Summary:
Recent advancements in clinical tools for blood cancers are highlighted in this article, adapted from the 14th edition of the annual AACR Cancer Progress Report (https://cancerprogressreport.aacr.org/progress/) to the US Congress and the public.
In the United States, an estimated 2,001,140 new cases of cancer will be diagnosed in 2024, and 611,720 cancer deaths are likely to occur. Of these cases, an estimated 116,400 new cases and 32,680 deaths would be a result of non–Hodgkin lymphomas and myelomas alone. Despite the ongoing burden of hematologic malignancies, incredible advancements in therapeutics continue to occur. From July 2023 through June 2024, 10 of the 30 newly FDA-approved anticancer agents were approved to treat forms of blood cancers (Fig. 1).
Figure 1.
Newly FDA-approved therapies and early clinical trial endpoints for blood cancers. Between July 1, 2023 and June 30, 2024, the FDA made several decisions that are providing new treatment options to patients with blood cancers. Newly approved therapeutics, expansions of previously approved therapeutics for a new blood cancer type, and newly defined clinical trial endpoints for blood cancers are listed. Note: Adapted from Sidebar 35 in the 2024 AACR Cancer Research Progress Report.
Advancements to Precision Therapy in the Treatment of Blood Cancers
In the 12 months covered by this report, the FDA made numerous decisions that are transforming the lives of patients with a wide array of hematologic cancers (Fig. 1).
Acute myeloid leukemia (AML) is the most commonly diagnosed leukemia in the United States, with 20,800 new cases anticipated in 2024 (https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2024/2024-cancer-facts-and-figures-acs.pdf). AML has only a 32% overall 5-year relative survival rate, the lowest among leukemias (https://seer.cancer.gov/statistics-network/explorer/application.html). Research has substantially increased our understanding of the biology of AML, in particular the different types of genetic mutations that promote AML development. This knowledge is fueling the emergence of molecularly targeted therapeutics for defined groups of patients with the disease.
Aberrations in the FLT3 gene, found in 25% to 30% of patients with AML, promote the growth and survival of AML cells, resulting in particularly poor patient outcomes (1). In July 2023, the FDA approved a new molecularly targeted therapeutic, quizartinib (Vanflyta), for treating adults who have newly diagnosed AML that tests positive for a mutation alteration in the FLT3 gene known as FLT3 internal tandem duplication. The approval was based on results from the QuANTUM-First phase III clinical trial (NCT02668653) showing that patients who received quizartinib along with standard chemotherapy lived more than twice as long as those who received standard treatment alone (2). Despite the promising clinical responses, quizartinib can cause several cardiac side effects and is therefore available only through a restricted program. The FDA expanded the use of the LeukoStrat CDx FLT3 Mutation Assay as a companion diagnostic to identify patients with AML positive for FLT3 lesions (internal tandem duplication and tyrosine kinase domain mutations D835 and I836) who are eligible for treatment with the new molecularly targeted therapeutic. Quizartinib is the third FLT3-targeted drug approved for the treatment of patients with AML and, along with midostaurin (Rydapt) and gilteritinib (Xospata) previously approved by the FDA, expands treatment options for the subset of patients with AML with the FLT3 alteration.
Myelodysplastic syndromes (MDS) are a diverse group of cancers marked by disrupted myeloid progenitor differentiation. Approximately 4 to 5 per 100,000 Americans are diagnosed with MDS annually, a higher incidence rate than that of several other hematologic malignancies, such as Hodgkin lymphomas (<3 per 100,000) and acute lymphocytic leukemias (ALL; <2 per 100,000; https://seer.cancer.gov/statistics-network/explorer/application.html?site=409&data_type=1&graph_type=2&compareBy=sex&chk_sex_1=1&rate_type=2&race=1&age_range=1&hdn_stage=101&advopt_precision=1&advopt_show_ci=on&hdn_view=0&advopt_show_apc=on&advopt_display=2). A third of patients diagnosed with MDS may progress to AML. In MDS, the decreased differentiation and shortened life spans of bone marrow–derived stem cells result in fewer mature blood cells in circulation. Patients with MDS who have symptoms such as anemia may receive curative treatments, including chemotherapy followed by stem cell transplant, or supportive care using molecularly targeted therapeutics and immunomodulating agents as well as blood transfusion and erythropoiesis-stimulating agents to improve their quality of life. Unfortunately, patients with MDS frequently become dependent on red blood cell (RBC) transfusions, which can be associated with long-term adverse health consequences. There is an urgent need to develop better treatments that can provide patients with long-term independence from continuously receiving RBC transfusions.
