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A Phase I Trial of Ipilimumab (IPI) in Patients (PTS) with Myelodysplastic Syndromes (MDS) after Hypomethylating Agent (HMAS) Failure
Guided Poster Presentations – 14th International Symposium on Myelodysplastic Syndromes / Leukemia Research 55 S1 (2017) S37–S44
our institution, and we compared their clinical outcomes with de novo MDS patients (n = 199). Methods: A retrospective analysis was performed with 266 consecutive patients (67 t-MDS, 199 de novo MDS) who received alloHCT from 2000 to 2015. Survival estimates were obtained using Kaplan-Meier method and multivariate analyses were performed to identify independent prognosticators. Pre-transplant t-MDS samples were analyzed using next generations sequencing (NGS) assay designed to target the entire coding sequence of 72 genes commonly mutated in lymphoid and myeloid malignancies. Results: The 5-year overall survival (OS) was not different between t-MDS and de novo MDS cases (49.9% vs. 53.9%, p = 0.61), and both cohorts had similar 5-year non-relapse mortality (NRM) and relapse rate (RR). This is despite higher-risk karyotype (61.2% vs. 31.7%, p < 0.001), higher proportion of Int-2/High IPSS (59.7% vs. 43.7%, p = 0.03), and more likely to receive reduced intensity conditioning (94% vs. 70.4%, p < 0.001) among t-MDS patients. In multivariate analysis for the entire cohort, t-MDS was not associated with OS ( p = 0.40). For t-MDS, younger age ( p = 0.016), and more recent era of alloHCT ( p = 0.01) were independently associated with longer RFS and OS whereas karyotypes, IPSS, and % blasts before HCT were not. Among 60 t-MDS patients with available pre-HCT DNA samples, TP53 mutation was the most common abnormality observed in 18 (30%) patients, and TP53 mutated t-MDS was enriched with complex and/or monosomal karyotype in contrast to TP53-wild tMDS ( p = 0.02). Interestingly, TP53 mutation did not impact OS or RFS among t-MDS in our transplanted cohort. Conclusion: AlloHCT is a curable treatment for a subset of t-MDS, with similar survival to de novo MDS despite higher-risk pretransplant features in t-MDS. No increased in NRM was observed in t-MDS despite prior exposure to cytotoxic therapy. While TP53 alteration was the most common mutation in t-MDS, the finding was not detrimental in our case-series, and subset of TP53-mutated t-MDS can be cured with alloHCT in contrast to prior reports.
64 A PHASE I TRIAL OF IPILIMUMAB (IPI) IN PATIENTS (PTS) WITH MYELODYSPLASTIC SYNDROMES (MDS) AFTER HYPOMETHYLATING AGENT (HMAS) FAILURE A. Zeidan1, H. Knaus2, T. Robinson2, J. Zeidner3, A. Blackford2, A. Duffield2, D. Rizzieri4, M. Frattini5, M.Y. Levy6, M. Schroeder7, A. Ferguson2, K. Sheldon2, A. Dezern2, I. Gojo2, S. Gore1, H. Streicher8, L. Luznik2, B.D. Smith2 1 Department of Medicine, Yale University, New Haven, USA; 2Johns Hopkins, Oncology, Baltimore, USA; 3University of North Carolina, Medicine, Raeligh, USA; 4Duke University, Medicine, Durham, USA; 5 Columbia University, Medicine, NYC, USA; 6Baylor College, Medicine, Houston, USA; 7Washington University, Medicine, St Louis, USA; 8 National Cancer Institute, CTEP, Bethesda, USA Background: Pts with HR-MDS after HMA failure have a poor overall survival (OS) of <6 months. Immune escape is associated with resistance to HMAs in MDS. We hypothesized that CTLA-4 blockade in these pts would be tolerable and lead to clinical responses. Methods: This investigator-initiated, CTEP-sponsored, multicenter phase 1b study enrolled pts after failure of HMAs. In doseescalation, ipi monotherapy was given at 2 dose levels (DL): 3 and 10 mg/kg. Four doses (every 3 weeks) were administered followed by a maintenance phase (4 doses every 3 months) for non-porgressors. Toxicities and responses were evaluated with CTCAE4 and IWG2006 criteria, respectively. OS was estimated using the Kaplan-Meier method. The impact on T-cells were studied by flow cytometry and TCR sequencing.
