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Update on a Phase 1/2 First-in-Human Study of the Menin-KMT2A (MLL) Inhibitor Ziftomenib (KO-539) in Patients with Relapsed or Refractory Acute Myeloid Leukemia
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Blood | November 28, 2022 | Volume: 140 | Issue: Supplement 1 | Pages: 153-156
Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19
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Schmidt, Andrew , Schoenfeld, Adam Jacob , Schwartz, Gary K. , Tucker, Matthew D. , Wotman, Michael T. , Thompson, Michael A. , Shah, Dimpy P. , Warner, Jeremy L. , Wise-Draper, Trisha Michel , Goel, Sanjay , Halmos, Balázs , Shapiro, Lauren C. , Shastri, Aditi , Sica, Roberto Alejandro , Henderson, Jeffrey P. , Stockerl‐Goldstein, Keith , Zhou, Alice Y. , Tadesse, Eyob, Gatson, Na Tosha , Loree, Jonathan M. , Lam, Barbara, Peters, Mary Linton B , Egan, Pamela , Farmakiotis, Dimitrios , Olszewski, Adam J. , Hatton, Edward, Rose, Suzanne J. , Pennell, Nathan A , Painter, Corrie , Li, Ang , Bitterman, Danielle S. , Florez, Narjust , Giordano, Antonio , Morgans, Alicia K. , Nohria, Anju , Saliby, Renée Maria , Van Allen, Eliezer M , Xu, Wenxin Vincent , Halabi, Susan , Graber, Jerome J. , Hawley, Jessica E. , Loggers, Elizabeth T , Lyman, Gary H , Nakasone, Elizabeth S. , Yeh, Albert C. , Makary, Mina S. , Rosenstein, Lori J. , Elias, Rawad , Fein, Joshua Alexander , Gadgeel, Shirish M. , Bhutani, Divaya , Hershman, Dawn L. , Alexander, Mariam, Reuben, Daniel Y. , De‐la‐Rosa‐Martinez, Daniel , Vilar‐Compte, Diana , McWeeney, Shannon K. , Peters, Solange , Nagaraj, Gayathri , Wehbe, Firas , Durbin, Eric B. , Nelson, Heather H. , Boland, Genevieve M. , Rosovsky, Rachel , Bekaii‐Saab, Tanios , Joyner, Michael J. , Senefeld, Jonathon W. , Mesa, Ruben A. , Ramirez, Amelie G , Shah, Pankil , Papenburg, Jesse , Vinh, Donald Cuong , Singh, Harpreet , Bao, Ting , O'Cearbhaill, Roisin E , Philip, John , Robson, Mark E. , Rosenberg, Jonathan E, Wilkins, Cy R. , Tamimi, Rulla M. , Dill, Jennifer, Chandrasekhar, Sanjay Amrith , Cabal, Angelo , Hsiao, Albert , Razavi, Pedram , Reid, Erin G , Rink, Cameron L. , Griffiths, Elizabeth A. , Jain, Prantesh , Moffitt, Melissa , O’Connor, Tracey L. , Smith, Laurie J, Zsíros, Emese , Jabbour, Salma K , Cook, Erin, Miller, Wilson H. , Wilchesky, Machelle , McNair, Christopher M. , Kloecker, Goetz Hans , Khaki, Ali Raza , Nagpal, Seema , Wu, Julie , Whaley, David, Jhawar, Sachin R, Palmer, Joshua D. , Stover, Daniel G. , Berenberg, Jeffrey L. , Fazio, Alyson, Huber, Kathryn E. , Small, Eric J. , Zhang, Sylvia , Andermann, Tessa M. , Jensen, Christopher Edward , Wood, William A. , Latif, Tahir , Shaikh, Hira , Abidi, Maheen Z. , Markham, Merry Jennifer , Acoba, Jared David , Nguyen, Ryan H, Pasquinelli, Mary M. , Vikas, Praveen , Zakharia, Yousef , Friese, Christopher R. , Su, Christopher , Zaman, Qamar U, Brown, Alaina J. , Crispens, Marta Ann , Croessmann, Sarah , Davis, Elizabeth J. , Duda, Stephany N. , Hausrath, Daniel J. , Li, Xuanyi , Prescott, Lauren Shore , Wang, Lucy Lu , Aboulafia, David M. , Hafez, Navid , Herbst, Roy S. , Stratton, Catherine
JAMA Oncology | November 3, 2022 | Volume: 9 | Issue: 1 | Pages: 128
ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701
Venetoclax Plus Gilteritinib for FLT3 -Mutated Relapsed/Refractory Acute Myeloid Leukemia
Daver, Naval , Perl, Alexander E. , Maly, Joseph, Ritchie, Ellen K. , Litzow, Mark R. , McCloskey, James, Smith, Catherine C. , Schiller, Gary J. , Bradley, Terrence, Tiu, Ramón V., Naqvi, Kiran , Brackman, Deanna J. , Siddani, Satya R., Wang, Jing , Chyla, Brenda , Lee, Paul , Altman, Jessica K. , Litzow, Mark R. , Smith, Catherine C , Dail, Monique , Chyla, Brenda , Altman, Jessica K , Daver, Naval , Levis, Mark J. , Dail, Monique
Journal of Clinical Oncology | July 18, 2022 | Volume: 40 | Issue: 35 | Pages: 4048-4059
PURPOSE The FMS-related tyrosine kinase 3 (FLT3) inhibitor gilteritinib is standard therapy for relapsed/refractory FLT3-mutated ( FLT3 mut ) acute myeloid leukemia (AML) but seldom reduces FLT3 mut burden or induces sustained efficacy. Gilteritinib combines synergistically with the BCL-2 inhibitor venetoclax in preclinical models of FLT3 mut AML. METHODS This phase Ib open-label, dose-escalation/dose-expansion study (ClinicalTrials.gov identifier: NCT03625505 ) enrolled patients with FLT3 wild-type and FLT3 mut (escalation) or FLT3 mut (expansion) relapsed/refractory AML. Patients received 400 mg oral venetoclax once daily and 80 mg or 120 mg oral gilteritinib once daily. The primary objectives were safety, identification of the recommended phase II dose, and the modified composite complete response (mCRc) rate (complete response [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery + morphologic leukemia-free state) using ADMIRAL phase III–defined response criteria. RESULTS Sixty-one patients were enrolled (n = 56 FLT3 mut ); 64% (n = 36 of 56) of FLT3 mut patients had received prior FLT3 inhibitor therapy. The recommended phase II dose was 400 mg venetoclax once daily and 120 mg gilteritinib once daily. The most common grade 3/4 adverse events were cytopenias (n = 49; 80%). Adverse events prompted venetoclax and gilteritinib dose interruptions in 51% and 48%, respectively. The mCRc rate for FLT3 mut patients was 75% (CR, 18%; CR with incomplete blood count recovery, 4%; CR with incomplete platelet recovery, 18%; and morphologic leukemia-free state, 36%) and was similar among patients with or without prior FLT3 inhibitor therapy (80% v 67%, respectively). The median follow-up was 17.5 months. The median time to response was 0.9 months, and the median remission duration was 4.9 months (95% CI, 3.4 to 6.6). FLT3 molecular response (< 10 −2 ) was achieved in 60% of evaluable mCRc patients (n = 15 of 25). The median overall survival for FLT3 mut patients was 10.0 months. CONCLUSION The combination of venetoclax and gilteritinib was associated with high mCRc and FLT3 molecular response rates regardless of prior FLT3 inhibitor exposure. Dose interruptions were needed to mitigate myelosuppression.
