Acute myeloid leukemia (AML) is a clonal hematopoietic disorder that results from genetic alterations in normal hematopoietic stem cells. These alterations interfere with normal cellular differentiation, leading to disproportionate proliferation of immature leukemic cells, termed blasts. AML is characterized by the presence of more than 20% blasts within the bone marrow.1 AML is the most common acute leukemia affecting adults, accounting for 80% of cases of adult leukemia.2,3 Approximately 21,380 new cases of AML are expected to be diagnosed in 2017 (11,960 in men, 9,420 in women).3
Naval G. Daver, MD, Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX was interviewed for his perspective on this topic.
Elizabeth Paczolt (EP): Can you please provide a brief review of the current therapy landscape in AML, including the new types of therapy that are being investigated and emerging?
Dr. Naval Daver: A number of new agents are now coming into clinical trials for AML. This comes after about 40 years during which time there were no new drugs aside from gemtuzumab ozogamicin, which was approved for a short period, taken off the market due to adverse events associated with it, [Update 09/15/17: and only recently approved again by the FDA, on September 1, 2017.] In the last 4 years, there have been a number of exciting new drugs that have shown promise as well as positive results in both phase 2 and phase 3 studies. The way I prefer to look at these drugs in AML is putting them into four major compartments. First are the immune-based therapies, chief among them monoclonal antibodies (mAbs): either conjugated to toxins or bispecific antibodies redirecting T-cells to fight against AML cells or immune checkpoint antibodies that unleash T-cells against AML. The second group that is of importance is the molecular-targeted therapies and chiefly, two among these: the FMS-like tyrosine kinase 3 (FLT3) inhibitors and the isocitrate dehydrogenase (IDH) inhibitors which are in clinical trials, some of them approaching submission for approval by the United States Food and Administration (FDA). The third group is the novel cytotoxic agents, one of which is a new fixed- dose combination of cytarabine idarubicin call CPX-351. The other is a drug called vosaroxin which has shown activity in first salvage AML in a phase 3 study. Finally, there are the novel epigenetic agents which include new or second-generation hypomethylating agents such as guadecitabine, as well as a new epigenetic targeted agents such as bromodomain inhibitors and histone deacetylase (HDAC) inhibitors, among others. That is a basic overview of the current treatment and upcoming new agents in AML.
EP: Let's take a more in-depth look at the immune-based agents, specifically the mAbs. Can you please discuss the history of these agents and their initial development?
Dr. Daver: The traditional way to use immunotherapies in AML has been to use mAbs that target particular antigens. New modalities include unleashing T-cells to fight against the tumor using immune checkpoint antibodies – these will be discussed in detail in other activities. Monoclonal antibodies are antibodies that are targeted toward leukemia-specific antigens. In AML, the leukemia-specific antigens would be CD33 and CD123, which are expressed on the majority of myeloid blasts and leukemic stem cells but not expressed (or expressed in lower levels) in normal tissue.5 Another is CD38, which has been associated with residual disease.6 And there is another emerging target, C-type lectin-like molecule (CLL1), which has also been found to be expressed on the majority of myeloid blasts and leukemic stem cells, but not expressed (or expressed in lower levels) in normal tissue or normal hematopoietic stem cells.5 Usually these monoclonal antibodies have a toxic payload attached to them, which they will deliver into the AML cell once they bind to that cell through the particular antigen. A number of different types of payloads have been used, including either bacterial-associated toxins such as pseudomonas or diphtheria toxins, or newer chemical compounds such as calicheamicin or pyrrolobenzodiazepine.7
The first mAb used for the treatment of AML was gemtuzumab ozogamicin (GO). This agent was an anti-CD33 antibody conjugated to a toxin called calicheamicin; this combination is referred to as an antibody-drug conjugate (ADC). GO trials actually started in the late 1990s, and initial data from a phase 2 multicenter trial demonstrated that as a single agent, GO had about 30% response rate with a relapse-free survival (RFS) of 6.8 months in first-relapsed AML in patients who had already received standard cytotoxic chemotherapy.8,9 Based on data from this trial and other supportive trials, GO was approved for use as monotherapy for the treatment of adults 60 years of age and older with recurrent AML who were not considered candidates for other chemotherapy, under the FDA's accelerated approval program in 2000.10 However, a confirmatory study performed subsequently found that the addition of GO to induction therapy or GO used as post-consolidation therapy did not demonstrate improvement in CR, RFS, post-consolidation disease-free survival (DFS), or overall survival (OS), but was associated with a higher incidence of induction mortality.11 In addition, the agent was associated with hepatotoxicity, including veno-occlusive disease which was found to have an occurrence rate of up to 10% from post-marketing surveillance data.8,10 Because of that, the drug had a short-lived period on the United States market and was withdrawn by the manufacturer.10
However, since that time, new clinical trials have provided additional data on the use of GO, including the phase 3 ALF-0701 study, which demonstrated an improvement in RFS and event-free survival (EFS) with the addition of GO to standard induction chemotherapy.12,13 In addition, other large randomized studies in Europe have shown improvement in OS in elderly patients considered ineligible for chemotherapy, as well as improvement in both EFS and RFS in adult patients with AML when combined with chemotherapy, especially in patients with intermediate and favorable cytogenetics. Because of this new data, the manufacturer is now submitting a reapplication to the FDA to bring GO back on the US market. A Prescription Drug User Fee Act (PDUFA) goal date for a decision on this application is expected in September 2017.13
EP: What can you tell us about other emerging mAbs that are currently undergoing investigation for AML?
