Acute Lymphoblastic Leukemia: Tyrosine Kinase Inhibitors Target Resistant Variant

Department of Pathology St. Jude Children's Research Hospital Memphis, TN 38105

St. Jude Children’s Research Hospital Interview with:
Dr. Charles Mullighan, M.D., MBBS(Hons), MSc
Department of Pathology
St. Jude Children’s Research Hospital
Memphis, TN 38105

MedicalResearch: What are the most important take home points from this study for practicing clinicians and their patients?

Dr. Mullighan: Acute lymphoblastic leukemia (ALL) remains a leading cause of cancer death in children, and the prognosis worsens with increasing age. Current therapies are inadequate for many patients. This study has defined the genetic basis of a recently described subtype of Acute lymphoblastic leukemia called Ph-like ALL. We show that the prevalence increases with rising age, and that in both children and young adults the disease is driven by a diverse range of genetic changes that activate kinase signaling, which fuels the growth of leukemia cells. Ph-like Acute lymphoblastic leukemia currently has a poor outcome. The activated kinases may be inhibited by currently approved tyrosine kinase inhibitors (TKIs). We have shown efficacy of these inhibitors in cell lines and experimental models, and in a series of patients with Ph-like Acute lymphoblastic leukemia treated with TKIs.

MedicalResearch: What is the clinical significance of the study and how can the information from the study be used in new approaches to patient care?

Dr. Mullighan: The study is clinically significant as Ph-like ALL currently has a poor outcome and new treatments are needed, and we have shown efficacy of TKIs in cases of refractory Ph-like ALL.

There are two key areas of clinical relevance.

The first is diagnosis. Ph-like ALL is characterized by a range of genetic alterations activating many tyrosine kinases. Despite this complexity, accurate diagnosis of Ph-like Acute lymphoblastic leukemia may be achieved by screening approaches followed by genetic testing, or ultimately, genome sequencing at diagnosis.

Secondly, this information is important not only to identify Ph-like ALL, but to direct patients to the appropriate TKI. In addition, while our data strongly suggest that TKI therapy will improve the success of ALL therapy, this requires formal testing in clinical trials. Such trials are under development in children and adults.

Finally, our results have shown that the frequency of Ph-like Acute lymphoblastic leukemia rises with age, which is likely to in part explain the poor outcome of Acute lymphoblastic leukemia with increasing age. However, there is limited information about the genetics of Acute lymphoblastic leukemia in older adults, for whom treatment outcomes are poor. Such studies are needed and ongoing. In the near future, we envisage that all patients will be tested for the presence of Ph-like Acute lymphoblastic leukemia to enable the most appropriate treatment to be delivered.

MedicalResearch: What recommendations do you have for future research as a result of this study?

Dr. Mullighan: A key priority is testing the efficacy of TKAs in prospective trials of Ph-like ALL and adults and children. Such trials will incorporate genomic approaches to identify Ph-like ALL and direct patients to the appropriate drug. A second important area of research is detailed genomic characterization of Acute lymphoblastic leukemia in adults. This includes adults age 40 and older, who experience poor outcomes of treatment. It is important to define the prevalence and nature of Ph-like Acute lymphoblastic leukemia in this group, and also to continue to examine the genetic basis of ALL patients lacking known driver lesions.

MedicalResearch: Do you have any additional comments?

Dr. Mullighan: The findings of this study were only possible with extensive collaboration between childhood and adult cooperative groups, and the genomic sequencing capabilities of the St Jude – Washington University Pediatric Cancer Genome Project and the NCI TARGET initiative.


Targetable Kinase-Activating Lesions in Ph-like Acute Lymphoblastic Leukemia

Kathryn G. Roberts, Ph.D., Yongjin Li, Ph.D., Debbie Payne-Turner, B.S., Richard C. Harvey, Ph.D., Yung-Li Yang, M.D., Deqing Pei, M.S., Kelly McCastlain, B.S., Li Ding, Ph.D., Charles Lu, Ph.D., Guangchun Song, M.S., Jing Ma, Ph.D., Jared Becksfort, M.S., Michael Rusch, B.A., Shann-Ching Chen, Ph.D., John Easton, Ph.D., Jinjun Cheng, M.D., Kristy Boggs, Ph.D., Natalia Santiago-Morales, B.S., Ilaria Iacobucci, Ph.D., Robert S. Fulton, Ph.D., Ji Wen, Ph.D., Marcus Valentine, B.A., Cheng Cheng, Ph.D., Steven W. Paugh, Ph.D., Meenakshi Devidas, Ph.D., I-Ming Chen, D.V.M., Shalini Reshmi, Ph.D., Amy Smith, B.S., Erin Hedlund, Ph.D., Pankaj Gupta, M.S., Panduka Nagahawatte, M.S., Gang Wu, Ph.D., Xiang Chen, Ph.D., Donald Yergeau, Ph.D., Bhavin Vadodaria, B.A., Heather Mulder, B.S., Naomi J. Winick, M.D., Eric C. Larsen, M.D., William L. Carroll, M.D., Nyla A. Heerema, Ph.D., Andrew J. Carroll, Ph.D., Guy Grayson, M.D., Sarah K. Tasian, M.D., Andrew S. Moore, M.D., Frank Keller, M.D., Melissa Frei-Jones, M.D., James A. Whitlock, M.D., Elizabeth A. Raetz, M.D., Deborah L. White, Ph.D., Timothy P. Hughes, M.D., Jaime M. Guidry Auvil, Ph.D., Malcolm A. Smith, M.D., Guido Marcucci, M.D., Clara D. Bloomfield, M.D., Krzysztof Mrózek, M.D., Jessica Kohlschmidt, Ph.D., Wendy Stock, M.D., Steven M. Kornblau, M.D., Marina Konopleva, M.D., Elisabeth Paietta, Ph.D., Ching-Hon Pui, M.D., Sima Jeha, M.D., Mary V. Relling, Pharm.D., William E. Evans, Pharm.D., Daniela S. Gerhard, Ph.D., Julie M. Gastier-Foster, Ph.D., Elaine Mardis, Ph.D., Richard K. Wilson, Ph.D., Mignon L. Loh, M.D., James R. Downing, M.D., Stephen P. Hunger, M.D., Cheryl L. Willman, M.D., Jinghui Zhang, Ph.D., and Charles G. Mullighan, M.D.

N Engl J Med 2014; 371:1005-1015September 11, 2014DOI: 10.1056/NEJMoa1403088