Assessment of Regional Variability in COVID-19 Outcomes Among Patients With Cancer in the United States
Hawley, Jessica E. , Sun, Tianyi , Chism, David D. , Duma, Narjust , Fu, Julie , Gatson, Na Tosha , Mishra, Sanjay , Nguyen, Ryan H., Reid, Sonya , Serrano, Oscar K. , Singh, Sunny , Venepalli, Neeta K. , Bakouny, Ziad , Bilen, Mehmet Asım , Choueiri, Toni K. , Dawsey, Scott J. , Fecher, Leslie A. , Flora, Daniel , Friese, Christopher R. , Glover, Michael , Gonzalez, Cyndi J, Goyal, Sharad , Khan, Hina, Lewis, Mark A. , McKay, Rana R. , Messing, Ian , Puc, Matthew , Ravindranathan, Deepak , Rhodes, Terence D., Rivera, Andrea Verghese, Roller, John , Shah, Sumit , Shaya, Justin , Streckfuss, Mitrianna, Wulff‐Burchfield, Elizabeth , Xie, Zhuoer , Shah, Dimpy P. , French, Benjamin , Verma, Amit , Gartrell, Benjamin A. , Ohri, Nitin , Butt, Omar H. , Campian, Jian , Fiala, Mark A. , Monahan, Ryan, Bohachek, Pamela, Mundt, Daniel , Tadesse, Eyob, Lammers, Philip E. , Prete, Salvatore A. Del , Bär, Michael , Gulati, Anthony P., Lo, K. M. Steve, Stratton, Jamie , Weinstein, Paul L., García, Jorge A. , Nakayama, John , Gupta, Shilpa , Ahluwalia, Manmeet S. , Lemmon, Christopher A. , Nizam, Amanda , Hoppenot, Claire , Bouchard, Gabrielle, Busser, Fiona, Connors, Jean M. , Curran, Catherine , Demetri, George D., Kelleher, Kaitlin M. , Shaw, Grace, Allen, Eli Van, Nuzzo, Pier Vitale , Zon, Rebecca L. , Zhang, Tian , Leighton, John, Grivas, Petros , Lynch, Ryan C. , Schweizer, Michael T. , Vinayak, Shaveta , Wagner, Michael J. , Clément, Jessica , Daher, Ahmad , Dailey, Mark, Jayaraj, Asha, Hsu, Emily , Menendez, Alvaro G. , Rathmann, Joerg, Accordino, Melissa , Alexander, Mariam P., Mushtaq, Sarah, Bernicker, Eric , Deeken, John F. , Shafer, Danielle , Gill, David , Low, Clarke A., Mashru, Sandeep H., Mansoor, Abdul-Hai, Zaren, Howard A. , Smith, Stephanie J., Akhtari, Mojtaba, Lau, Eric , Reeves, Mark E. , Elms, Destry, Altman, Jessica K. , Gurley, Michael, Mulcahy, Mary F. , Kulkarni, Amit , Shah, Surbhi , Rosovsky, Rachel , Reynolds, Kerry L. , Bardia, Aditya , Gainor, Justin F. , Zubiri, Leyre , Bonnen, Mark , Mahadevan, Daruka , Salazar, Mary, Faller, Bryan A. , Ajmera, Archana , Brouha, Sharon S. , Cabal, Angelo , Kligerman, Seth , Weissmann, Lisa B., Jani, Chinmay , Thomson, Carey C. , Knoble, Jeanna, Glace, Mary Grace, Stauffer, Karen, Zacks, Rosemary, Blau, Sibel , Menon, Harry, Rovito, Marc A., Elshoury, Amro, Misdary, Christian, Shah, Mansi , Mahmood, Sana , Mico, Vasil, Logan, Barbara, Mandapakala, Chaitanya, Cabebe, Elwyn C., Jha, Alokkumar , Schapira, Lidia , Wu, Julie , Subbiah, Suki , Lopes, Gilberto , Revankar, Sanjay G. , Addison, Daniel , Chen, James L. , Karivedu, Vidhya , Lustberg, Maryam B. , Wall, Sarah , Williams, Nicole , Kasi, Anup , Edwin, Natasha, Smits, Melissa, Owenby, Susie, Doroshow, Deborah B. , Galsky, Matthew D. , Zhu, Huili , Sueyoshi, Mark, Riess, Jonathan W. , Patel, Kanishka G. , Rubinstein, Samuel M. , Ahmad, Syed A. , Grover, Punita , Kharofa, Jordan , Marcum, Michelle, Park, Cathleen, Geiger, Christoper L., Bishnoi, Rohit , Russ, Atlantis Dawn, Rho, Young Soo , Feldman, Lawrence , Hoskins, Kent , Gantt, Gerald, Liu, Li , Khan, Mahir, Nguyen, Ryan H., Schwartz, Candice, Mavromatis, Blanche H., Bijjula, Ragneel R., Cheng, Alex , Duda, Stephany N. , Enriquez, Kyle T. , Gillaspie, Erin A. , Hennessy, Cassandra , Johnson, Douglas B. , Slosky, David, Solórzano, Carmen C. , Vega-Luna, Karen, Kennecke, Hagen F. , Schroeder, Brett A., Carducci, Theresa M., Goldsmith, Karen J., Loon, Susan Van, Topaloĝlu, Ümit , Alimohamed, Saif, Rice, Robert, Cabalona, Wilhelmina D., Pilar, Christine, Peddi, Prakash , Rosen, L, McCollough, Briana Barrow, LoRusso, Patricia , Masters, Tyler, Choueiri, Toni K , Bakouny, Ziad , Hawley, Jessica E , Mishra, Sanjay , Wu, Julie T , Xie, Zhuoer , Zubiri, Leyre , Gatson, Na Tosha N , Fiala, Mark A , Ahluwalia, Manmeet S , Lustberg, Maryam , Nguyen, Ryan H., Bashir, Babar , Caimi, Paolo F. , Hálfdánarson, Þorvarður R. , Hershman, Dawn L. , Labaki, Chris , Pennell, Nathan A , Schwartz, Gary K. , Thompson, Michael A. , Yu, Peter Paul , Warner, Jeremy L. , Hwang, Clara , Halmos, Balázs , Goel, Sanjay , Sica, Roberto Alejandro , Thakkar, Astha , Stockerl‐Goldstein, Keith , Henderson, Jeffrey P. , Zhou, Alice Y. , Panagiotou, Orestis A. , Egan, Pamela , Farmakiotis, Dimitrios , Olszewski, Adam J. , Loaiza‐Bonilla, Arturo , Bar, Michael H., Rose, Suzanne J. , Barnholtz‐Sloan, Jill S. , Li, Ang , Giordano, Antonio , Nohria, Anju , Schmidt, Andrew , Xu, Vincent Eric , Halabi, Susan , Lyman, Gary H , Graber, Jerome J. , Khaki, Ali Raza , Loggers, Elizabeth T , Nakasone, Elizabeth S. , Tachiki, Lisa , Yeh, Albert C. , Huynh‐Le, Minh‐Phuong , Rosenstein, Lori J. , Dailey, Mark, Elias, Rawad , Gadgeel, Shirish M. , Bhutani, Divaya , Reuben, Daniel Y. , Alexander, Mariam, Nagaraj, Gayathri , Berg, Stephanie , Morgans, Alicia K. , Wehbe, Firas , Durbin, Eric B. , Nelson, Heather H. , Sachs, Zohar , Boland, Genevieve M. , Bekaii‐Saab, Tanios , Desai, Aakash , Mesa, Ruben A. , Ramirez, Amelie G , Shah, Pankil , Hsiao, Albert , Rink, Cameron L. , Joshi, Monika , Griffiths, Elizabeth A. , Jabbour, Salma K , McNair, Christopher M. , Kloecker, Goetz Hans , Stover, Daniel G. , Gatti-Mays, Margaret Elena , Jhawar, Sachin R. , Palmer, Joshua D. , Wotman, Michael T. , Fazio, Alyson, Huber, Kathryn E. , Wood, William A. , Jensen, Christopher Edward , Kumar, Vaibhav , Wise-Draper, Trisha Michel , Gulati, Shuchi , Latif, Tahir , Shaikh, Hira , Bowles, Daniel W. , Markham, Merry Jennifer , Shah, Chintan , Acoba, Jared David , Nguyen, Ryan H., Pasquinelli, Mary M. , Vikas, Praveen , Zaman, Qamar U., Davis, Elizabeth J. , Hausrath, Daniel J. , Hsu, Chih–Yuan , Li, Xuanyi , Rini, Brian I. , Shyr, Yu , Tucker, Matthew D. , Wang, Lucy Lu , Aboulafia, David M. , Schroeder, Brett , Hafez, Navid , Herbst, Roy S. , Stratton, Catherine
JAMA Network Open | January 4, 2022 | Volume: 5 | Issue: 1 | Pages: e2142046
Gilteritinib clinical activity in relapsed/refractory FLT3 mutated acute myeloid leukemia previously treated with FLT3 inhibitors
Rahman, Zaid Abdel , Grenet, Justin , Boisclair, Stéphanie , Bewersdorf, Jan Philipp , Barth, Dylan , Fraga, Martina , Bixby, Dale L. , Zeidan, Amer M. , Desai, Pankil , Mannis, Gabriel N. , Deutsch, Yehuda E., Dinner, Shira, Frankfurt, Olga, Litzow, Mark R. , Al‐Kali, Aref , Foran, James M. , Sproat, Lisa Z., Jovanovic, Borko, Perl, Alexander E. , Altman, Jessica K. , Rahman, Zaid H. Abdel , Numan, Yazan , Abdel Rahman, Zaid, Bewersdorf, Jan P , Yilmaz, Musa , Litzow, Mark R. , Daver, Naval , Altman, Jessica K , Abdel Rahman, Zaid H , Zeidan, Amer M , Collins, Cailin T. , Yılmaz, Musa , Abaza, Yasmin , Daver, Naval
American Journal of Hematology | January 4, 2022 | Volume: 97 | Issue: 3 | Pages: 322-328
AbstractGilteritinib is approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML) with an FLT3‐mutation (FLT3mut+). However, the gilteritinib phase 3 ADMIRAL study (Perl et al NEJM 2019) was conducted prior to widespread adoption of either midostaurin as a component of standard intensive induction and consolidation or posttransplant FLT3 inhibitor maintenance. We performed a retrospective analysis using data from 11 US centers and where we identified 113 patients who received gilteritinib alone or as combination therapy for the treatment of R/R FLT3mut+ AML. The composite complete remission (CR) rate (CRc, defined as CR + CRi + CR with incomplete platelet recovery [CRp]) was 48.7% (n = 55). The CRc rate after treatment with gilteritinib in patients who were treated with only prior 7+3 and midostaurin with or without consolidation was 58% with a median survival of 7.8 months. Survival was longest in patients who obtained a CR, particularly a cMRD (clinical minimal or measurable residual disease) negative response; this remained significant after censoring at the time of stem cell transplant. The mitogen‐activated protein kinase pathway activating mutations that are known for gilteritinib resistance (NRAS, KRAS, and PTPN11) had lower CRc (35% vs. 60.5%) and lower median overall survival than patients' whose leukemia did not express these mutations (4.9 months vs. 7.8 months) (HR 2.4; 95% CI 1. 5.4) p value <.01.
