AML

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.

Disclaimer

The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Hemedicus or Frontline Medical Communications. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.

Disclaimer

The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Hemedicus or Frontline Medical Communications. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

Release Date: July 15, 2018
Expiration Date: July 14, 2019

Note: This activity is no longer available for credit

Introductory Comments: (Duration: 9 minutes)

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, MD

Presentation: (Duration: 39 minutes)

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA

Provided by:

Learning Objectives

• Review clinical data and individual case studies to determine where CAR T-cell therapy might be appropriate in the treatment of adult and pediatric patients with leukemia, lymphoma, and multiple myeloma.

• Discuss the management of cytotoxicity of CAR T-cell therapy.

Target Audience

Hematologists, oncologists, and other members of the healthcare team who treat or manage patients with hematologic malignancies.

Statement of Need

It is critical that clinicians managing patients with acute leukemia and other hematologic malignancies are cognizant of exciting breakthroughs and are also able to integrate recent progress into practice. However, given the overwhelming influx of data, it is no surprise that many hematology professionals face difficulties in identifying the most relevant findings for clinical practice. Hematologists are unable to stay abreast of the latest evidence on investigational agents. Educational programs are thus crucial to address this important professional practice gap.

Faculty

Carl H. June, MD
Richard W. Vague Professor in Immunotherapy
Perelman School of Medicine
University of Pennsylvania
Philadelphia, PA
Disclosures: Consultant: Novartis; Grant/Research support and royalties/IPR: Novartis
Stockholder: Tmunity Therapeutics, Inc.

Aaron P. Rapoport, MD
Bone Marrow Transplant Program
University of Maryland School of Medicine
Baltimore, Maryland
Disclosures: No relevant financial relationships with a commercial supporter

Permissions

• Slide 3: Complex tumor, host and environmental factors govern the strength and timing of anti-cancer immune responses
  • Reprinted from Immunity, Vol 39/No 1, Chen DS, Mellman I, Oncology meets immunology: the cancer-immunity cycle, pp 1-10, 2013, with permission from Elsevier
• Slide 9: Genes differentially expressed in CART19 cellular infusion products from CLL patients
  • From Fraietta JA, Lacey SF, Orlando EJ, . . . June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571
• Slide 10: Characterization of CLL CAR T cells in NSG CLL model
  • Same as slide 9
• Slide 15: First adult ALL patient
  • Photos originally published in Kaiser Health News/Photo courtesy of Dr Keith Eaton. Available at: https://khn.org/news/cascade-of-costs-could-push-new-gene-therapy-above-1-million-per-patient/
• Slide 21: Efficient trafficking of CTL019 T Cells to CNS in ALL
  • From N Engl J Med, Grupp SA, Kalos M, Barrett D, . . V. June CH, Chimeric antigen receptor-modified T cells for acute lymphoid leukemia, Volume No 368, pp 1509-1518. Copyright © 2013 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.
• Slide 26: Long-term persistence and expression of CTL019 is associated with durable remission in leukemia: Predictive Biomarker
  • From Porter DL, Hwang WT, Frey NV . . . June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015; 7(303):303ra139. Reprinted with permission from AAAS.
• Slide 28: Rapid massive expansion of clonal CART cell population in patient #10
  • Initially published in Fraietta JA, Nobles CL, Sammons MA, . . . June CH, Melenhors JJ. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 2018; 558(7709):307-312
• Slide 29: Mapping CAR integration site in Pt #10
  • Same as slide 28.
• Slide 31: Long-term stable persistence of TET2-deficient CAR T cells in Pt #10
  • Same as slide 28
• Slide 32: Epigenetic and genetic changes uncovered by ATAC-seq in Pt #10
  • Same as slide 28.
• Slide 33: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 34: TET2 knock down in healthy donor T cells
  • Same as slide 28.
• Slide 36: CAR T for myeloma: BCMA
  • From Rickert RC, Jellusova J, Miletic AV. Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 2011; 244(1):115-33. Reprinted with permission from John Wiley and Sons.
• Slide 38: CAR T for myeloma: Patient #1
  • Photo originally published by UT Southwestern Medical Center. Available at: https://www.utsouthwestern.edu/newsroom/articles/year-2018/wright-car-t.html
• Slide 39: Autoimmunity is the “Achilles’ Heel” of immunotherapy
  • First published in June CH, Warshauer JT, and Bluestone JA. Is autoimmunity the Achilles’ heel of cancer immunotherapy? Nat Med 2017;23(5):540-7
• Slide 41: Multiplex CRISPR /Cas9 editing: Universal T cells TCR, HLA, PD-1, CTLA-4 and Fas
  • From Ren J, Zhang X, Liu X, Fang C, Jiang S, June CH, Zhao Y. A versatile system for rapid multiplex genome-edited CAR T cell generation. Oncotarget 2017; 8:17002-17011.
• Slide 45: CAR T-cell trials for cancer are now global
  • From June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018; 359:1361-1365. Reprinted with permission from AAAS.

Disclaimer

The content and views presented in this educational activity are those of the author and do not necessarily reflect those of Hemedicus or Frontline Medical Communications. This material is prepared based upon a review of multiple sources of information, but it is not exhaustive of the subject matter. Therefore, healthcare professionals and other individuals should review and consider other publications and materials on the subject matter before relying solely upon the information contained within this educational activity.