Dr. Daver: Since GO, there have been other exciting mAbs that have come into development. The first among them is probably the drug SGN-33A, also called vadastuximab talirine. This is also an mAb directed toward CD33, conjugated to the toxin pyrrolobenzodiazepine. There have been phase 1 studies with SGN-33A monotherapy in patients who have relapsed or refractory AML where response ranged from 25% to 35%, including CR, CR with incomplete platelet or neutrophil recovery (CRi), partial response (PR), and morphologic leukemia-free status (MLFS).14 However, the most exciting data came when it was used in front-line therapy in patients with AML over 65 years of age, who received a combination of SGN-33A with either azacitidine or decitabine. Results showed an overall response rate (ORR) of approximately 76%.15 Putting this into historical perspective, the expected ORR with single-agent azacitidine in a similar population would be 20% to 30%. Here we see a doubling, or even a tripling, of the response rate in a very similar population when the azacitidine is combined with VT.15 [Update 01/15/18: The phase 3 study discussed here has been terminated: There is now a phase 3 study that has begun enrollment, a double-blinded randomized study in multiple centers in the United States where patients older than 65 years of age will be randomized to receive either azacitidine — which is considered the standard of care per the National Comprehensive Cancer Network (NCCN) guidelines — or azacitidine in combination with SGN-33A, which is hoped to demonstrate an OS benefit in addition to the improved response rates seen in phase 2. If superiority for OS is proven, this combination would likely be approved for front-line therapy in the older AML population.] There is also another study with SGN-33A looking at a younger or fitter AML population (18 to 65 years of age), and this is a combination of SGN-33A with standard induction therapy comprising 7 days of cytarabine and 3 days of an anthracycline (7+3).16 It must be noted that in late 2016, the FDA put a hold on clinical trials of SGN-33A due to concern about its use in patients who underwent allogeneic stem cell transplant (ASCT) prior to or after treatment with the agent. This occurred because 6 patients had been identified with hepatotoxicity in the ASCT treatment setting, with 4 deaths among this group. However, this hold was lifted in March 2017, and ongoing combination therapy and monotherapy trials will be continued (although studies of SGN-33A in pre- and post-ASCT patients with AML will be discontinued).17 [Update 01/15/18: Data was presented at EHA 2017 related to a phase 1b study of SGN-33A in combination with standard 7 + 3 induction therapy. Among 42 evaluable patients, the CR+CRi (CRc) rate was 76%.18]
Another approach that has been very active in acute lymphoblastic leukemia (ALL) is the use of bispecific T-cell engaging antibodies (BiTEs). One of these is blinatumomab, which has recently received approval for the treatment of pediatric and adolescent patients with Philadelphia chromosome-negative (Ph-) relapsed or refractory B-cell precursor ALL.20 This is an attractive concept now being translated into the AML world, with multiple different BiTE constructs being evaluated in AML. These include CD3 X CD33 BiTEs as well as a CD3 X CD123 BiTEs, and other bispecific antibody conjugates that are in clinical trials. Again, since these are in phase 1, the data is very early.5,16 One of the concerns with BiTEs is that they do not directly attack the tumor antigen or tumor cells, but instead activate T-cells and bring them close to tumor cells to induce killing of the tumor cells. A concern is that in this process we may see overactivation of the T-cells or other AML tumor microenvironment cells (macrophages, monocytes) that often express CD33, CD123 resulting in a cytokine release syndrome, and indeed in the first studies, we are seeing early evidence of cytokine release.5 Strategies to mitigate these occurrences such as reducing the tumor burden before starting the BiTE, or early intervention and/or premedication with steroids, are being considered. If cytokine release can be overcome, these could be very promising active agents and could potentially be combined with other immune/molecular agents. Ongoing investigation into all of these mAbs may provide new pathways to therapy that could markedly improve outcomes in patients with AML.