In normal cells, telomeres prevent DNA damage by acting as protective caps to chromosomal DNA as well as a sensor to limit replication, shortening each replication cycle and inhibiting cell division or triggering apoptosis when too short. It is widely known that most cancer cells evade this regulatory mechanism by upregulating the telomere-restoring enzyme telomerase. In June 2024, the FDA approved imetelstat (Rytelo) for the treatment of adult patients with lower-risk MDS with transfusion-dependent anemia who require four or more RBC units over 8 weeks and for whom erythropoiesis-stimulating agents are not an option. This is the first approval of a molecularly targeted therapeutic that works by blocking telomerase activity. As a telomerase inhibitor, imetelstat works by preventing telomerase from performing its telomere-restoring function, thereby killing cancerous cells causing MDS in the bone marrow. However, research indicates that the anticancer effect of imetelstat may also be driven by a novel cell death–promoting mechanism independent of telomere shortening (3). FDA approval was based on the findings of the phase III clinical trial IMerge (NCT02598661), which showed significantly improved RBC transfusion independence among certain patients with MDS treated with imetelstat compared with the control group (4).
Myelofibrosis is a rare type of blood cancer with an incidence rate of 1.5 cases per 100,000 people in the United States (https://rarediseases.org/rare-diseases/primary-myelofibrosis/). In more than 50% of cases, myelofibrosis is driven by mutations in the JAK2 gene. In September 2023, the FDA approved a new JAK2-targeted therapeutic, momelotinib (Ojjaara), for treating certain patients who have myelofibrosis. Myelofibrosis is one of a group of six blood cancers called chronic myeloproliferative neoplasms: chronic myelogenous leukemia, polycythemia vera, primary myelofibrosis, essential thrombocythemia, chronic neutrophilic leukemia, and chronic eosinophilic leukemia. In some cases, polycythemia vera and essential thrombocythemia progress to become myelofibrosis. In this situation, the disease is referred to as secondary myelofibrosis.
Myelofibrosis usually develops slowly, with abnormal blood cells and fibers building up inside the bone marrow, leading to a low number of blood cells (anemia). In response, the spleen begins to produce blood cells, causing it to enlarge dramatically, a condition known as splenomegaly. Patients with myelofibrosis are categorized based on several risk factors. Patients with one to four risk factors—including being 65 years of age or older; having anemia; experiencing fever, night sweats, or weight loss; having high white blood cell counts; and having at least 1% of blood cells being cancerous—are classified as having intermediate-risk disease. Patients with four or more risk factors are classified as having high-risk disease. Momelotinib was approved for treating intermediate- or high-risk myelofibrosis, including secondary myelofibrosis in adults with anemia. The approval was based on results from the phase III clinical trial MOMENTUM (NCT04173494), which showed that treatment with momelotinib significantly reduced spleen volume and reduced myelofibrosis-related symptoms compared with the placebo (5).
Clinical efforts over the decades have significantly improved the 5-year survival rates of children and adolescents with hematologic malignancies, such as those with Hodgkin lymphoma, non–Hodgkin lymphoma, and leukemia (https://seer.cancer.gov/statistics-network/explorer/application.html). However, a need for targeted therapies to be approved for pediatric cancers, such as pediatric chronic myeloid leukemia (CML), is vital for improving clinical care. The molecularly targeted therapeutic bosutinib (Bosulif), which was approved for adults with CML, was approved in September 2023 for pediatric patients with CML who have certain biomarkers and who have CML that is newly diagnosed or resistant or intolerant to prior therapy.
Immunotherapies
Engineered to bind to immune cells and cancer cells simultaneously, T cell–engaging bispecific antibodies are one class of anticancer immunotherapeutics that are moving rapidly from the laboratory to clinical practice. By acting as a connector, T cell–engaging bispecific antibodies bring cancer cells into close proximity with T cells, which are then activated and eliminate the cancer cells. The first of these agents blinatumomab (Blincyto) was approved by the FDA in December 2014 for treating certain patients with a type of ALL called B-cell ALL (6). Unprecedented advances in genetic engineering, molecular biology, and immunology over the past decade have led to a rapid proliferation in this innovative new area of cancer medicine. Between July 1, 2023 and June 30, 2024, the FDA approved three new T cell–engaging bispecific antibodies for the treatment of multiple myeloma and follicular lymphoma.
Two of these T cell–engaging bispecific antibodies were approved for the treatment of patients with multiple myeloma. As one of the most common blood cancers in the United States, an estimated 35,780 new multiple myeloma cases are expected to be diagnosed in 2024 and 12,540 people will succumb to the disease, with the burden disproportionally higher in the Black population (https://seer.cancer.gov/statistics-network/explorer/application.html). In recent years, the development and FDA approval of new therapeutics—including proteasome inhibitors like bortezomib (Velcade) and carfilzomib (Kyprolis), immunomodulatory agents like lenalidomide (Revlimid) and pomalidomide (Pomalyst), and immunotherapeutics like the CD38-targeted daratumumab (Darzalex)—have improved outcomes for patients. Despite these advances, unfortunately, many patients whose disease initially responds to the new therapeutics eventually experience relapse owing to treatment resistance.