A supplemental new drug application (sNDA) for venetoclax (Venclexta) used in combination with either a hypomethylating agent or low-dose cytarabine (LDAC) for previously untreated acute myeloid leukemia has been submitted to the Food and Drug Administration by Genentech, which developed it.

Specifically, the sNDA is for these drug combinations in the treatment of AML patients ineligible for intensive chemotherapy, according to the announcement from Genentech.

The sNDA is based on results of two trials that included patients in this population. In the phase 1b M14-358 (NCT02203773), venetoclax was combined with either azacitidine or decitabine; patients treated with 400 mg of venetoclax had a complete remission rate of 73%, and the median overall survival across all doses of venetoclax was 17.5 months. Low white blood cell count with fever, low white blood cell count, anemia, low platelet count, and decreased potassium levels were the most common grade 3/4 adverse events (occurring in 10% or more of patients). In the phase 1b/2 study M14-387 (NCT02287233), venetoclax was used in combination with LDAC; patients treated with a 600-mg dose of venetoclax showed a complete response rate of 62%, and a median overall survival of 11.4 months. Low white blood cell count with fever, decreased potassium levels, pneumonia, disease progression, decreased phosphate levels, high blood pressure, and sepsis were the most common grade 3/4 adverse events seen in this study.

This sNDA follows FDA breakthrough therapy designations, based on these same trials, for these uses of venetoclax with either hypomethylating agents or LDAC. The FDA also recently approved venetoclax in combination with rituximab (Rituxan) for treatment of patients who have chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p depletion, and have been treated with at least one prior therapy.

“AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible,” said Sandra Horning, MD, chief medical officer at Genentech.

More information is included in the full release.

[email protected]

A supplemental new drug application (sNDA) for venetoclax (Venclexta) used in combination with either a hypomethylating agent or low-dose cytarabine (LDAC) for previously untreated acute myeloid leukemia has been submitted to the Food and Drug Administration by Genentech, which developed it.

Specifically, the sNDA is for these drug combinations in the treatment of AML patients ineligible for intensive chemotherapy, according to the announcement from Genentech.

The sNDA is based on results of two trials that included patients in this population. In the phase 1b M14-358 (NCT02203773), venetoclax was combined with either azacitidine or decitabine; patients treated with 400 mg of venetoclax had a complete remission rate of 73%, and the median overall survival across all doses of venetoclax was 17.5 months. Low white blood cell count with fever, low white blood cell count, anemia, low platelet count, and decreased potassium levels were the most common grade 3/4 adverse events (occurring in 10% or more of patients). In the phase 1b/2 study M14-387 (NCT02287233), venetoclax was used in combination with LDAC; patients treated with a 600-mg dose of venetoclax showed a complete response rate of 62%, and a median overall survival of 11.4 months. Low white blood cell count with fever, decreased potassium levels, pneumonia, disease progression, decreased phosphate levels, high blood pressure, and sepsis were the most common grade 3/4 adverse events seen in this study.

This sNDA follows FDA breakthrough therapy designations, based on these same trials, for these uses of venetoclax with either hypomethylating agents or LDAC. The FDA also recently approved venetoclax in combination with rituximab (Rituxan) for treatment of patients who have chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p depletion, and have been treated with at least one prior therapy.

“AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible,” said Sandra Horning, MD, chief medical officer at Genentech.

More information is included in the full release.

[email protected]

A supplemental new drug application (sNDA) for venetoclax (Venclexta) used in combination with either a hypomethylating agent or low-dose cytarabine (LDAC) for previously untreated acute myeloid leukemia has been submitted to the Food and Drug Administration by Genentech, which developed it.

Specifically, the sNDA is for these drug combinations in the treatment of AML patients ineligible for intensive chemotherapy, according to the announcement from Genentech.

The sNDA is based on results of two trials that included patients in this population. In the phase 1b M14-358 (NCT02203773), venetoclax was combined with either azacitidine or decitabine; patients treated with 400 mg of venetoclax had a complete remission rate of 73%, and the median overall survival across all doses of venetoclax was 17.5 months. Low white blood cell count with fever, low white blood cell count, anemia, low platelet count, and decreased potassium levels were the most common grade 3/4 adverse events (occurring in 10% or more of patients). In the phase 1b/2 study M14-387 (NCT02287233), venetoclax was used in combination with LDAC; patients treated with a 600-mg dose of venetoclax showed a complete response rate of 62%, and a median overall survival of 11.4 months. Low white blood cell count with fever, decreased potassium levels, pneumonia, disease progression, decreased phosphate levels, high blood pressure, and sepsis were the most common grade 3/4 adverse events seen in this study.

This sNDA follows FDA breakthrough therapy designations, based on these same trials, for these uses of venetoclax with either hypomethylating agents or LDAC. The FDA also recently approved venetoclax in combination with rituximab (Rituxan) for treatment of patients who have chronic lymphocytic leukemia or small lymphocytic lymphoma, with or without 17p depletion, and have been treated with at least one prior therapy.

“AML is an aggressive disease with the lowest survival rate of all leukemias, and we look forward to working closely with the FDA to bring this potential option to patients with this very difficult-to-treat blood cancer as soon as possible,” said Sandra Horning, MD, chief medical officer at Genentech.

More information is included in the full release.

[email protected]

Cincinnati Children’s

Preclinical research has revealed a potential therapeutic target for MLL-rearranged acute myeloid leukemia (AML).