S43
Results: 29 pts from 7 centers were enrolled. Mean age (SD) was 67 (8) years. Most had IPSS high/int-2 (55%), 45% had int-1. Three of 6 pts in DL1 and 4 of 5 pts in DL2 experienced grade [G] 2–4 immunerelated adverse events [IRAEs] that were reversible with drug discontinuation or systemic steroids. The DL1 (3mg/kg) was expanded with no G2–4 IRAEs reported in the 18 additional pts. A total of 15 deaths occurred due to disease progression or other complications but none attributed to ipilimumab. In total, 52% received all 4 induction doses, and 24% received ≥1 maintenance dose. Best objective responses were 2 marrow complete responses (mCR, 7%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 6 pts (21%) and for ≥54 weeks in 3 pts (10%). Five pts (17%) subsequently underwent allogeneic transplantation (alloSCT) without evidence of excessive toxicity. Median OS (censoring at alloSCT) was 294 days (95%CI, 240–671+) and 400 days (95%CI, 240–671+) for those who received maintenance (n = 7). Pts who achieved PSD and mCR had significantly increased expression of ICOS, a marker of T-cell activation [Figure]. Conclusions: However, ipi monotherapy efficacy is limited after HMA failure and combination-based approaches should be considered. Increased frequencies of ICOS expression might predict clinical benefit.
65 RUNX1 LOSS OF FUNCTION DRIVES RESISTANCE TO LENALIDOMIDE IN DEL(5Q) MYELODYSPLASTIC SYNDROME PATIENTS S. Martinez-Høyer1, A. Mo1, R. Docking2, J. Li2, S. Chan2, P. Umlandt1, M. Fuller1, M. Jädersten3, E. Hellström-Lindberg3, U. Platzbecker4, J. Parker2, A. Karsan1,2 1 Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 W 10th Ave, Vancouver, BC, V5Z1L3, Canada; 2Pathology and Laboratory Medicine, University of British Columbia, 675 W 10th Ave, Vancouver, BC, V5Z1L3, Canada; 3Unit of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 4University Hospital Carl Gustav Carus, Dresden, Germany Deletion of the long arm of chromosome 5 (del(5q)) is the most common karyotypic alteration in myelodysplastic syndromes (MDS). The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) patients, achieving transfusion independence and remission in two-thirds of treated patients. Despite its efficacy, 50% of LEN-treated patients eventually relapse within an interval of 2–3 years after treatment, which is associated with the presence of TP53 mutations. Since TP53 mutation cannot explain all relapse cases, there is a need to identify novel drivers of LEN resistance in del(5q) patients. We have compared whole genome sequencing data of paired samples from six del(5q) patients who have been treated with LEN and eventually became resistant to the treatment. We identified 2 patients with mutations in TP53 gene (R273S and C238Y). The remaining four presented RUNX1 alterations: two patients had protein coding mutations in RUNX1 (K83Q and D171N) and two had a significant reduction in RUNX1, but not TP53, transcript levels. Furthermore, transcriptome analysis of paired samples revealed recurrent upregulation of pathways related to cell cycle progression at relapse, such as MYC and mTORC1. To assess the relevance of RUNX1 loss-of-function (LOF) in the response to LEN, we used the CRISPR/Cas9 system to generate RUNX1 knock-out (KO) cell lines derived from the LEN-sensitive de (5q) cell line MDS-L. RUNX1 KO del(5q) cells presented reduced sensitivity to LEN treatment as shown by increased cell cycle entry and reduced apoptosis compared to wt control cells. These results were validated with different shRNAs against RUNX1 in KG-1a del (5q) cells. In parallel with their reduced promoter transactivation
