FEATURES
Immune checkpoint receptor – blockade also is being studied in AML and other myeloid malignancies , though results have been disappointing thus far . Immune checkpoint inhibition – or removing the inhibitory signals on the T cells that the cancer has produced – is widely used in solid tumor oncology with multiple agents having received FDA approval , and is more recently finding its way into hematology . Investigators have reported encouraging results with anti – programmed death 1 ( PD-1 ) antibodies in classical Hodgkin lymphoma and anti – PD-1 in combination with other agents in non-Hodgkin lymphoma and multiple myeloma . 4-6
Checkpoint inhibition as a monotherapy for AML and MDS has unfortunately shown limited clinical efficacy . To boost effectiveness , investigators are looking at combining checkpoint inhibitors with hypomethylating agents ( HMAs ) such as azacitidine and decitabine .
“ We know azacitidine and decitabine have their own anti-tumor activity , but we also know that they modulate the immune system by multiple mechanisms , including upregulation of inhibitory immune checkpoint molecule expression , specifically PD1 / PD-L1 , which are targets for the immune checkpoint inhibitors ,” Dr . Daver explained . 7 Several trials at his center and elsewhere are evaluating the efficacy of HMAs combined with either CTLA-4 , PD-1 , or PD-L1 blocking antibodies , including ipilimumab , nivolumab , pembrolizumab , and durvalumab .
Reports presented at recent medical meetings suggest that toxicities associated with these agents are manageable for most patients . For example , the combination of azacitidine and nivolumab produced what trial investigators felt was an “ encouraging ” response rate and survival in patients with relapsed AML and poor-risk features , compared with historic survival rates in this population . 8
“ Looking at this combination in patients with newly diagnosed or relapsed MDS , we ’ re seeing very similar data ,” Dr . Daver said , noting that approximately 75 percent of patients in the frontline setting responded to this treatment regimen .
“ With the immune checkpoint inhibitors , we see less toxicity than with the CAR T-cell products ,” he added . “ And the good thing is that patients usually respond quickly to steroids and do not require the use of more potent immunosuppressive agents .”
More experience with these agents will continue to improve their clinical use , Dr . Daver said . “ Over time , we ’ ve become adept at identifying the toxicities and treating them early with steroids , and most patients can continue to receive the PD-1 or CTLA-4 inhibitor . Awareness , early recognition , and rapid treatment are very important with immunotherapies in general .”
Naked No Longer : Directed ADCs T-cell harnessing works best in patients who have an adequate population of “ manipulable ” T cells , such as frontline and early salvage patients , Dr . Daver noted .
Other options under investigation are the directed antibodydrug conjugates ( ADCs ), which consist of a monoclonal antibody chemically linked to a drug . This class of agents combines the cytotoxic activity of chemotherapy drugs with the selectivity of targeted monoclonal antibodies . In AML , the most commonly used targets for ADCs are the myeloid surface antigens CD33 and CD123 .
“ ADCs are not dependent on a patient ’ s own T-cell population to fight against a tumor , but they act more like cytotoxic therapies and target a particular antigen ,” explained Dr . Daver . “ These monoclonal antibodies are linked to a toxic payload , either bacterial or chemical , and once the antibodies attach to the AML antigen , they are basically internalized into the AML cells and the toxin is released , resulting in cell death .”
Many of the first-generation monoclonal antibodies evaluated in AML were “ naked ,” in that they relied on antibody-dependent , cell-mediated cytotoxicity , as rituximab and other anti-CD20 antibodies do successfully in lymphomas . However , in AML , naked antibodies demonstrated limited antileukemic activity . Now , researchers are focusing on developing conjugated antibodies engineered to deliver a bacterial , viral , or chemical payload to leukemic blasts and / or LSCs .
Last year saw the re-approval of the CD33-targeted ADC gemtuzumab ozogamicin ( GO ) for frontline and relapsed AML . GO was initially approved by the FDA in 2000 , but was voluntarily withdrawn from market in June 2010 when a phase III trial of GO plus chemotherapy failed to show benefit over chemotherapy alone . However , after several European phase III trials showed improved event-free survival , and in some studies , improved OS when GO was added to chemotherapy , the drug was approved in September 2017 for newly diagnosed or relapsed / refractory CD33-positive AML and in pediatric patients at least 2 years of age . 9
“ GO is already being widely used in combination with induction chemotherapy for AML , or as a single agent in relapsed AML , but there are newer ADCs in development that could offer additional options ,” Dr . Daver said . “ In the next few years , we may have 20 to 40 percent of AML patients being treated with an ADC added to induction therapy or in the relapsed setting .” — By Debra Beck ●
REFERENCES
1 . Surveillance , Epidemiology , and End Results . “ Cancer Stat Facts : Leukemia - Acute Myeloid Leukemia ( AML ).” Accessed March 28 , 2018 , from https :// seer . cancer . gov / statfacts / html / amyl . html .
2 . Budde L , Song JY , Kim Y , et al . Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123- specific CAR T cells : a first-in-human clinical trial . Abstract # 811 . Presented at the 2017 ASH Annual Meeting , December 11 , 2017 ; Atlanta .
3 . Cellectis . “ FDA Lifts Clinical Hold on Cellectis Phase 1 Clinical Trials with UCART123 in AML and BPDCN .” Accessed April 3 , 2018 , from http :// www . cellectis . com / en / press / fda-lifts-clinical-hold-on-cellectis-phase-1-clinicaltrials-with-ucart123-in-aml-and-bpdcn .
4 . Daver N , Basu S , Garcia-Manero G , et al . Phase Ib / II study of nivolumab in combination with azacitidine ( AZA ) in patients ( pts ) with relapsed acute myeloid leukemia ( AML ). Abstract # 763 . Presented at the 2016 ASH Annual Meeting , December 6 , 2016 ; San Diego .
5 . Merryman RW , Armand P , Wright KT , Rodig SJ . Checkpoint blockade in Hodgkin and non-Hodgkin lymphoma . Blood Adv . 2017 November 10 .
6 . Rosenblatt J , Avigan D . Targeting the PD-1 / PD-L1 axis in multiple myeloma : a dream or a reality . Blood . 2017 ; 129:275-9 .
7 . Daver N , Boddu P , Garcia-Manero G , et al . Hypomethylating agents in combination with immune checkpoint inhibitors in acute myeloid leukemia and myelodysplastic syndromes . Leukemia . 2018 February 22 . [ Epub ahead of print ]
8 . Daver N , Garcia-Manero G , Basu S , et al . Nivolumab ( nivo ) with azacytidine ( AZA ) in patients ( pts ) with relapsed acute myeloid leukemia ( AML ) or frontline elderly AML . Abstract # 1345 . Presented at the 2017 ASH Annual Meeting , December 9 , 2017 ; Atlanta .
9 . U . S . Food and Drug Administration . “ FDA approves Mylotarg for treatment of acute myeloid leukemia .” Accessed April 4 , 2018 , from https :// www . fda . gov / NewsEvents / Newsroom / PressAnnouncements / ucm574507 . htm .
20 Focus on Myeloid Malignancies