The target—F-box protein S-phase kinase-associated protein 2 (Skp2)—degrades another protein called p27Kip1 that is important to the formation of healthy blood cells.

This finding was published in the Journal of Experimental Medicine.

“Our work provides a complete mechanistic look into the function of genetic and molecular programs driving this leukemia, and it exploits these processes to identify actionable therapeutic targets,’’ said study author H. Leighton Grimes, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

For this work, Dr Grimes and his colleagues performed biochemical analyses of cells from AML patients. This gave the researchers comprehensive information about the targets and functions of the miR-196 molecular signaling pathway.

The team inserted mimics of miR-196 into MLL-AF9 leukemia cells to incorporate them into the cellular machinery. The group then lysed the cells for analyses, which revealed molecular targets of miR-196 in the leukemia cells.

Next, the researchers screened AML cells in mice for miR-196 targets. These experiments showed that certain microRNA targets are more important than others in the maintenance and spread of leukemia stem cells (LSCs).

Computer-assisted analysis of the Molecular Signature Database (a shared multi-institutional resource) allowed the researchers to identify sets of genes that show up in high numbers in MLL-AF9 leukemia.

Additional biochemical testing revealed that miR-196 directly targets and inhibits Cdkn1b/p27Kip1, which controls molecular programming in LSCs that allows them to maintain aggressive MLL-AF9 leukemia.

When miR-196 targets Cdkn1b/p27Kip1, it accelerates MLL-AF9 progression by abnormally linking stem cell activity with the growth of leukemia cells.

With the data suggesting that elevation of p27Kip1 protein levels may be therapeutic to AML patients, the researchers investigated a related molecular pathway that also regulates p27Kip1.

This investigation yielded the treatment target Skp2, which degrades the p27 protein and lowers its expression.

The researchers tested an experimental Skp2 inhibitor, SLZ P1041, on human AML cell lines and found the drug killed AML cells in a dose-dependent manner.

The team also tested SLZ P1041 in combination with other inhibitors—IBET-151, palbociclib, and MI-1. The most consistent synergies were with the combination of SLZ P1041 and MI-1, an inhibitor of the interaction between Menin and MLL.

“We still have extensive additional testing to conduct in laboratory animal models of AML before knowing if [targeting Skp2] will translate to patient care,” Dr Grimes said.

Cincinnati Children’s

Preclinical research has revealed a potential therapeutic target for MLL-rearranged acute myeloid leukemia (AML).

The target—F-box protein S-phase kinase-associated protein 2 (Skp2)—degrades another protein called p27Kip1 that is important to the formation of healthy blood cells.

This finding was published in the Journal of Experimental Medicine.

“Our work provides a complete mechanistic look into the function of genetic and molecular programs driving this leukemia, and it exploits these processes to identify actionable therapeutic targets,’’ said study author H. Leighton Grimes, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

For this work, Dr Grimes and his colleagues performed biochemical analyses of cells from AML patients. This gave the researchers comprehensive information about the targets and functions of the miR-196 molecular signaling pathway.

The team inserted mimics of miR-196 into MLL-AF9 leukemia cells to incorporate them into the cellular machinery. The group then lysed the cells for analyses, which revealed molecular targets of miR-196 in the leukemia cells.

Next, the researchers screened AML cells in mice for miR-196 targets. These experiments showed that certain microRNA targets are more important than others in the maintenance and spread of leukemia stem cells (LSCs).

Computer-assisted analysis of the Molecular Signature Database (a shared multi-institutional resource) allowed the researchers to identify sets of genes that show up in high numbers in MLL-AF9 leukemia.

Additional biochemical testing revealed that miR-196 directly targets and inhibits Cdkn1b/p27Kip1, which controls molecular programming in LSCs that allows them to maintain aggressive MLL-AF9 leukemia.

When miR-196 targets Cdkn1b/p27Kip1, it accelerates MLL-AF9 progression by abnormally linking stem cell activity with the growth of leukemia cells.

With the data suggesting that elevation of p27Kip1 protein levels may be therapeutic to AML patients, the researchers investigated a related molecular pathway that also regulates p27Kip1.

This investigation yielded the treatment target Skp2, which degrades the p27 protein and lowers its expression.

The researchers tested an experimental Skp2 inhibitor, SLZ P1041, on human AML cell lines and found the drug killed AML cells in a dose-dependent manner.

The team also tested SLZ P1041 in combination with other inhibitors—IBET-151, palbociclib, and MI-1. The most consistent synergies were with the combination of SLZ P1041 and MI-1, an inhibitor of the interaction between Menin and MLL.

“We still have extensive additional testing to conduct in laboratory animal models of AML before knowing if [targeting Skp2] will translate to patient care,” Dr Grimes said.

Cincinnati Children’s

Preclinical research has revealed a potential therapeutic target for MLL-rearranged acute myeloid leukemia (AML).

The target—F-box protein S-phase kinase-associated protein 2 (Skp2)—degrades another protein called p27Kip1 that is important to the formation of healthy blood cells.

This finding was published in the Journal of Experimental Medicine.

“Our work provides a complete mechanistic look into the function of genetic and molecular programs driving this leukemia, and it exploits these processes to identify actionable therapeutic targets,’’ said study author H. Leighton Grimes, PhD, of Cincinnati Children’s Hospital Medical Center in Ohio.