- Kumar CC. Genetic abnormalities and challenges in the treatment of acute myeloid leukemia. Genes & Cancer. 2011;2(2):95-107.
- Yamamoto JF, Goodman MT. Patterns of leukemia incidence in the United States by subtype and demographic characteristics, 1997-2002. Cancer Causes Control. 2008;19(4):379-390.
- Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67(1):7-30.
- National Cancer Institute. Adult Acute Myeloid Leukemia Treatment–for health professionals (PDQ®). (January 20, 2017). Available at: https://www.cancer.gov/types/leukemia/hp/adult-aml-treatment-pdq#section/_46.
- Hoseini SS, Cheung NK. Acute myeloid leukemia targets for bispecific antibodies. Blood Cancer J. 2017;7(4):e552.
- Wang L, Gao L, Xu S, et al. FISH+CD34+CD38- cells detected in newly diagnosed acute myeloid leukemia patients can predict the clinical outcome. J Hematol Oncol. 0213;6(1):85.
- Kim EG, Kim KM. Strategies and advancement in antibody-drug conjugate optimization for targeted cancer therapies. Biomol Ther (Seoul). 2015;23(6):493-509.
- Nabhan C, Rundhaugen L, Jatoi M, et al. Gemtuzumab ozogamicin (Mylotarg™) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease. Ann Oncol. 2004;15(8):1231-1236.
- Sievers EL, Larson RA, Stadtmauer EA et al. Efficacy and safety ofgemtuzumab ozogamicin in patients with CD33-positive acutemyeloid leukemia in first relapse. J Clin Oncol. 2001;19(13):3244-3254.
- National Cancer Institute. Gemtuzumab ozogamicin voluntarily withdrawn from U.S. markets. (June 24, 2010). Available at: https://www.cancer.gov/about-cancer/treatment/drugs/fda-gemtuzumab-ozogamicin.
- Petersdorf S, Kopecky K, Stuart RK, et al. Preliminary Results of Southwest Oncology Group Study S0106: An International Intergroup Phase 3 Randomized Trial Comparing the Addition of Gemtuzumab Ozogamicin to Standard Induction Therapy Versus Standard Induction Therapy Followed by a Second Randomization to Post-Consolidation Gemtuzumab Ozogamicin Versus No Additional Therapy for Previously Untreated Acute Myeloid Leukemia. Blood. 2009;114:abstract 790.
- Castaigne S, Pautas C, Terré C, et al. Final analysis of the ALFA 0701 study. Blood. 2014;123:abstract 376.
- ADC Revies (Journal of Antibody Drug Conjugates). Pfizer resubmits application for gemtuzumab ozogamicin to European and American regulators. (February 6, 2017). Available at: https://adcreview.com/news/pfizer-resubmits-application-gemtuzumab-ozogamicin-european-american-regulators/.
- Update 01/17/18: The abstract originally cited here has now been published: Stein AS, Walter RB, Erba HP, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33 positive acute myeloid leukemia (AML). Blood. 2017 Dec 1. pii: blood-2017-06-789800. doi: 10.1182/blood-2017-06-789800. [Epub ahead of print].
- Fathi A, Erba H, Lancet J, et al. SGN-CD33A in combination with hypomethylating agents: a novel, well-tolerated regimen with high remission rate in older patients with AML. Presented at: 21st Congress of the European Hematology Association; Copenhagen, Denmark; June 9-12, 2016. Abstract S503.
- ClinicalTrials.gov. Available at: www.clinicaltrials.gov.
- Black A. FDA lifts clinical hold on Seattle Genentics' AML trials. (March 7, 2017). Available at: http://www.raredr.com/news/hold-lifted-seattle-trials.
- Levy MY, Stein AS, Vasu S, et al. A phase 1b study of the combination of vadastuximab talirine and 7+3 induction therapy for patients with newly diagnosed acute myeloid leukemia (AML). Presented at: 22nd Congress of the European Hematology Association; Madrid, Spain; June 22-25, 2017. Abstract S793.
- Uy GL, Godwin J, Rettig MP, et al. Preliminary Results of a Phase 1 Study of Flotetuzumab, a CD123 x CD3 Bispecific Dart® Protein, in Patients with Relapsed/Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome. Presented at: 59th Annual Meeting and Exposition of the American Society of Hematology; Atlanta, GA; December 9-12, 2017. Abstract 637.
- Broderick JM. FDA approves blinatumomab for pediatric acute lymphoblastic leukemia. (September 1, 2016). Available at: http://www.onclive.com/web-exclusives/fda-approves-blinatumomab-for-pediatric-acute-lymphoblastic-leukemia.