Acute myelogenous leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN) are aggressive and often fatal hematological malignancies. The cure rate for AML is around 50%, and patients who do not respond to first-line treatment or experience relapse have poor survival outcomes. Outcomes are even worse for patients with BPDCN, a rare malignancy with few approved treatments. But recently discovered molecular targets have led to new treatment options for AML, BPDCN, and other leukemias; and clinical trials of these treatments are under way.
"There have been several key, exciting developments in the past couple of years," said Naveen Pemmaraju, M.D., an associate professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. "A couple of novel therapeutic targets now enable us to offer targeted therapy for BPDCN patients, who have few treatment options, and for some AML patients."
The therapeutic targets CD123 and BCL2 are proteins expressed at much higher levels on some leukemic cells than on healthy cells. Treatments that target CD123 are the subject of ongoing clinical trials for AML and BPDCN patients, and an agent that targets BCL2 is being used in clinical trials for AML patients and is being explored as a therapeutic option for BPDCN by Dr. Pemmaraju and colleagues.
CD123, a receptor for the immune cytokine interleukin-3, is overexpressed on the surface of some malignant cells, including the majority of AML and BPDCN cells. Clinical trials at MD Anderson are exploring the recombinant fusion protein SL-401, chimeric antigen receptor (CAR) T cells, and the drug-antibody conjugate IMGN632 as targeted therapies against CD123 for patients with AML and BPDCN.
Current trials at MD Anderson are exploring SL-401 as a first-line therapy for BPDCN patients, as salvage therapy for BPDCN patients whose disease has persisted or recurred after standard chemotherapy, and as consolidation therapy for AML patients whose disease responded to standard chemotherapy.
SL-401 was the first anti-CD123 agent to be used in a clinical trial for patients with BPDCN. In a pilot trial of SL-401, more than half the patients with BPDCN experienced a complete response.
These promising results led to a phase I/II trial of SL-401 (No. 2013-0979), which is currently enrolling patients with previously untreated or relapsed or refractory BPDCN at MD Anderson and other institutions.
In the current trial, patients receive an intravenous infusion of SL-401 on days 1-5 of each 21-day cycle. Patients continue treatment until disease progression or intolerable adverse effects occur.
The trial's preliminary findings were presented at the American Society of Hematology's annual meeting in December 2017 by Dr. Pemmaraju and colleagues, including Marina Konopleva, M.D., Ph.D., a professor in the Department of Leukemia and MD Anderson's principal investigator of the trial. Of 32 evaluable patients with BPDCN, responses were seen in 27 (84%): 19 patients experienced a complete response, and eight experienced a partial response.
"SL-401 is a particularly active drug that has given us some hope and direction in this rare disease because almost all patients with BPDCN have leukemic cells that express CD123," Dr. Pemmaraju said.
Dr. Konopleva is also leading a clinical trial (No. 2014-0860) of SL-401 as consolidation therapy for patients with AML who experienced a complete response (defined as less than 5% blast cells in the bone marrow) to standard chemotherapy but have minimal residual disease or other risk factors for relapse and are not candidates for stem cell transplant. The goals of this phase I/II trial are to determine the maximum tolerated dose of SL-401, evaluate changes in minimal residual disease status, and assess relapse-free and overall survival. Dr. Konopleva and colleagues will also look for changes in the expression of CD123 and other stem cell and disease markers in bone marrow samples taken before and after treatment with SL-401.
CAR T cells
Another investigational treatment for patients with AML or BPDCN is UCART123, an off-the-shelf allogeneic CAR T cell product that is genetically engineered to target CD123. A multi-institutional phase I trial (No. 2016-0840) of UCART123 is now enrolling patients with newly diagnosed or relapsed or refractory BPDCN, and an additional treatment arm will soon begin enrolling patients with relapsed or refractory AML.
In the phase I trial, patients receive a cytotoxic lymphodepleting regimen, which destroys existing T cells and other lymphocytes that might interfere with the CAR T cells, followed by a single infusion of UCART123. The trial's primary outcome measure is the safety of the novel treatment approach, with special emphasis on adverse events such as cytokine release syndrome, tumor lysis syndrome, and graft-versus-host disease, which are known to be associated with CAR T cell therapy for hematological malignancies.
"This is the first trial of CAR T cell therapy that was specifically initiated for patients with BPDCN," Dr. Pemmaraju said.
IMGN632 combines an anti-CD123 antibody with a DNA alkylating agent. A first-in-human trial (No. 2017-0855) of this drug-antibody conjugate recently began enrolling patients with relapsed or refractory AML, BPDCN, and other CD123-positive hematological malignancies at MD Anderson. In the trial, researchers led by Hagop Kantarjian, M.D., a professor in and chair of the Department of Leukemia, seek to find the maximum tolerated dose of IMGN632 and the recommended dose for future trials. The researchers will also observe IMGN632's ability to provoke an immune response.
