abl tyrosine kinase, has dramatically changed the management of chronic myeloid leukemia (CML). More than 10,000 patients worldwide have been treated with imatinib in clinical trials, and a large body of information has accumulated about the use of this drug. The purpose of this article is to review practical guidelines in regard to optimal dosing, monitoring, managing common side effects such as myelosuppression, and potential drug interactions. The treatment recommendations are intended to optimize therapy with imatinib while taking into account a patient’s specific circumstances.

e14546Background: Acute myeloid leukemia (AML) is a candidate for novel therapeutics, specifically immune checkpoint (IC) inhibitors. V-domain Ig Suppressor of T cell Activation (VISTA) is a novel ...

7047 Background: PON, an approved oral tyrosine kinase inhibitor (TKI), has potent activity against native BCR-ABL and resistant mutants, including T315I. A phase 1 trial evaluated PON safety and a...

7073 Background: Outcomes in adult Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ALL) remain poor with a 5 year overall survival of less than 40%. Addition of the targeted BCR-A...

7063 Background: Ponatinib is a potent oral pan–BCR-ABL tyrosine kinase inhibitor (TKI) that is active against native and mutated forms of BCR-ABL. The safety and anti-leukemic activity of ponatinib in patients (pts) with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) were evaluated in a phase I clinical trial. Methods: Pts (N=81) with resistant/refractory hematologic malignancies were enrolled in this ongoing, open-label, dose escalation, phase I study. Ponatinib was dosed once daily (2–60 mg). 65 pts had Ph+ leukemia and are included in the present analysis (data as of 9 Nov 2012). Median follow-up was 25 (0.5–44) mos. Results: The median age of pts was 55 yrs; median time since diagnosis was 6.5 yrs. Pts were heavily pretreated (94% had received ≥2 prior TKIs, 62% ≥3). 65% had baseline BCR-ABL mutations. 46% (67% chronic phase [CP] CML) of pts remained on study. Progression and adverse events (AEs) were the most common reasons for discontinuation (17% each). The most common treatment-related AEs were rash (42%), thrombocytopenia (34%), arthralgia (20%), and increased lipase (20%). Significant anti-leukemic activity was observed (Table). Responses (major cytogenetic response [MCyR] for CP-CML or major hematologic response [MaHR] for accelerated phase [AP] CML, blast phase [BP] CML, or Ph+ ALL) were observed against the following mutations detected in >1 pt at baseline: 14/19 T315I, 4/7 F317L, 2/4 G250E, 2/2 M244V, 2/2 M35IT, and 1/2 F359V. Among CP-CML pts, 73% with complete cytogenetic response (CCyR) and 63% with major molecular response (MMR) are estimated to maintain response at 2 yrs (Kaplan-Meier). Of 28 CP-CML pts with CCyR, 25 remained on study (19 with continuous CCyR); of 22 pts with MMR, 21 remained on study (15 with continuous MMR). Updated data will be presented. Conclusions: Significant and durable responses were observed in heavily pretreated CP-CML pts, regardless of mutation status, and ponatinib was generally well tolerated. Clinical trial information: NCT00660920. [Table: see text]

9555 Background: Despite advances in treatment and outcomes in pediatric acute lymphoblastic leukemia, there continue to be subsets of patients that are refractory to standard intensive chemotherapy. Therefore, novel agents are needed to further advance treatment for this disease. YM155 (Astellas) is a selective suppressant of survivin expression. Survivin has been shown to be over-expressed in malignant cells and in relapsed ALL. Early adult phase I/II studies show promise in both tolerability and possible efficacy in B-cell malignancies. Methods: Fresh diagnostic leukemic patient samples, ALL cell lines, and xenograft samples were obtained and subjected to YM155 at doses ranging from 1nM to 10µM. Samples were then tested for viability using standard methane-thiosulfate, apoptosis using Guava nexin Annexin V binding, protein expression using immunoblot, and P53 activation with phospho-flow cytometry. Results: The median IC50 for viability and apoptosis for the samples are: NCI standard risk ALL 5.3nM ±3.47, NCI high risk ALL 91.76 nM ±93.42, T-ALL 336.6nM ±147.7, AML 333.6nM ±489, Ph+ALL xenografts 3.8nM ±1.04, and ALL cell lines 18.5nM ±135. Ph+ALL samples, including primary patient, xenograft, and dasatinib (BMS) resistant samples remain significantly sensitive to YM155. For dasatinib sensitive samples, combination therapy suggests an additive effect by isobologram analysis. Immunoblot and RT2-PCR Arrays (Qiagen) identify that multiple protein expression are decreased with YM155 treatment. Conclusions: Our data supports the model of the use of YM155 as a treatment for ALL including an added benefit in combination with dasatinib in Ph+ALL. Although initial studies suggested that YM155 is a selective suppressant of survivin, subsequent studies are beginning to identify off target effects. These off target effects may enhance the drugs potential for activating cell death. Finally, we show that screening primary samples with YM155 has the potential to select a target population that is more sensitive to YM155 treatment. Future studies will be designed to develop YM155 as an additional therapeutic agent for pediatric acute lymphoblastic leukemia.