For this work, Dr Grimes and his colleagues performed biochemical analyses of cells from AML patients. This gave the researchers comprehensive information about the targets and functions of the miR-196 molecular signaling pathway.

The team inserted mimics of miR-196 into MLL-AF9 leukemia cells to incorporate them into the cellular machinery. The group then lysed the cells for analyses, which revealed molecular targets of miR-196 in the leukemia cells.

Next, the researchers screened AML cells in mice for miR-196 targets. These experiments showed that certain microRNA targets are more important than others in the maintenance and spread of leukemia stem cells (LSCs).

Computer-assisted analysis of the Molecular Signature Database (a shared multi-institutional resource) allowed the researchers to identify sets of genes that show up in high numbers in MLL-AF9 leukemia.

Additional biochemical testing revealed that miR-196 directly targets and inhibits Cdkn1b/p27Kip1, which controls molecular programming in LSCs that allows them to maintain aggressive MLL-AF9 leukemia.

When miR-196 targets Cdkn1b/p27Kip1, it accelerates MLL-AF9 progression by abnormally linking stem cell activity with the growth of leukemia cells.

With the data suggesting that elevation of p27Kip1 protein levels may be therapeutic to AML patients, the researchers investigated a related molecular pathway that also regulates p27Kip1.

This investigation yielded the treatment target Skp2, which degrades the p27 protein and lowers its expression.

The researchers tested an experimental Skp2 inhibitor, SLZ P1041, on human AML cell lines and found the drug killed AML cells in a dose-dependent manner.

The team also tested SLZ P1041 in combination with other inhibitors—IBET-151, palbociclib, and MI-1. The most consistent synergies were with the combination of SLZ P1041 and MI-1, an inhibitor of the interaction between Menin and MLL.

“We still have extensive additional testing to conduct in laboratory animal models of AML before knowing if [targeting Skp2] will translate to patient care,” Dr Grimes said.

Henrique Orlandi Mourao

Researchers say they have found ways to identify patients with a high risk of developing acute myeloid leukemia (AML).

The researchers used basic clinical and laboratory data to identify patients 6 to 12 months before AML presentation.

Using genetic information, the researchers were able to identify high-risk patients several years before AML presentation.

“This long time window gives us the first opportunity to think about how to prevent AML,” said John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

However, Dr Dick and his colleagues noted that neither the genetic method nor the clinical data method were entirely accurate in identifying patients who would develop AML.

The researchers described both methods in Nature.

The team’s work began with the goal of distinguishing patients who will develop AML from patients who simply develop age-related clonal hematopoiesis.

“We wanted to know if there was any difference between these 2 groups in the genetics of their ‘normal’ blood samples taken at enrollment,” Dr Dick said. “To find out, we developed a gene-sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The researchers analyzed samples from 95 patients who ultimately developed AML and 414 age- and gender-matched controls. The samples from AML patients were obtained an average of 6.3 years before AML diagnosis.

The researchers found that pre-AML cases had more mutations per sample, higher variant allele frequencies, and a higher frequency of certain mutations than controls. Specifically, pre-AML cases had a significantly greater frequency of DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1, and IDH2 mutations.

The researchers used these findings to develop a model for predicting AML. They tested the model in a validation cohort of 29 pre-AML cases and 262 controls, as well as in a cohort combining the validation and discovery cohorts. The model predicted AML development with 41.9% sensitivity and 95.7% specificity.

However, the researchers said widespread use of this model would not be practical because AML is so rare. The team said millions of people would need to undergo screening to identify a few pre-AML cases, and there would be “many” false-positives.

Therefore, the researchers developed a model using clinical information from electronic health records—particularly blood counts. This model was able to predict AML development 6 to 12 months before diagnosis with a sensitivity of 25.7% and specificity of 98.2%.

The researchers said these results suggest clinical data can be used to identify patients with a high risk of AML who may benefit from targeted genetic screening. And combining clinical and genetic information in a single model could improve predictive accuracy.

“Our study provides, for the first time, evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease,” said study author George Vassiliou, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that, one day, AML prevention would provide a compelling alternative to treatment.”

Henrique Orlandi Mourao

Researchers say they have found ways to identify patients with a high risk of developing acute myeloid leukemia (AML).

The researchers used basic clinical and laboratory data to identify patients 6 to 12 months before AML presentation.

Using genetic information, the researchers were able to identify high-risk patients several years before AML presentation.

“This long time window gives us the first opportunity to think about how to prevent AML,” said John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

However, Dr Dick and his colleagues noted that neither the genetic method nor the clinical data method were entirely accurate in identifying patients who would develop AML.

The researchers described both methods in Nature.

The team’s work began with the goal of distinguishing patients who will develop AML from patients who simply develop age-related clonal hematopoiesis.

“We wanted to know if there was any difference between these 2 groups in the genetics of their ‘normal’ blood samples taken at enrollment,” Dr Dick said. “To find out, we developed a gene-sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The researchers analyzed samples from 95 patients who ultimately developed AML and 414 age- and gender-matched controls. The samples from AML patients were obtained an average of 6.3 years before AML diagnosis.

The researchers found that pre-AML cases had more mutations per sample, higher variant allele frequencies, and a higher frequency of certain mutations than controls. Specifically, pre-AML cases had a significantly greater frequency of DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1, and IDH2 mutations.