Venetoclax in Combination with Gilteritinib Demonstrates Molecular Clearance of FLT3 mutation in Relapsed/Refractory FLT3-Mutated Acute Myeloid Leukemia
Perl, Alexander E. , Maly, Joseph, Ritchie, Ellen K. , Litzow, Mark R. , McCloskey, James, Schiller, Gary J. , Bradley, Terrence, Tiu, Ramón V., Naqvi, Kiran , Siddani, Satya R., Chyla, Brenda , Lee, Paul, Altman, Jessica K. , Daver, Naval , Levis, Mark J. , Smith, Catherine C. , Dail, Monique , Wang, Jing , Lee, Paul
Blood | November 23, 2021 | Volume: 138 | Issue: Supplement 1 | Pages: 691-691
Abstract Gilteritinib (Gilt), a FLT3 tyrosine kinase inhibitor (TKI), is approved for the treatment of relapsed/refractory (R/R) FLT3-mutated (FLT3 +)acute myeloid leukemia (AML). However, long-term survival is limited by the development of drug resistance mutations in persistent FLT3 + clones. Combination regimens may deepen response and improve outcomes. Venetoclax (Ven), a BCL-2 inhibitor, is approved in combination with hypomethylating agents for newly diagnosed AML not suitable for standard induction therapy. FLT3 + AMLhas been associated with clinical resistance to Ven. Still, FLT3 TKIs + Ven have demonstrated synthetic lethality in preclinical models, prompting this multicenter, open-label, phase 1b trial (NCT03625505) to evaluate Ven + Gilt for R/R AML. Here, we report final response and survival endpoints, and molecular clearance among patients (pts) treated at the recommended phase two dose (RP2D). The study design has been previously described (Daver, et al. ASH 2020, Abstract 333). Pts in the dose expansion cohort received Ven 400 mg + Gilt 120 mg (RP2D) daily in 28-day cycles, following Ven ramp-up. The primary endpoint was mCRc (complete response [CR] + CR with incomplete platelet recovery [CRp] + CR with incomplete blood count recovery [CRi] + morphologic leukemia-free state) to align with the ADMIRAL phase III trial (Perl, et al. NEJM 2019). Baseline co-mutations and serial FLT3 internal tandem duplications (ITD) allelic burden were assessed using the MyAML panel (Invivoscribe, San Diego, CA) and FLT3-ITD MRD assay with sensitivities of 5% and 0.001%, respectively. As of the data cut off of January 31, 2021, 54 pts were treated at the RP2D. Fifty-two pts (as assessed locally) had FLT3 +AML; 41 had FLT3-ITD only, 8 had tyrosine kinase domain only, 3 had both mutations, and 2 were FLT3 wild type (wt). Additional baseline characteristics are in Table 1. Grade 3 or 4 AEs occurred in 51 (94.4%) pts, and 39 (72.2%) pts had serious AEs. Grade 3 or 4 cytopenias occurred in 43 (79.6%) pts. AEs of special interest included tumor lysis syndrome (2 [3.7%]) and QT prolongation (1 [1.9%]). AEs leading to dosing interruptions (Ven, 27 [50%]; Gilt, 26 [48.1%]), reductions (Ven, 3 [5.6%]; Gilt, 4 [7.4%]), and discontinuation (Ven, 7 [13%]; Gilt, 7 [13%]) were reported for both study drugs. There was 1 treatment-emergent death of typhlitis. Among FLT3 + pts with post-baseline assessments (51/52), mCRc was achieved by 38 pts (74.5%; CR/CRp/CRi, 19 [37.3%] pts), with a median follow-up time of 12 mo (range: 0.8 - 20.1). The mCRc in pts with prior TKI (32) or prior Ven (10) use were 78.1% and 60%, respectively. The mOS among all FLT3 +pts was 10 mo (95%CI: 6.6, NE), with a median DoR (mDoR) of 5.4 mo (95% CI: 3.3, 6.6). Pts with FLT3-ITD had a mOS of 10.5 mo (95%CI: 6.8, NE), and a mDoR of 5.6 mo (95% CI: 3.3, 8.3). For the 14 pts who had a transplant, the mOS was not reached (95%CI: 10.0, NE) vs 6.89 mo (95%CI: 3.0, 10.5) for those who did not have a transplant (37). The mOS for pts with prior TKI or Ven was 9.6 (95% CI: 4.3, NE) and 10.5 mo (95% CI: 2.0, NE), respectively, with a mDoR of 9.6 (95% CI: 4.3, NE) and 6.2 mo (95% CI: 2.6, NE), respectively. The 60-day mortality rate was 11.8% (95% CI: 4.4, 23.9). The mCRc for NPM1 + and NPM1wt were 92.3% and 61.1%, respectively. mCRc for DNMT3A + and DMNT3A wt pts were 82.4% and 64.3%, respectively. WT1 + and WT1 wt mCRc were 66.7% and 77.3%, respectively. The mCRc for NPM1 + and DNMT3A + co-mutated pts was 100%. In a post hoc analysis of the 30 analyzable mCRc pts with at least one follow-up MRD assessment, 17 (56.7%) achieved molecular clearance defined as FLT3 allelic burden < 10 -2. The mOS of pts achieving mCRc with FLT3 allelic burden of < 10 -2 vs mCRc with FLT3 allelic burden ≥ 10 -2 (Figure 1) was not reached (95% CI: 9.76, NE) vs 6.83 mo (4.21, NE). Ven + Gilt achieved high mCRc in patients with R/R FLT3 + AML, with or without prior TKI exposure, and an encouraging mOS. FLT3 mutation clearance was seen in a majority of patients and associated with longer OS. Encouraging remission rates were observed across many genotypes and were particularly high among pts with NPM1 + +/- DNMT3A co-mutation. Cytopenias were common but manageable with appropriate Ven or Gilt dosing modifications. Serial NGS molecular data, as well as updated survival data will be presented at the meeting. Figure 1 Figure 1. Disclosures Daver: Hanmi: Research Funding; Abbvie: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Perl: Actinium: Consultancy; Genentech: Consultancy; Roche: Consultancy; Astellas: Consultancy, Research Funding; Forma: Consultancy; Syndax: Consultancy; Loxo: Consultancy; Fujifilm: Research Funding; Arog: Research Funding; BMS/Celgene: Consultancy; AbbVie: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Levis: Amgen, Astellas Pharma, Daiichi-Sankyo, FujiFilm, and Menarini: Honoraria; Astellas and FujiFilm: Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Ritchie: Astellas: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria; Celgene/BMS: Consultancy, Other: travel support, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; NS Pharma: Research Funding; Incyte: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Jazz: Consultancy, Research Funding; Protaganist: Consultancy, Honoraria; ARIAD Pharmaceuticals: Ended employment in the past 24 months, Speakers Bureau; Pfizer: Consultancy, Research Funding. Litzow: Astellas: Research Funding; Omeros: Other: Advisory Board; Pluristem: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Jazz: Other: Advisory Board; Biosight: Other: Data monitoring committee. McCloskey: Jazz: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Smith: AbbVie: Research Funding; Revolutions Medicine: Research Funding; Daiichi Sankyo: Consultancy; FUJIFILM: Research Funding; Astellas Pharma: Consultancy, Research Funding; Amgen: Honoraria. Schiller: Takeda: Research Funding; Trovagene: Research Funding; Tolero: Research Funding; Ono: Consultancy; Novartis: Consultancy, Research Funding; ASH foundation: Other: Chair-unpaid; Pfizer: Current equity holder in publicly-traded company, Research Funding; Incyte: Consultancy; Sanofi: Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Ono-UK: Consultancy, Research Funding; Karyopharm: Research Funding; Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Onconova: Research Funding; Mateon: Research Funding; Sangamo: Research Funding; Samus: Research Funding; Regimmune: Research Funding; PrECOG: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Agios: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; Sellas: Research Funding; Geron: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; FujiFilm: Research Funding; Forma: Research Funding; Delta-Fly: Research Funding; Deciphera: Research Funding; Daiichi-Sankyo: Research Funding; Constellation Pharmaceuticals: Research Funding; Celator: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Arog: Research Funding; Actuate: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Abbvie: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Bradley: AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tiu: Astellas Pharma: Current Employment; Eli Lilly and Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Naqvi: Genentech/Roche: Current Employment, Current holder of stock options in a privately-held company. Dail: Genentech/Roche: Current Employment, Current equity holder in publicly-traded company. Siddani: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Wang: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Chyla: AbbVie: Current Employment, Current equity holder in publicly-traded company. Lee: AbbVie: Current Employment, Current holder of stock options in a privately-held company. Altman: Astellas: Consultancy, Other: Advisory Board, Research Funding; AbbVie: Consultancy, Other: Advisory Board, Research Funding; Biosight: Consultancy, Other: Travel fees, Research Funding; Daiichi Sankyo: Consultancy; Kura Oncology: Consultancy; Syros: Consultancy; Theradex: Consultancy, Other: Advisory boards; GlycoMimetics: Other: Participation on an advisory board; ALZ Oncology: Research Funding; Amgen: Research Funding; Aprea: Research Funding; BMS: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Immunogen: Research Funding; Kartos: Research Funding; Kura: Research Funding. OffLabel Disclosure: Venetoclax is a B-cell lymphoma 2 inhibitor approved in combination with azacitidine, or decitabine, or low-dose cytarabine for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are age 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Gilteritinib is a kinase inhibitor indicated for the treatment of adult patients who have relapsed or refractory acute myeloid leukemia (AML) with an FLT3 mutation as detected by an FDA-approved test.
Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS)
Kantarjian, Hagop M. , Begna, Kebede H. , Altman, Jessica K. , Goldberg, Stuart L. , Strickland, Stephen A. , Arellano, Martha , Claxton, David F. , Baer, Maria R. , Gautier, Marc, Berman, Ellin , Seiter, Karen , Solomon, Scott R. , Schiller, Gary J. , Luger, Selina M. , Butrym, Aleksandra , Gaïdano, Gianluca , Thomas, Xavier , Montesinos, Pau , Rizzieri, David A. , Quick, Donald P., Gaur, Rakesh , Maness, Lori J., Kadia, Tapan M. , Chiao, Judy H. , Sekeres, Mikkael A , Strickland, Stephen Anthony , Arellano, Martha L , Claxton, David F , Baer, Maria R , Berman, Ellin , Seiter, Karen , Solomon, Scott R , Schiller, Gary J , Luger, Selina M , Butrym, Aleksandra , Gaidano, Gianluca , Thomas, Xavier G , Montesinos, Pau , Rizzieri, David A , Venugopal, Parameswaran , Gaur, Rakesh , Kadia, Tapan M , Ravandi, Farhad , Buyse, Marc E , Chiao, Judy H , Kantarjian, Hagop , Goldberg, Stuart L. , Sekeres, Mikkael A. , Buyse, Marc
Cancer | August 23, 2021 | Volume: 127 | Issue: 23 | Pages: 4421-4431
BackgroundAcute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low‐intensity therapy, to elderly patients with newly diagnosed AML.MethodsThis randomized, open‐label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1‐hour intravenous infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1‐hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109/L and ≥10 × 109/L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1‐year survival. The trial is registered at ClinicalTrials.gov (NCT01303796).ResultsBetween October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109/L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017).ConclusionsThe regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109/L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed.