In August 2023, the FDA approved two T cell–engaging bispecific antibodies, talquetamab-tgvs (Talvey) and elranatamab-bcmm (Elrexfio), for adult patients with multiple myeloma that have relapsed after, or never responded to, at least four prior lines of therapy. Both antibodies attach to a molecule called CD3 on T cells with one arm. With the second arm, talquetamab-tgvs attaches to a protein, G protein–coupled receptor, family C, group 5, member D (GPRC5D), and elranatamab-bcmm attaches to a protein called B-cell maturation antigen (BCMA). Both GPRC5D and BCMA are present at high levels on the surface of most multiple myeloma cells. By attaching to these molecules on T cells and myeloma cells, the T cell–engaging bispecific antibodies bring the two cell types together, directing the T cells to home in on the myeloma cells. As a result, T cells are activated, and they destroy the adjacent myeloma cells.
Talquetamab-tgvs is the first FDA-approved therapeutic that targets GPRC5D and has been transformative for patients with multiple myeloma. The approval was based on a clinical trial in which patients received either 0.4 or 0.8 mg/kg of the therapeutic subcutaneously, following step-up doses, until disease progression or unacceptable toxicity. Step-up dosing is an approach used in the treatment with T cell–engaging bispecific antibodies, whereby the dose administered to a patient is increased incrementally before reaching the target dose level. This helps the body’s immune system to be primed gradually, thereby reducing the risk of severe immune-related adverse events. Among both groups, receiving either 0.4 or 0.8 mg/kg of the therapeutic, more than 70% of patients responded to the treatment (https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma).
The approval of elranatamab-bcmm was based on the MagnetisMM-3 clinical trial (NCT04649359) in which nearly 58% of patients responded to the therapeutic. This is the second FDA approval of a BCMA-targeted T cell–engaging bispecific antibody for patients with multiple myeloma who have received at least four prior lines of therapy. The first teclistamab-cqyv (Tecvayli) was approved in October 2022 (https://cancerprogressreport.aacr.org/wp-content/uploads/sites/2/2023/10/AACR_CPR_2023_102423.pdf). Historically, multiple myeloma that has progressed following multiple classes of treatment has been extremely challenging to treat. Therefore, recent approvals of talquetamab-tgvs (Talvey) and elranatamab-bcmm (Elrexfio) have brought hope to patients by providing them with new and effective treatment options.
It is important to note that immunotherapeutics, including CAR-T cells, ICIs, and T cell–engaging bispecific antibodies, may cause serious adverse side effects, some of which could be life-threatening if not managed immediately and appropriately by trained medical professionals. In fact, FDA approvals of all three T cell–engaging bispecific antibodies discussed above come with a warning of life-threatening adverse events, such as cytokine release syndrome and neurologic toxicity. Because of these risks, talquetamab-tgvs and elranatamab-bcmm are available only through a restricted program, called the Risk Evaluation and Mitigation Strategy (REMS).
Antibody–drug conjugates are an emerging class of molecularly targeted therapeutics that use an antibody to deliver an attached cytotoxic chemotherapeutic directly to the cancer cells that have the antibody’s target on their surfaces. Once the antibody attaches to its target on the surface of a cancer cell, the antibody–drug conjugate is internalized by the cells. This leads to the chemotherapeutic being released from the antibody and killing the cancer cell. The precision of antibody targeting reduces the side effects of the chemotherapeutic compared with traditional systemic delivery. Inotuzumab ozogamicin (Besponsa) is an antibody–drug conjugate comprising a CD22-targeted antibody linked to the chemotherapeutic calicheamicin. It was approved in August 2017 for treating adults with B-cell ALL. Subsequent studies have shown that inotuzumab ozogamicin is also effective in children and adolescents. Based on findings from a clinical trial in which 42% of patients who received inotuzumab ozogamicin achieved a complete remission, meaning they had no evidence of cancer, in March 2024, the FDA approved the therapeutic for pediatric patients ages 1 year and older with CD22-positive B-cell ALL that has relapsed or stopped responding to treatments.
Patients who receive inotuzumab ozogamicin may need a stem cell transplant to ensure durable cancer remission. Although treatment with inotuzumab ozogamicin increases the risk of developing serious liver toxicities in certain patients, it increases treatment options for a group of patients with ALL who may be ineligible for CAR T-cell therapy and have no remaining options.