The researchers used these findings to develop a model for predicting AML. They tested the model in a validation cohort of 29 pre-AML cases and 262 controls, as well as in a cohort combining the validation and discovery cohorts. The model predicted AML development with 41.9% sensitivity and 95.7% specificity.

However, the researchers said widespread use of this model would not be practical because AML is so rare. The team said millions of people would need to undergo screening to identify a few pre-AML cases, and there would be “many” false-positives.

Therefore, the researchers developed a model using clinical information from electronic health records—particularly blood counts. This model was able to predict AML development 6 to 12 months before diagnosis with a sensitivity of 25.7% and specificity of 98.2%.

The researchers said these results suggest clinical data can be used to identify patients with a high risk of AML who may benefit from targeted genetic screening. And combining clinical and genetic information in a single model could improve predictive accuracy.

“Our study provides, for the first time, evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease,” said study author George Vassiliou, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that, one day, AML prevention would provide a compelling alternative to treatment.”

Henrique Orlandi Mourao

Researchers say they have found ways to identify patients with a high risk of developing acute myeloid leukemia (AML).

The researchers used basic clinical and laboratory data to identify patients 6 to 12 months before AML presentation.

Using genetic information, the researchers were able to identify high-risk patients several years before AML presentation.

“This long time window gives us the first opportunity to think about how to prevent AML,” said John Dick, PhD, of Princess Margaret Cancer Centre in Toronto, Ontario, Canada.

However, Dr Dick and his colleagues noted that neither the genetic method nor the clinical data method were entirely accurate in identifying patients who would develop AML.

The researchers described both methods in Nature.

The team’s work began with the goal of distinguishing patients who will develop AML from patients who simply develop age-related clonal hematopoiesis.

“We wanted to know if there was any difference between these 2 groups in the genetics of their ‘normal’ blood samples taken at enrollment,” Dr Dick said. “To find out, we developed a gene-sequencing tool that captured the most common genes that get altered in AML and sequenced all the 500 blood samples.”

The researchers analyzed samples from 95 patients who ultimately developed AML and 414 age- and gender-matched controls. The samples from AML patients were obtained an average of 6.3 years before AML diagnosis.

The researchers found that pre-AML cases had more mutations per sample, higher variant allele frequencies, and a higher frequency of certain mutations than controls. Specifically, pre-AML cases had a significantly greater frequency of DNMT3A, TET2, SRSF2, ASXL1, TP53, U2AF1, JAK2, RUNX1, and IDH2 mutations.

The researchers used these findings to develop a model for predicting AML. They tested the model in a validation cohort of 29 pre-AML cases and 262 controls, as well as in a cohort combining the validation and discovery cohorts. The model predicted AML development with 41.9% sensitivity and 95.7% specificity.

However, the researchers said widespread use of this model would not be practical because AML is so rare. The team said millions of people would need to undergo screening to identify a few pre-AML cases, and there would be “many” false-positives.

Therefore, the researchers developed a model using clinical information from electronic health records—particularly blood counts. This model was able to predict AML development 6 to 12 months before diagnosis with a sensitivity of 25.7% and specificity of 98.2%.

The researchers said these results suggest clinical data can be used to identify patients with a high risk of AML who may benefit from targeted genetic screening. And combining clinical and genetic information in a single model could improve predictive accuracy.

“Our study provides, for the first time, evidence that we can identify people at risk of developing AML many years before they actually develop this life-threatening disease,” said study author George Vassiliou, PhD, of the Wellcome Trust Sanger Institute in Hinxton, UK.

“We hope to build on these findings to develop robust screening tests for identifying those at risk and drive research into how to prevent or stall progression towards AML. Our aspiration is that, one day, AML prevention would provide a compelling alternative to treatment.”

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

For patients with non–high-risk acute promyelocytic leukemia (APML), the combination of an oral arsenic formulation and all-trans retinoic acid (ATRA) was noninferior to standard therapy with intravenous arsenic trioxide and ATRA, results of a randomized phase 3 trial show.

Among 109 patients with APML from one of 14 centers in China, the 2-year event-free survival rate after a median follow-up of 32 months was 97% for patients randomized to receive oral arsenic realgar-Indigo naturalis formula (RIF) plus ATRA, and 94% for patients randomized to IV arsenic trioxide plus ATRA, reported Hong-Hu Zhu, MD, of Peking University People’s Hospital in Beijing, China, and his colleagues.

“Our results suggest that non–high-risk acute promyelocytic leukemia can be cured using complete oral arsenic plus ATRA without conventional chemotherapy,” the investigators wrote. The report was published in The Lancet Oncology. “Although longer-term follow-up is needed to draw firm conclusions, our results support previously reported clinical and experimental evidence indicating that ATRA and arsenic act synergistically to eradicate acute promyelocytic leukemia.”

The combination of IV arsenic trioxide and ATRA has revolutionized the care of patients with APML, producing complete and durable remissions in more than 95% of patients with non–high-risk disease, defined as white blood cell counts of 10 x 10⁹/L or less. The trial was designed to see whether an easier-to-administer all-oral regimen could be similarly efficacious and safe, the investigators said.

A total of 109 patients with newly diagnosed APML were randomly assigned on 2:1 basis to receive either RIF-ATRA (72 patients) or arsenic trioxide ATRA (37). Three patients in the oral arm and one in the arsenic trioxide arm did not receive the assigned therapy, but instead received ATRA and chemotherapy.