As is the case with CD123, the anti-apoptotic protein BCL2 is expressed at higher levels by AML, BPDCN, and other leukemia cells than by normal cells. The BCL2 inhibitor venetoclax is approved by the U.S. Food and Drug Administration to treat relapsed chronic lymphocytic leukemia and has shown activity against AML in clinical trials at MD Anderson and elsewhere.
Current trials are exploring combinations of venetoclax with other treatments for AML in various subsets of patients. "We feel that venetoclax is a general sensitizer to many types of therapies, and its favorable safety profile makes it easy to combine with many types of treatments," Dr. Konopleva said.
In one trial (No. 2016-0979), patients 18-65 years old with newly diagnosed or relapsed or refractory AML receive venetoclax with the standard intensive chemotherapy regimen fludarabine, cytarabine, filgrastim, and idarubicin (FLAG-IDA). This phase I trial, led by Courtney DiNardo, M.D., an assistant professor in the Department of Leukemia, will evaluate the safety and tolerability of the drug combination and make a preliminary assessment of the regimen's efficacy.
Other trials are evaluating venetoclax combinations in patients 60 years or older with AML who cannot tolerate standard intensive chemotherapy regimens. One of these trials (No. 2015-0898) is evaluating the safety and efficacy of venetoclax in combination with either cobimetinib, which inhibits the MEK kinase pathway, or idasanutlin, a small-molecule inhibitor of the oncogenic protein MDM2. Dr. Konopleva and colleagues, including Naval Daver, M.D., an associate professor in the Department of Leukemia, presented the preliminary results of the nonrandomized trial's dose-escalation phase at the American Society of Hematology's annual meeting in December 2017. The overall response rates (complete responses plus complete responses with incomplete platelet recovery or incomplete hematological recovery) were 20% and 33% for the cobimetinib and idasanutlin arms, respectively. For both treatment arms, however, the response rates were higher for patients treated with the doses that will be used in the trial's expansion phase than for patients treated with lower doses.
Two phase III trials of venetoclax focus on treatment-naïve AML patients 60 years or older who are ineligible for standard chemotherapy because of age (75 years or older) or comorbidities. In one trial (No. 2016-0985), patients are randomly assigned to receive the hypomethylating agent azacitidine plus venetoclax or placebo. In the other trial (No. 2017-0398), patients are randomly assigned to receive low-dose chemotherapy with cytarabine plus venetoclax or placebo.
"Combinations of venetoclax with low-dose cytarabine or a hypomethylating agent show tolerable safety profiles and very exciting activity for elderly AML patients who are unable to undergo intensive chemotherapy," Dr. Konopleva said.
To assess whether venetoclax might also be effective against BPDCN, a multi-institutional group of researchers including Drs. Pemmaraju and Konopleva tested venetoclax in BPDCN cell lines and mouse models. After these preclinical studies confirmed the drug's activity, Dr. Pemmaraju and his colleagues offered venetoclax as an off-label treatment to two patients with relapsed or refractory BPDCN who had exhausted all other treatment options. Both patients responded to venetoclax, although one died of a condition that predated the venetoclax treatment.
"Based on the results we saw in the two BPDCN patients treated with venetoclax, we're pursuing a clinical trial of the drug for patients with BPDCN," Dr. Pemmaraju said. He said the trial may begin enrolling patients this spring.
More clinical trials of treatment combinations that target CD123 or BCL2 are on the horizon for patients with AML or BPDCN. For example, SL-401 combined with the hypomethylating agent azacytidine showed synergy against AML in preclinical studies, and a clinical trial of this combination for patients with relapsed AML is expected to open soon.
In addition, the outcomes of current trials of venetoclax with various treatments in other hematological malignancies might eventually lead to trials of similar combinations in patients with AML or BPDCN. One ongoing trial (No. 2017-0025) for patients with B cell lymphomas combines venetoclax with etoposide, cyclophosphamide, and doxorubicin at doses that are adjusted for each cycle plus prednisone, vincristine, and rituximab. Another trial (No. 2015-0860) combines venetoclax with the BTK inhibitor ibrutinib for patients with chronic lymphocytic leukemia.
"The combination of CD123 or BCL2 inhibition with various other treatment strategies will likely play an important role in the treatment of AML and BPDCN," Dr. Konopleva said. "Our task will be to determine which subpopulations of patients are most likely to benefit from which treatment combinations."
Montero J, Stephansky J, Cai T, et al. Blastic plasmacytoid dendritic cell neoplasm is dependent on BCL2 and sensitive to venetoclax. Cancer Discov. 2017;7:156-164.
Pemmaraju N. Novel pathways and potential therapeutic strategies for blastic plasmacytoid dendritic cell neoplasm (BPDCN): CD123 and beyond. Curr Hematol Malig Rep. 2017;12:510-512.
OncoLog, February 2018, Volume 63, Issue 2