Association of Convalescent Plasma Therapy With Survival in Patients With Hematologic Cancers and COVID-19
Shah, Pankil , Rubinstein, Samuel M. , Joyner, Michael J. , Choueiri, Toni K. , Flora, Daniel , Gulati, Anthony P., Koshkin, Vadim S. , Papadopoulos, Esperanza B. , Robilotti, Elizabeth , Su, Christopher , Wulff‐Burchfield, Elizabeth , Xie, Zhuoer , Yu, Peter Paul , Mishra, Sanjay , Senefeld, Jonathon W. , Shah, Dimpy P. , Verma, Amit , Gartrell, Benjamin A. , Ohri, Nitin , Butt, Omar H. , Campian, Jian , Fiala, Mark A. , Monahan, Ryan, Bohachek, Pamela, Mundt, Daniel , Streckfuss, Mitrianna, Tadesse, Eyob, Lammers, Philip E. , Revankar, Sanjay G. , Khan, Hina, Prete, Salvatore A. Del , Angevine, Anne H., Bär, Michael , Lo, KM Steve, Stratton, Jamie , Weinstein, Paul L., García, Jorge A. , Nakayama, John , Gupta, Shilpa , Ahluwalia, Manmeet S. , Dawsey, Scott J. , Nizam, Amanda , Lemmon, Christopher A. , Hoppenot, Claire , Bakouny, Ziad , Bouchard, Gabrielle, Busser, Fiona, Conners, Jean M, Curran, Catherine , Demetri, George D., Kelleher, Kaitlin M. , Shaw, Grace, Nuzzo, Pier Vitale , Zon, Rebecca L. , Zhang, Tian , Grivas, Petros , Lynch, Ryan C. , Schweizer, Michael T. , Tachiki, Lisa ML, Vinayak, Shaveta , Wagner, Michael J. , Yeh, Albert C. , Goyal, Sharad , Clément, Jessica , Daher, Ahmad , Dailey, Mark E., Hsu, Emily , Menendez, Alvaro G. , Rathmann, Joerg, Serrano, Oscar K. , Jayaraj, Asha, Accordino, Melissa , Mushtaq, Sarah, Bernicker, Eric , Deeken, John F. , Shafer, Danielle , Lewis, Mark A. , Rhodes, Terence D., Gill, David , Low, Clarke A., Nagle, Sarah , Hayes‐Lattin, Brandon , Nemecek, Eneida R. , Zaren, Howard A. , Smith, Stephanie J., Akhtari, Mojtaba, Lau, Eric , Reeves, Mark E. , Elms, Destry, Altman, Jessica K. , Gurley, Michael, Mulcahy, Mary F. , Kulkarni, Amit , Shah, Surbhi, Rosovsky, Rachel , Reynolds, Kerry L. , Bardia, Aditya , Gainor, Justin F. , Zubiri, Leyre , Bonnen, Mark , Mahadevan, Daruka , Salazar, Mary, Belenkaya, Rimma , Riely, Gregory J. , Faller, Bryan A. , McKay, Rana R. , Ajmera, Archana , Cabal, Angelo , Shaya, Justin , Weissmann, Lisa B., Jani, Chinmay , Chen, James L. , Jhawar, Sachin R, Lustberg, Maryam B. , Pillainayagam, Clement, Wall, Sarah , Williams, Nicole , Karivedu, Vidhya , Addison, Daniel , Menon, Harry, Rovito, Marc A., Elshoury, Amro, Shah, Mansi , Mahmood, Sana , Mico, Vasil, Rivera, Andrea Verghese, Miller, Chaim , Cabebe, Elwyn C., Glover, Michael , Jha, Alokkumar , Schapira, Lidia , Shah, Sumit , Subbiah, Suki , Logan, Barbara, Lopes, Gilberto , Russell, Karen , Stith, Brittany, Smits, Melissa, Edwin, Natasha, Chism, David D. , Owenby, Susie, Doroshow, Deborah B. , Galsky, Matthew D. , Zhu, Huili , Fu, Julie , Patel, Kanishka G. , Riess, Jonathan W. , Kwon, Daniel H. , Islam, Jessica Y. , Ahmad, Syed A. , Grover, Punita , Kharofa, Jordan , Marcum, Michelle, Park, Cathleen, Geiger, Christopher L., Bishnoi, Rohit , Feldman, Lawrence , Hoskins, Kent , Gantt, Gerald, Khan, Mahir, Nguyen, Ryan H, Schwartz, Candice, Venepalli, Neeta K. , Kasi, Anup , Fecher, Leslie A. , Mavromatis, Blanche H., Bijjula, Ragneel R., Cheng, Alex , French, Benjamin , Gillaspie, Erin A. , Hennessy, Cassandra , Johnson, Douglas B. , Reid, Sonya , Slosky, David, Solórzano, Carmen C. , Vega-Luna, Karen, Enriquez, Kyle T. , Sun, Tianyi , Carducci, Theresa M., Puc, Matthew , Loon, Susan Van, Goldsmith, Karen J., Rice, Robert, Cabalona, Wilhelmina D., Pilar, Christine, McCollough, Briana Barrow, Peddi, Prakash , Rosen, L, Bilen, Mehmet Asım , Ravindranathan, Deepak , LoRusso, Patricia , Masters, Tyler, Choueiri, Toni K , Bakouny, Ziad , Mishra, Sanjay , Yeh, Albert C , Xie, Zhuoer , Zubiri, Leyre , Su, Christopher , Fiala, Mark A , Joyner, Michael J , Senefeld, Jonathon W , Ahluwalia, Manmeet S , Lustberg, Maryam , Thompson, Michael A. , Henderson, Jeffrey P. , Griffiths, Elizabeth A. , Hwang, Clara , Warner, Jeremy L. , Halmos, Balázs , Goel, Sanjay , Sica, Roberto Alejandro , Thakkar, Astha , Stockerl‐Goldstein, Keith , Zhou, Alice Y. , Tadesse, Eyob, Panagiotou, Orestis A. , Egan, Pamela , Farmakiotis, Dimitrios , Olszewski, Adam J. , Loaiza‐Bonilla, Arturo , Bar, Michael H, Lo, K. M. Steve, Caimi, Paolo F. , Barnholtz‐Sloan, Jill S. , Pennell, Nathan A , Li, Ang , Giordano, Antonio , Nohria, Anju , Schmidt, Andrew , Van Allen, Eliezer M , Xu, Wenxin Vincent , Halabi, Susan , Lyman, Gary H , Graber, Jerome J. , Khaki, Ali Raza , Loggers, Elizabeth T , Nakasone, Elizabeth S. , Tachiki, Lisa M, Gatson, Na Tosha , Huynh‐Le, Minh‐Phuong , Rosenstein, Lori J. , Elias, Rawad , Gadgeel, Shirish M. , Hawley, Jessica E. , Hershman, Dawn L. , Bhutani, Divaya , Schwartz, Gary K. , Reuben, Daniel Y. , McWeeney, Shannon K. , Nagaraj, Gayathri , Berg, Stephanie , Morgans, Alicia K. , Wehbe, Firas , Durbin, Eric B. , Nelson, Heather H. , Boland, Genevieve M. , Hálfdánarson, Þorvarður R. , Bekaii‐Saab, Tanios , Desai, Aakash , Mesa, Ruben A. , Ramirez, Amelie G , Philip, John , Gatti-Mays, Margaret Elena , Jhawar, Sachin R, Palmer, Joshua D. , Stover, Daniel G. , Joshi, Monika , Jabbour, Salma K , Bashir, Babar , McNair, Christopher M. , Wu, Julie , Kloecker, Goetz Hans , Fazio, Alyson, Kumar, Vaibhav , Wood, William A. , Gulati, Shuchi , Wise-Draper, Trisha Michel , Bowles, Daniel W. , Markham, Merry Jennifer , Shah, Chintan , Acoba, Jared David , Rho, Young Soo, Nguyen, Ryan H, Pasquinelli, Mary M. , Vikas, Praveen , Friese, Christopher R. , Zaman, Qamar U, Davis, Elizabeth J. , Hausrath, Daniel J. , Hsu, Chih–Yuan , Li, Xuanyi , Rini, Brian I. , Shyr, Yu , Tucker, Matthew D. , Wang, Lucy Lu , Hafez, Navid , Herbst, Roy S. , Stratton, Catherine