For induction, RIF was delivered 60 mg/kg daily in an oral divided dose; arsenic trioxide was delivered 0.15 mg/kg daily in an IV. ATRA was delivered 25 mg/m² daily in an oral divided dose. Treatments were used until complete remissions were achieved.

Consolidation was home based and consisted of the same daily doses of RIF or arsenic trioxide in a 4-week-on/4-week-off regimen for four cycles, plus ATRA in the same daily dose in a 2-week-on/2-week-off regimen for seven cycles.

In a modified intention-to-treat analysis with 105 patients, 2-year EFS rates (the primary endpoint) were 97% with oral arsenic and 94% with arsenic trioxide. The percentage difference in EFS was 2.7% and RIF met the prespecified requirement for noninferiority because the lower limit of the 95% confidence interval (-5.8%) was greater than the noninferiority margin of –10%. The noninferiority of the oral formulation was confirmed in a per-protocol analysis, the investigators noted.

Grade 3 or 4 hepatotoxicities during induction were seen in 9% of patients treated with RIF-ATRA versus 14% of patients in the arsenic trioxide–ATRA group. Grade 3 or 4 infections occurred in 23% and 42% of patients, respectively.

Two patients in the arsenic trioxide–ATRA group died during induction therapy, one from hemorrhage and one from thrombocytopenia. There were no deaths during induction in the RIF-ATRA arm and no additional deaths in either arm during the consolidation phase.

All of the 103 surviving patients achieved complete remissions after consolidation.

The investigators acknowledged that the study was limited by a median follow-up time that was too short to allow definitive conclusions about overall survival. They plan to compare the costs of the two regimens in a future study.

SOURCE: Zhu HH et al. Lancet Oncol 2018;19:871-9.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Individuals who develop acute myeloid leukemia (AML) may have somatic mutations detectable years before diagnosis, a newly published analysis shows.

Mutations in IDH1, IDH2, TP53, DNMT3A, TET2, and spliceosome genes at baseline assessment increased the odds of developing AML with a median follow-up of 9.6 years in the study, which was based on blood samples from participants in the Women’s Health Initiative (WHI).

The findings suggest a “premalignant landscape of mutations” that may precede overt AML by many years, according to Pinkal Desai, MD, assistant professor of medicine at Cornell University and oncologist at New York–Presbyterian/Weill Cornell Medical Center, New York, and her coauthors.

“The ability to detect and identify high-risk mutations suggests that monitoring strategies for patients, as well as clinical trials of potentially preventative or disease-intercepting interventions should be considered,” wrote Dr. Desai and her colleagues. The report was published in Nature Medicine.

Their analysis comprised 212 women who participated in the WHI who were healthy at the baseline evaluation but went on to develop AML during follow-up. They performed deep sequencing on peripheral blood DNA for these cases and for 212 age-matched controls.

Women who developed AML were more likely than were controls to have mutations in baseline assessment (odds ratio, 4.86; 95% confidence interval, 3.07-7.77), and had demonstrated greater clonal complexity versus controls (comutations in 46.8% and 5.5%, respectively; odds ratio, 9.01; 95% CI, 4.1-21.4), investigators found.

©GunarsB/Thinkstock

All 21 patients with TP53 mutations went on to develop AML, as did all 15 with IDH1 or IDH2 mutations and all 3 with RUNX1 mutations. Multivariate analysis showed that TP53, IDH1 and IDH2, TET2, DNMT3A and several spliceosome genes were associated with significantly increased odds of AML versus controls.

Based on these results, Dr. Desai and colleagues proposed that patients at increased AML risk should be followed in long-term monitoring studies that incorporate next-generation sequencing.

“Data from these studies will provide a robust rationale for clinical trials of preventative intervention strategies in populations at high risk of developing AML,” they wrote.

In clinical practice, monitoring individuals for AML-associated mutations will become more feasible as costs decrease and new therapies with favorable toxicity profiles are introduced, they added.

“Molecularly targeted therapy is already available for IDH2 mutations and is under development for mutations in other candidate genes found in this study including IDH1, TP53 and spliceosome genes,” they wrote.

The authors reported having no relevant financial disclosures. The WHI program is funded by the National Institutes of Health.

SOURCE: Desai P et al. Nat Med. 2018;24:1015-23.

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

Image by Volker Brinkmann

Preclinical research suggests ibrutinib could treat G-CSFR-mutant myeloid disorders.

“Mutations in G-CSFR have a harmful effect on the production of neutrophils and are reported in patients with several blood disorders, including severe congenital neutropenia, chronic neutrophilic leukemia, and acute myeloid leukemia,” said Ken Greis, PhD, of the University of Cincinnati in Ohio.

“Unfortunately, despite years of research, the malignant signaling of the mutated G-CSFRs is not well understood.”

With this in mind, Dr Greis and his colleagues created a comprehensive signaling network of normal and mutated G-CSFR. Their goal was to understand how abnormal cellular signaling from the mutant receptors results in disease development.

The researchers described this work in Leukemia.

“We are able to look at . . . phosphorylation that results in phosphate groups being attached to the amino acid tyrosine (Tyr) in proteins,” Dr Greis explained. “These phosphorylation events (pTyr) can act as switches to activate or inactivate proteins and/or specific cellular processes.”