Rapidly Delivering Safe and Effective Therapies to Patients: A New Surrogate for Clinical Trial Efficacy
Thanks to incredible advances in cancer treatment, many patients with common cancer types are living longer and fuller lives following diagnosis. Continued progress against cancer requires researchers to innovate how they measure whether a novel therapy is safe and effective in a timely manner. To this end, there has been an increasing shift from using the gold standard endpoint of overall survival to earlier endpoints like progression-free survival, overall response rate, and duration of response to achieve an accelerated approval designation from the FDA. As one example, at a recent Oncologic Drugs Advisory Committee of the FDA, the committee unanimously voted in favor of using minimal residual disease negativity as an early endpoint to support accelerated approval for multiple myeloma (https://cancerletter.com/regulatorynews/20240426_1/). With improvements in clinical care over the decades, most patients with myeloma are expected to live many years after diagnosis. However, this poses a challenge to the development of more clinical drugs, as clinical trials would take far longer to complete. With this FDA approval, minimal residual disease can act as a surrogate to measure clinical trial efficacy, revealing in a much shorter timespan whether a therapeutic regimen for multiple myeloma is effective or not, thereby progressing clinical research at a more efficient rate.
The progress against blood cancers highlighted in the AACR Cancer Progress Report 2024 is a testament to the power of interdisciplinary collaborations among all stakeholders deeply committed to improving public health and maintaining our nation’s status as a beacon of innovative cancer science and medicine. To maintain and accelerate this momentum, researchers are continually leveraging scientific discoveries and technological innovations to deliver lifesaving therapeutics for patients with cancer. The future of cancer science and medicine is promising.
AACR Cancer Progress Report 2024 Steering Committee
Patricia M. LoRusso, DO, PhD (hc), FAACR
Chair
AACR President 2024–2025
Professor of Medicine
Chief of the Early Phase Clinical Trials Program
Yale University
Associate Center Director of Experimental Therapeutics
Yale Cancer Center
New Haven, Connecticut
Cathy J. Bradley, PhD
Paul A. Bunn, Jr. Endowed Chair in Cancer Research
Professor and Dean, Colorado School of Public Health
Deputy Director, University of Colorado Cancer Center
Denver, Colorado
John L. Cleveland, PhD
Center Director and Executive Vice President
Moffitt Cancer Center and Research Institute
Professor and George V. Cortner and Theodore J. Couch
Endowed Chair
USF Health Morsani College of Medicine
Tampa, Florida
Maximilian Diehn, MD, PhD
Jack, Lulu, and Sam Willson Professor
Vice Chair of Research
Division Chief of Radiation and Cancer Biology
Department of Radiation Oncology
Stanford University School of Medicine
Stanford, California
Jane C. Figueiredo, PhD
Professor, Departments of Medicine and Computational
Biomedicine
Director, Community and Population Health Research
Samuel Oschin Comprehensive Cancer Institute
Member, Cedars-Sinai Cancer
Cedars-Sinai Medical Center
Los Angeles, California
Christopher Flowers, MD, MS
Division Head, Division of Cancer Medicine
Chair, Professor, Department of Lymphoma/Myeloma
John Brooks Williams and Elizabeth Williams Distinguished
University Chair in Cancer Medicine
MD Anderson Cancer Center
Houston, Texas
Margaret Foti, PhD, MD (hc)
Chief Executive Officer
American Association for Cancer Research
Philadelphia, Pennsylvania
Hedvig Hricak, MD, PhD, Dr (hc) (m)
Carroll and Milton Petrie Endowed Chair of Radiology
Professor Gerstner Sloan Kettering Graduate School of
Biomedical Sciences
Memorial Sloan Kettering Cancer Center
New York, New York
Adana A. M. Llanos, PhD, MPH
Associate Professor
Department of Epidemiology
Mailman School of Public Health
Co-Leader, Cancer Population Science, Herbert Irving
Comprehensive Cancer Center
Columbia University Irving Medical Center
New York, New York
Michael Pignone, MD, MPH
Rebecca and John Kirkland Distinguished Professor of Medicine
Vice Chair for Quality and Innovation, Duke Department of
Medicine
ACS Clinical Research Professor
Duke Cancer Institute
Duke University
Durham, North Carolina
Kimberly Stegmaier, MD
Vice Chair of Pediatric Oncology Research
Co-Director, Pediatric Hematologic Malignancy Program (Basic and Translational Research)
Ted Williams Chair
Professor of Pediatrics
Dana-Farber Cancer Institute and Boston Children’s Hospital
Boston, Massachusetts
Kiran Turaga, MD, MPH
Professor of Surgery (Oncology)
Division Chief, Surgical Oncology, Surgery
Assistant Medical Director, Clinical Trials Office
Yale School of Medicine
New Haven, Connecticut
Marcel R.M. van den Brink, MD, PhD
President, City of Hope Los Angeles and City of Hope National
Medical Center
Deana and Steve Campbell Chief Physician Executive
Distinguished Chair
Chief Physician Executive
City of Hope National Medical Center
Los Angeles, California
Authors’ Disclosures
No disclosures were reported.
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