our institution, and we compared their clinical outcomes with de novo MDS patients (n = 199). Methods: A retrospective analysis was performed with 266 consecutive patients (67 t-MDS, 199 de novo MDS) who received alloHCT from 2000 to 2015. Survival estimates were obtained using Kaplan-Meier method and multivariate analyses were performed to identify independent prognosticators. Pre-transplant t-MDS samples were analyzed using next generations sequencing (NGS) assay designed to target the entire coding sequence of 72 genes commonly mutated in lymphoid and myeloid malignancies. Results: The 5-year overall survival (OS) was not different between t-MDS and de novo MDS cases (49.9% vs. 53.9%, p = 0.61), and both cohorts had similar 5-year non-relapse mortality (NRM) and relapse rate (RR). This is despite higher-risk karyotype (61.2% vs. 31.7%, p < 0.001), higher proportion of Int-2/High IPSS (59.7% vs. 43.7%, p = 0.03), and more likely to receive reduced intensity conditioning (94% vs. 70.4%, p < 0.001) among t-MDS patients. In multivariate analysis for the entire cohort, t-MDS was not associated with OS ( p = 0.40). For t-MDS, younger age ( p = 0.016), and more recent era of alloHCT ( p = 0.01) were independently associated with longer RFS and OS whereas karyotypes, IPSS, and % blasts before HCT were not. Among 60 t-MDS patients with available pre-HCT DNA samples, TP53 mutation was the most common abnormality observed in 18 (30%) patients, and TP53 mutated t-MDS was enriched with complex and/or monosomal karyotype in contrast to TP53-wild tMDS ( p = 0.02). Interestingly, TP53 mutation did not impact OS or RFS among t-MDS in our transplanted cohort. Conclusion: AlloHCT is a curable treatment for a subset of t-MDS, with similar survival to de novo MDS despite higher-risk pretransplant features in t-MDS. No increased in NRM was observed in t-MDS despite prior exposure to cytotoxic therapy. While TP53 alteration was the most common mutation in t-MDS, the finding was not detrimental in our case-series, and subset of TP53-mutated t-MDS can be cured with alloHCT in contrast to prior reports.
64 A PHASE I TRIAL OF IPILIMUMAB (IPI) IN PATIENTS (PTS) WITH MYELODYSPLASTIC SYNDROMES (MDS) AFTER HYPOMETHYLATING AGENT (HMAS) FAILURE A. Zeidan1, H. Knaus2, T. Robinson2, J. Zeidner3, A. Blackford2, A. Duffield2, D. Rizzieri4, M. Frattini5, M.Y. Levy6, M. Schroeder7, A. Ferguson2, K. Sheldon2, A. Dezern2, I. Gojo2, S. Gore1, H. Streicher8, L. Luznik2, B.D. Smith2 1 Department of Medicine, Yale University, New Haven, USA; 2Johns Hopkins, Oncology, Baltimore, USA; 3University of North Carolina, Medicine, Raeligh, USA; 4Duke University, Medicine, Durham, USA; 5 Columbia University, Medicine, NYC, USA; 6Baylor College, Medicine, Houston, USA; 7Washington University, Medicine, St Louis, USA; 8 National Cancer Institute, CTEP, Bethesda, USA Background: Pts with HR-MDS after HMA failure have a poor overall survival (OS) of <6 months. Immune escape is associated with resistance to HMAs in MDS. We hypothesized that CTLA-4 blockade in these pts would be tolerable and lead to clinical responses. Methods: This investigator-initiated, CTEP-sponsored, multicenter phase 1b study enrolled pts after failure of HMAs. In doseescalation, ipi monotherapy was given at 2 dose levels (DL): 3 and 10 mg/kg. Four doses (every 3 weeks) were administered followed by a maintenance phase (4 doses every 3 months) for non-porgressors. Toxicities and responses were evaluated with CTCAE4 and IWG2006 criteria, respectively. OS was estimated using the Kaplan-Meier method. The impact on T-cells were studied by flow cytometry and TCR sequencing.