“By evaluating pTyr activity in the normal versus mutant receptor cells, we can produce a network similar to a wiring diagram of cellular regulation. Observed disruptions at any of the nodes in the network for the mutated receptors can then be investigated further to understand and perhaps target the abnormal signaling corresponding to the disease.”

This analysis of pTyr activity revealed that G-CSFR mutants had aberrant activation of BTK, as well as abnormal kinetics of canonical STAT3, STAT5, and MAPK phosphorylation.

“When we first got these results, one of the most exciting things was that BTK was already the target of an FDA-approved drug, ibrutinib . . .,” said study author H. Leighton Grimes, PhD, of the University of Cincinnati.

The researchers tested ibrutinib in cells with mutant and wild-type G-CSFR and found the drug killed the mutant cells but not the wild-type cells. This was the case in myeloid progenitor 32D cell lines and primary human CD34+ umbilical cord blood cells.

“Progenitor cells expressing mutated G-CSFR in animal models and in human blood cells also showed enhanced sensitivity to ibrutinib compared to the normal G-CSFR, thus confirming that the mutated cells could likely be eliminated by treatment with ibrutinib and may represent an effective therapy for these patients,” Dr Grimes said.

Ibrutinib also demonstrated synergy with the JAK1/2 inhibitor ruxolitinib. G-CSFR-mutant CD34+ cells were sensitive to each drug alone, but combining them “dramatically enhanced” the sensitivity, according to the researchers.

“These data demonstrate the strength of global proteomics approaches, like the pTyr profiling used here, in dissecting cancer-forming pathways and points to the possibility that ibrutinib could be an effective therapy for myeloid leukemias with G-CSFR mutations,” Dr Greis said.

“Further studies are needed to determine if these findings will be applicable in patient samples, but the hope is that clinical trials are just around the corner, since we’re investigating a drug that has already been found to be safe by the FDA.”

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

STOCKHOLM – For fit, older patients with acute myeloid leukemia (AML), a combination of venetoclax and attenuated-dose induction chemotherapy is tolerable and associated with high response rates, results of the phase 1b CAVEAT trial have suggested.

There was one dose-limiting toxicity in a patient in cohort E (600 mg venetoclax). There were three deaths, all from sepsis, during the induction period (within 42 days) and one after 42 days. The deaths occurred in cohorts C, D, and E.

At the time of data cutoff, two patients had completed treatment, six were continuing, and 33 had discontinued. The primary reason for discontinuation was disease relapse, followed by refractory disease, adverse events, dose-limiting toxicity, or physician/patient decision.

Other adverse events included infections, including grade 3 infections in all 16 patients treated at the 400 mg and 600 mg levels, as well as sepsis, febrile neutropenia, and grade 3 rapid atrial fibrillation in two patients treated in the 400 mg and 600 mg venetoclax cohorts.“Overall, the impression from the investigators was that this is a very deliverable and well-tolerated regimen,” Dr. Wei said.

The overall combined CR/CRi rate was 71%, including CR/CRi in all 9 patients in the 200 mg venetoclax dose cohort.

“Even just with 1 week of monotherapy venetoclax exposure, 25% of patients had a 50% reduction in their bone marrow blasts,” Dr. Wei said.

Median overall survival among the 37 evaluable patients was 7.7 months. Among 12 patients who achieved a CR, the median overall survival was 18.5 months, and among the 12 patients with a CRi, the median overall survival was 7.7 months. For the remaining 13 patients, the median overall survival was 6.3 months.

Survival was significantly better for patients who were treatment-naive prior to venetoclax and chemotherapy, at a median of 18.6 months, compared with 3.8 months for patients who had previously received a hypomethylating agent and/or low-dose cytarabine (P = .0018).

Dose expansion of the 600-mg cohort is ongoing to provide better perspectives on efficacy.

The findings provide evidence that venetoclax monotherapy has cytoreductive potential and support future exploration of venetoclax in combination with 7+3 chemotherapy in younger, fit adults with AML, Dr. Wei said.

The study was supported by AbbVie/Genentech, the Victorian Cancer Agency, and the National Health and Medical Research Council of Australia. Dr. Wei reported research support and advisory board activities with AbbVie and other companies.

SOURCE: Wei AH et al. EHA Congress, Abstract S1564.

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

Photo by Rhoda Baer

The US Food and Drug Administration (FDA) has granted regenerative medicine advanced therapy (RMAT) designation for romyelocel-L, a myeloid progenitor cell therapy that doesn’t require HLA matching.

Romyelocel-L (CLT-008) is being developed as prophylaxis for serious bacterial and fungal infections in patients with de novo acute myeloid leukemia (AML) who develop neutropenia while receiving induction chemotherapy.

The FDA grants RMAT designation to therapies intended to treat serious or life-threatening conditions if there is preliminary clinical evidence that the therapies could address unmet medical needs.

RMAT designation provides similar advantages as breakthrough therapy designation, including early interactions with the FDA to discuss potential ways to accelerate the development of a therapy toward regulatory approval.

The FDA granted romyelocel-L RMAT designation based on a randomized, phase 2 trial of newly diagnosed AML patients who received induction consisting of cytarabine and an anthracycline.

Results from this trial were presented at the 2018 ASCO Annual Meeting (abstract 7043).