JAMA Oncology | August 19, 2021 | Volume: 7 | Issue: 8 | Pages: 1167
Clinical features and survival outcomes in patients with chronic myelomonocytic leukemia arising in the context of germline predisposition syndromes
Martin, Emma C. St. , Wudhikarn, Kitsada , Mangaonkar, Abhishek A. , Tefferi, Ayalew , Gangat, Naseema , Altman, Jessica K. , Godley, Lucy A. , Patnaik, Mrinal M. , St Martin, Emma C , Mangaonkar, Abhishek A. , Hogan, William, Tefferi, Ayalew , Patnaik, Mrinal , Godley, Lucy A , Ferrer, Alejandro , Hogan, William J. , Lasho, Terra L.
American Journal of Hematology | May 24, 2021 | Volume: 96 | Issue: 9 | Pages: No page available
Ivosidenib (AG-120) in Mutant IDH1 AML and Advanced Hematologic Malignancies: Results of a Phase 1 Dose Escalation and Expansion Study
Stein, Eytan M. , Swords, Ronan , Altman, Jessica K. , Collins, Robert H. , Mannis, Gabriel N. , Donnellan, Will, Pigneux, Arnaud , Fathi, Amir T. , Stein, Anthony S. , Prince, Gabrielle T., Foran, James M. , Arellano, Martha , Slack, James L., Yen, Katharine , Kapsalis, Stephanie M., Goldwasser, Meredith A., Agresta, Sam, Attar, Eyal C. , Tallman, Martin S. , Stone, Richard M. , DiNardo, Courtney D. , Botton, Stéphane de , Roboz, Gail J. , Mims, Alice S , Pollyea, Daniel Aaron , Uy, Geoffrey L. , Erba, Harry Paul , Traer, Elie , Stuart, Robert K. , Sekeres, Mikkael A. , Liu, Hua , Kantarjian, Hagop M.
Blood | April 6, 2021 | Volume: 130 | Issue: Suppl_1 | Pages: 725-725
10.1182/blood.v130.suppl_1.725.725
Abstract BACKGROUND: Recurrent isocitrate dehydrogenase (IDH) 1 mutations are observed in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120), a potent, selective, oral, small-molecule inhibitor of the mutant IDH1 (mIDH1) protein, is a promising therapeutic candidate for the treatment of patients with mIDH1 AML. Through inhibition of mIDH1, ivosidenib suppresses the abnormal production of the oncometabolite 2-hydroxyglutarate (2-HG), leading to clinical responses via differentiation of malignant cells. AIM: To report safety and efficacy data from the first-in-human phase 1 study of ivosidenib in patients with mIDH1 advanced hematologic malignancies including relapsed/refractory (R/R) AML (NCT02074839). This is the first report of data from the 4 expansion cohorts, with a total of 258 patients treated on study. METHODS: The ongoing phase 1 study assesses the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of ivosidenib in mIDH1 hematologic malignancies. Enrollment was completed on May 8, 2017. During dose escalation, patients received ivosidenib as a single agent orally once daily (QD) or twice daily (BID) in 28-day cycles. The MTD was not reached and 500 mg QD was selected as the recommended dose to be tested in 4 expansion cohorts: R/R AML (Arms 1 and 4, where Arm 1 patients are those with relapse after transplantation, second or later relapse, resistance to initial induction or reinduction treatment, or relapse within 1 year of initial treatment, and Arm 4 patients have R/R AML but are not eligible for Arm 1); untreated AML (Arm 2); and other advanced hematologic malignancies including myelodysplastic syndrome (MDS) (Arm 3). Updated safety data will be presented for all patients. Efficacy outcomes will be presented for all R/R AML patients treated at 500 mg QD across the dose escalation and expansion cohorts who received their first dose of ivosidenib at least 6 months prior to the analysis cut-off date of May 12, 2017, as well as for the poorest prognosis Arm 1 subset. Efficacy data for all treated patients from the other expansion cohorts (untreated AML and other advanced hematologic malignancies including MDS) will also be presented. RESULTS: In all, 258 patients (78 in dose escalation, 180 in expansion) were treated with ivosidenib. As of May 12, 2017, 62 of 258 (24%) patients were continuing on treatment. The median duration of exposure to ivosidenib was 3.5 months (range 0.1-33.5). Twenty-two (8.5%) patients discontinued treatment to proceed to allogeneic stem cell transplantation. Treatment was well tolerated; the most common adverse events (AEs) (n=258) of any grade irrespective of causality occurring in ≥20% of patients were diarrhea (33%), leukocytosis (30%), nausea (30%), fatigue (29%), febrile neutropenia (25%), dyspnea (24%), anemia (23%), QT prolongation (23%), peripheral edema (22%), pyrexia (21%), and decreased appetite (20%). The majority of these AEs were grades 1-2 and reported as unrelated to treatment. Differentiation syndrome (DS) was observed in 29 of 258 (11.2%) patients, including grade ≥3 DS in 14 (5.4%); study drug was held owing to DS in 11 patients (4.3%), and no instances of DS led to permanent treatment discontinuation or death. The primary efficacy endpoint for R/R AML is the CR+CRh rate, i.e., the rate of complete remission (CR