10503 Background: A challenge in delivering personalized cancer care to the clinic is identifying tumor genotypes that predict response to targeted therapeutics. Methods: In 2008, we established a ...

6508 Background: Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with proven preclinical and clinical activity against imatinib resistant BCR-ABL mutations. Methods: CA180013 is an open-label Phase II study of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients (pts) with CP-CML. Between February-August 2005, 424 pts were recruited from 75 centers worldwide. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity. Evaluations were weekly blood counts for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. The primary endpoint was rate of major cytogenetic response (MCyR; ≤35% Philadelphia pos. metaphases) in IM-R pts. Results: Data are currently available from the first 186 pts (127 IM-R, 59 IM-I) accrued prior to May 12, 2005. Median age was 59 yrs (range 24–79); 46% were male. Median time from diagnosis of CML was 64 months. Of the IM-R pts, 72% received IM >3 yrs, and 72% had >600 mg/day of IM. Overall, 70% had received prior interferon alpha. 62 (33%) pts achieved a prior MCyR to IM. With ≥6 months of follow up, 168 (90%) pts had a complete hematologic response (CHR). MCyR were achieved in 83 (45%) pts including 40 (31%) of IM-R pts, and 43 (73%) of IM-I pts. Mutations in the BCR-ABL domain were found in 65/176 (37%) pts; 57 (88%) achieved CHR, and 24 (37%) MCyR. Molecular response analysis is ongoing. 160 (86%) pts remain on study without progression. Grade 3/4 neutropenia or thrombocytopenia was reported in 83 (45%) pts and 85 (46%) pts with onset after 4–8 weeks of therapy in most pts. Temporary dose interruptions occurred in 146 (78%), and dose reductions in 96 (52%) pts with a median daily of 108 (range 19–169) mg. Non-hematologic toxicity consisted mainly of Grade 1/2 diarrhea, headache, superficial edema, and pleural effusion, with ≤2% Grade 3/4. There was no cross-intolerance between dasatinib and IM. Conclusions: Dasatinib demonstrated substantial hematologic and cytogenetic activity in IM-R and IM-I pts with CP-CML. An updated analysis of 424 pts with ≥6 months of follow up will be presented. [Table: see text]

6506 Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed patients (pts) with CML-CP (O’ Brien et al, NEJM 2003). 1,106 pts were randomized between June 2000 and Jan 2001 to either IM 400 mg or IFN+Ara-C with 553 pts to each treatment. This abstract is based on data collected up to 54 months after last patient had been recruited on IM. 60-months (5-year) data will be available for presentation. Methods: Evaluations included complete hematologic response (CHR), complete/partial cytogenetic response (CCyR/PCyR - defined as 0% / 1–35% Ph+ metaphases respectively), major cytogenetic response (MCyR=CCyR+ PCyR), major molecular response (MMR) - defined as ≥ 3 log reduction of BCR-ABL transcript levels from the standardized baseline, time to progression - defined as loss of CHR/MCyR, evolution to accelerated phase/blast crisis (AP/BC), or death due to any cause during treatment, and overall survival. Results: With a median follow-up of 54-months, 72% of the 553 randomized pts remain on initial IM treatment (5% of pts discontinued due to adverse events, 9.5% due to unsatisfactory therapeutic effect and 11% due to other reasons another 2.5% crossed over to IFN+Ara-C). Overall, the cumulative best response rates of CHR, MCyR and CCyR are 97%, 88% and 82%, respectively. The overall estimated survival was 90% (93% when censored at bone marrow transplant). An estimated 84% of pts have not progressed on treatment and 93% of pts were free from progression to AP/BC. The annual rate of progression to AP/BC of < 1% in the fourth year was lower than each of the first three years (1.5, 2.8, and 1.6%, respectively). Of the pts with MCyR at 12 months (n=436), an estimated 96% were free of progression to AP/BC at 54 months whereas it was only 81% for the 73 pts who did not achieve a MCyR at 12 months (p< 0.001). No patient with a MMR within 12 months progressed to AP/BC within 54 months. Conclusions: This analysis confirms the high rates and durability of responses to IM. Encouragingly, the rate of progression in the fourth year was lower than in each of the preceding three years. Results further demonstrate the beneficial effect of cytogenetic and molecular responses on long-term outcomes. [Table: see text]