The trial enrolled 163 AML patients and randomized them, on the first day of induction, to receive:

• Daily granulocyte colony-stimulating factor (G-CSF) starting on day 14 (n=84)
• Romyelocel-L (7.5 x 10⁶cells/kg) on day 9 plus daily G-CSF starting on day 14 (n=79).

Patients received G-CSF until neutrophil recovery to at least 500/µL.

Baseline characteristics were well balanced between the treatment arms.

There were 120 evaluable patients—59 in the romyelocel-L arm and 61 in the control arm.

The study’s primary endpoint was days in a febrile episode (DFE). The mean DFE from day 9 to 28 was 6.46 days in the romyelocel-L arm and 6.86 days in the control arm (P=0.350). The mean DFE for days 15 to 28 was 2.36 and 3.90, respectively (P=0.020).

The incidence of microbiologically or clinically diagnosed infection from day 9 to 28 was 35.6% in the romyelocel-L arm and 47.5% in the control arm, a decrease of 25% (P=0.089).

From day 15 to 28 the incidence of infection was 6.8% in the romyelocel-L arm and 27.9% in the control arm, a decrease of 76% (P=0.002).

There were no infectious deaths in the romyelocel-L arm but 2 deaths attributed to pneumonia in the control arm.

The mean hospital stay was 25.5 days in the romyelocel-L arm and 28.7 days in the control arm (P=0.002).

The proportion of patients with serious adverse events (AEs) was 14% in the romyelocel-L arm and 18% in the control arm. The proportion of patients with infectious serious AEs was 50% and 77%, respectively.

The most frequent treatment-emergent AEs (in the romyelocel-L and control arms, respectively) were febrile neutropenia (31.4% and 31%), diarrhea (25.7% and 32.4%), hypokalemia (31.4% and 25.4%), hypophosphatemia (21.4% and 23.9%), and pyrexia (22.9% and 22.5%).

There were no cases of graft-versus-host disease.  

AML cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for CPX-351 (Vyxeos™), a liposomal formulation that delivers a fixed ratio (1:5) of daunorubicin and cytarabine.

The CHMP is recommending approval of CPX-351 (44 mg/100 mg) for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes.

The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

The marketing authorization application for CPX-351 is supported by data from 5 studies, including a phase 3 study.

Data from the phase 3 study were presented at the 2016 ASCO Annual Meeting and are available in the US prescribing information for CPX-351. (The following data are taken from the prescribing information.)

This trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

They received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

AML cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for CPX-351 (Vyxeos™), a liposomal formulation that delivers a fixed ratio (1:5) of daunorubicin and cytarabine.

The CHMP is recommending approval of CPX-351 (44 mg/100 mg) for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes.

The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

The marketing authorization application for CPX-351 is supported by data from 5 studies, including a phase 3 study.

Data from the phase 3 study were presented at the 2016 ASCO Annual Meeting and are available in the US prescribing information for CPX-351. (The following data are taken from the prescribing information.)

This trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

They received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.

AML cells

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended marketing authorization for CPX-351 (Vyxeos™), a liposomal formulation that delivers a fixed ratio (1:5) of daunorubicin and cytarabine.

The CHMP is recommending approval of CPX-351 (44 mg/100 mg) for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia or AML with myelodysplasia-related changes.

The CHMP’s recommendation will be reviewed by the European Commission, which has the authority to approve medicines for use in the European Union, Norway, Iceland, and Liechtenstein.

The European Commission usually makes a decision within 67 days of the CHMP’s recommendation.

The marketing authorization application for CPX-351 is supported by data from 5 studies, including a phase 3 study.

Data from the phase 3 study were presented at the 2016 ASCO Annual Meeting and are available in the US prescribing information for CPX-351. (The following data are taken from the prescribing information.)

This trial enrolled 309 patients, ages 60 to 75, with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes.

They received CPX-351 (n=153) or cytarabine and daunorubicin (7+3; n=156).

The complete response rate was 38% in the CPX-351 arm and 26% in the 7+3 arm (P=0.036).

The rate of hematopoietic stem cell transplant was 34% in the CPX-351 arm and 25% in the 7+3 arm.

The median overall survival was 9.6 months in the CPX-351 arm and 5.9 months in the 7+3 arm (P=0.005).

All-cause 30-day mortality was 6% in the CPX-351 arm and 11% in the 7+3 arm. Sixty-day mortality was 14% and 21%, respectively.

Six percent of patients in both arms had a fatal adverse event (AE) on treatment or within 30 days of therapy that was not in the setting of progressive disease.

The rate of AEs that led to discontinuation was 18% in the CPX-351 arm and 13% in the 7+3 arm. AEs leading to discontinuation in the CPX-351 arm included prolonged cytopenias, infection, cardiotoxicity, respiratory failure, hemorrhage, renal insufficiency, colitis, and generalized medical deterioration.

The most common AEs (incidence ≥ 25%) in the CPX-351 arm were hemorrhagic events, febrile neutropenia, rash, edema, nausea, mucositis, diarrhea, constipation, musculoskeletal pain, fatigue, abdominal pain, dyspnea, headache, cough, decreased appetite, arrhythmia, pneumonia, bacteremia, chills, sleep disorders, and vomiting.

The most common serious AEs (incidence ≥ 5%) in the CPX-351 arm were dyspnea, myocardial toxicity, sepsis, pneumonia, febrile neutropenia, bacteremia, and hemorrhage.