according to modified IWG 2003 criteria plus CR with partial hematologic recovery, defined as CR except absolute neutrophil count >0.5 × 109/L [500/µL] and platelet count >50 × 109/L [50,000/µL]). Among 125 Arm 1 R/R AML patients receiving ivosidenib 500 mg QD across dose escalation and expansion who received their first dose at least 6 months prior to the analysis cutoff date, the CR+CRh rate was 30.4% (95% CI 22.5%, 39.3%), including CR in 27 (21.6%) and CRh in 11 (8.8%) patients. Median duration of CR+CRh was 8.2 months (95% CI 5.5, 12.0), and duration of CR was 9.3 months (95% CI 5.6, 18.3). The overall response rate (CR+CRi/CRp+PR+MLFS) was 41.6% (95% CI 32.9%, 50.8%) (52/125 patients). CONCLUSION: Ivosidenib monotherapy is well tolerated in patients with mIDH1 AML and other advanced hematologic malignancies. In a high-risk, molecularly defined R/R AML patient population with unmet medical need, ivosidenib induced durable remissions and improved patient outcomes. These findings support the role of ivosidenib as an effective, oral, targeted treatment for patients with mIDH1 AML. Disclosures DiNardo: Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. De Botton: Pfizer: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Servier: Honoraria; Agios: Honoraria, Research Funding. Stein: GSK: Other: Advisory Board, Research Funding; Constellation Pharma: Research Funding; Seattle Genetics: Research Funding; Agios Pharmaceuticals, Inc.: Consultancy, Research Funding; Celgene Corporation: Consultancy, Other: Travel expenses, Research Funding; Pfizer: Consultancy, Other: Travel expenses; Novartis: Consultancy, Research Funding. Roboz: AbbVie, Agios, Amgen, Amphivena, Array Biopharma Inc., Astex, AstraZeneca, Celator, Celgene, Clovis Oncology, CTI BioPharma, Genoptix, Immune Pharmaceuticals, Janssen Pharmaceuticals, Juno, MedImmune, MEI Pharma, Novartis, Onconova, Pfizer, Roche Pharmace: Consultancy; Cellectis: Research Funding. Mims: Novartis: Honoraria. Pollyea: Takeda, Ariad, Alexion, Celgene, Pfizer, Pharmacyclics, Gilead, Jazz, Servier, Curis: Membership on an entity's Board of Directors or advisory committees; Agios, Pfizer: Research Funding. Altman: Syros: Consultancy; NCCN: Other: Educational speaker; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Collins: Celgene Corporation: Research Funding; Agios: Research Funding; Arog: Research Funding; BMS: Research Funding. Mannis: Curis: Honoraria; Juno: Research Funding; Agios: Research Funding; Amgen: Honoraria. Uy: GlycoMimetics: Consultancy; Novartis: Consultancy, Other: Travel Suppport; Boehringer Ingelheim: Consultancy. Fathi: Juno: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Medimmune: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stein: Amgen: Consultancy, Speakers Bureau; Stemline: Consultancy. Erba: Celgene: Consultancy, Other: Chair, Scientific Steering Committee , Speakers Bureau; Incyte: all research support paid to University of Alabama, Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Daiichi Sankyo: Consultancy, Other: all research support paid to University of Alabama, Research Funding; ImmunoGen: Consultancy, Other: all research support paid to University of Alabama, Research Funding; MacroGen: Consultancy; Ono: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Sunesis: Consultancy; Millennium/Takeda: Consultancy, Other: all research support paid to University of Alabama, Research Funding; Agios: Other: all research support paid to University of Alabama, Research Funding; Juno: Other: all research support paid to University of Alabama, Research Funding; Astellas: Other: all research support paid to University of Alabama, Research Funding; Celator: Other: all research support paid to University of Alabama, Research Funding; Janssen: Other: all research support paid to University of Alabama, Research Funding; Glycomimetics: Other: Chair, Data and Safety Monitoring Committee. Traer: ImmunoGen: Consultancy; Tolero: Consultancy; Notable Labs: Equity Ownership. Stuart: Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Consultancy, Honoraria; Agios: Research Funding; Celator/Jazz: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; Bayer: Research Funding; Novartis: Research Funding; Incyte: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; MedImmune: Research Funding; Cantex: Research Funding; Astellas: Research Funding. Arellano: Cephalon Oncology: Research Funding. Sekeres: Celgene: Membership on an entity's Board of Directors or advisory committees. Yen: Agios: Employment, Equity Ownership. Kapsalis: Agios: Employment, Equity Ownership. Liu: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Goldwasser: Agios: Employment, Equity Ownership. Agresta: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Attar: Agios: Employment, Equity Ownership. Stone: Novartis: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Abbvie: Consultancy; Fuji Film: Consultancy; Jazz: Consultancy; Astellas: Consultancy; Pfizer: Consultancy; Arog: Consultancy; Ono: Consultancy; Agios: Consultancy; Sumitomo: Consultancy. Kantarjian: ARIAD: Research Funding; Bristol-Meyers Squibb: Research Funding; Delta-Fly Pharma: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Novartis: Research Funding.