Common molecular genetic mutations in AML
FEATURE
Some patients will experience both CRS and neurotoxicity – together or in sequential order – but , despite these side effects , most patients recover after careful monitoring and supportive care , Dr . Goff said . “ Two patients required intubation because they were unable to maintain their mental status enough to protect their airways ,” she noted , “ but even without additional treatment to stop the T cells with steroids , these patients recovered .”
Ready for Prime Time ?
Despite the promise seen in B-cell cancers , CAR T-cell
TP53 2 %
PTEN 2 %
KRAS 2 %
PHF6 3 %
ASXL1 3 %
MLL-PTD 5 %
RUNX1 5 % therapy is only in its infancy . There are still many unanswered questions and ways in which the therapies might be improved or their use extended to other cancers .
“ We don ’ t even know yet if the response rates we have seen will be replicated once the therapy starts being used more widely ,” said Dr . Goff .
Assuming these therapies receive regulatory approval , myriad issues surround the implementation of such a groundbreaking therapy . Who will deliver the therapy ? Where will the cell processing be done ? How does one mass produce a time- , labor- , and technology-intensive
Common molecular genetic mutations in AML
FLT3 ( ITD , TKD ) 37 %
NPM1 29 %
personalized therapy ? How can efficacy and safety be ensured throughout the process ? What will it cost ?
Clinically , Dr . Goff does not see CAR T-cell therapy as being more complicated than hematopoietic cell transplantation , and , in some ways , it may be less complicated . Both are highly individualized and require complex chemotherapy regimens , and they need to be performed at centers used to dealing with life-threatening side effects .
“ I don ’ t know if CAR T-cell therapy will ever become a firstline option because there are many patients who go into remission with standard chemotherapy ,” Dr . Goff said , “ but I think , in a world where transplant is a feasible option , CAR T-cell therapy is no more difficult .”
CAR T cells might not yet be poised to overtake chemotherapy as the standard of care , but they are looking promising as treatment for certain patients with no other feasible options .
“ The success seen in lymphoma and leukemia is not necessarily going to translate to more common cancers , even though we are still actively investigating its use in those settings ,” Dr . Goff said . “ The durability of the responses we ’ ve seen thus far is very good , so we now have something that is very effective for a population of patients in search of salvage therapy .” — By Debra L . Beck ●
KIT 6 %
IDH1 7 %
IDH2 8 %
WT1 8 %
TET2 8 %
CEBPA 9 %
NRAS 10 %
DNMT3A 23 %
Adapted from Patel 2012 . 5
Molecular genetic testing may be an important factor that can be utilized to facilitate clinical decision-making 4
REFERENCES
1 . Maude SL , Teachey DT , Porter DL , et al .. CD19-targeted chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia . Blood . 2015 ; 125:4017-23 .
2 . Turtle CJ , Hanafi LA , Berger C , et al . Immunotherapy of non- Hodgkin ’ s lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor-modified T cells . Sci Transl Med . 2016 ; 8:355ra116 .
3 . Maus MV , Levine BL . Chimeric antigen receptor T-cell therapy for the community oncologist . Oncologist . 2016 ; 21:608-17 .
4 . Kochenderfer J , Somerville R , Lu T , et al . Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma . Abstract # LBA3010 . Presented at the 2016 ASCO Annual Meeting , June 7 , 2016 ; Chicago , Illinois .
5 . Neelapu SS , Locke FL , Bartlett N , et al . Kte-C19 ( anti-CD19 CAR T cells ) induces complete remissions in patients with refractory diffuse large B-cell lymphoma ( DLBCL ): results from the pivotal phase 2 ZUMA-1 . Abstract # LBA-6 . Presented at the 2016 ASH Annual Meeting , December 6 , 2016 ; San Diego , California .
6 . Grupp SA , Maude SL , Shaw PA , et al . Durable remissions in children with relapsed / refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor ( CTL019 ). Abstract # 681 . Presented at the 2015 ASH Annual Meeting , December7 , 2015 ; Orlando , Florida .
References : 1 . National Cancer Institute . SEER Stat Fact Sheets : Acute Myeloid Leukemia ( AML ). http :// seer . cancer . gov / statfacts / html / amyl . html . Accessed September 20 , 2016 . 2 . Deschler B , Lübbert M . Acute myeloid leukemia : epidemiology and etiology . Cancer . 2006 ; 107 ( 9 ): 2099-2107 . 3 . Ferrara F , Schiffer CA . Acute myeloid leukaemia in adults . Lancet . 2013 ; 381 ( 9865 ): 484-495 . 4 . Referenced with permission from the NCCN Clinical Practice Guidelines In Oncology ( NCCN Guidelines ® ) for Acute Myeloid Leukemia V . 2.2016 . © National Comprehensive Cancer Network , Inc 2016 . All rights reserved . Accessed September 20 , 2016 . To view the most recent and complete version of the guideline , go online to NCCN . org . NATIONAL COMPREHENSIVE CANCER NETWORK ® , NCCN ® , NCCN GUIDELINES ® , and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network , Inc . 5 . Patel JP , Gönen M , Figueroa ME , et al . Prognostic relevance of integrated genetic profiling in acute myeloid leukemia . N Engl J Med . 2012 ; 366 ( 12 ): 1079-1089 .
7 . Kochenderfer JN , Dudley ME , Kassim SH , et al . Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor . J Clin Oncol . 2015 ; 33:540-9 .
8 . Teachey DT , Lacey SF , Shaw PA , et al . Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia . Cancer Discov . 2016 ; 6:664-79 .
9 . Children ’ s Hospital of Philadelphia . Relapsed leukemia : Emily ’ s story . Accessed December 4 , 2016 from http :// www . chop . edu / stories / relapsed-leukemia-emilys-story .
10 . Grupp SA , Kalos M , Barrett D , et al . Chimeric antigen receptormodified T cells for acute lymphoid leukemia . N Engl J Med . 2013 ; 368:1509-18 .
Novartis Pharmaceuticals Corporation East Hanover , New Jersey 07936-1080
© 2016 Novartis 9 / 16 MLA-1148431
ASH Clinical News 33