S43
Results: 29 pts from 7 centers were enrolled. Mean age (SD) was 67 (8) years. Most had IPSS high/int-2 (55%), 45% had int-1. Three of 6 pts in DL1 and 4 of 5 pts in DL2 experienced grade [G] 2–4 immunerelated adverse events [IRAEs] that were reversible with drug discontinuation or systemic steroids. The DL1 (3mg/kg) was expanded with no G2–4 IRAEs reported in the 18 additional pts. A total of 15 deaths occurred due to disease progression or other complications but none attributed to ipilimumab. In total, 52% received all 4 induction doses, and 24% received ≥1 maintenance dose. Best objective responses were 2 marrow complete responses (mCR, 7%). Prolonged stable disease (PSD) for ≥46 weeks occurred in 6 pts (21%) and for ≥54 weeks in 3 pts (10%). Five pts (17%) subsequently underwent allogeneic transplantation (alloSCT) without evidence of excessive toxicity. Median OS (censoring at alloSCT) was 294 days (95%CI, 240–671+) and 400 days (95%CI, 240–671+) for those who received maintenance (n = 7). Pts who achieved PSD and mCR had significantly increased expression of ICOS, a marker of T-cell activation [Figure]. Conclusions: However, ipi monotherapy efficacy is limited after HMA failure and combination-based approaches should be considered. Increased frequencies of ICOS expression might predict clinical benefit.
65 RUNX1 LOSS OF FUNCTION DRIVES RESISTANCE TO LENALIDOMIDE IN DEL(5Q) MYELODYSPLASTIC SYNDROME PATIENTS S. Martinez-Høyer1, A. Mo1, R. Docking2, J. Li2, S. Chan2, P. Umlandt1, M. Fuller1, M. Jädersten3, E. Hellström-Lindberg3, U. Platzbecker4, J. Parker2, A. Karsan1,2 1 Michael Smith Genome Sciences Centre, BC Cancer Agency, 675 W 10th Ave, Vancouver, BC, V5Z1L3, Canada; 2Pathology and Laboratory Medicine, University of British Columbia, 675 W 10th Ave, Vancouver, BC, V5Z1L3, Canada; 3Unit of Hematology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden; 4University Hospital Carl Gustav Carus, Dresden, Germany Deletion of the long arm of chromosome 5 (del(5q)) is the most common karyotypic alteration in myelodysplastic syndromes (MDS). The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) patients, achieving transfusion independence and remission in two-thirds of treated patients. Despite its efficacy, 50% of LEN-treated patients eventually relapse within an interval of 2–3 years after treatment, which is associated with the presence of TP53 mutations. Since TP53 mutation cannot explain all relapse cases, there is a need to identify novel drivers of LEN resistance in del(5q) patients. We have compared whole genome sequencing data of paired samples from six del(5q) patients who have been treated with LEN and eventually became resistant to the treatment. We identified 2 patients with mutations in TP53 gene (R273S and C238Y). The remaining four presented RUNX1 alterations: two patients had protein coding mutations in RUNX1 (K83Q and D171N) and two had a significant reduction in RUNX1, but not TP53, transcript levels. Furthermore, transcriptome analysis of paired samples revealed recurrent upregulation of pathways related to cell cycle progression at relapse, such as MYC and mTORC1. To assess the relevance of RUNX1 loss-of-function (LOF) in the response to LEN, we used the CRISPR/Cas9 system to generate RUNX1 knock-out (KO) cell lines derived from the LEN-sensitive de (5q) cell line MDS-L. RUNX1 KO del(5q) cells presented reduced sensitivity to LEN treatment as shown by increased cell cycle entry and reduced apoptosis compared to wt control cells. These results were validated with different shRNAs against RUNX1 in KG-1a del (5q) cells. In parallel with their reduced promoter transactivation