What kills CLL?

Immunotherapy
For Leukemia Cancer

What Makes Immunotherapy for Leukemia a Promising Treatment?

Alex Huang, MD
Case Western Reserve University School of Medicine and Rainbow Babies & Children’s Hospital

Immunotherapy for leukemia provides several treatment options, and ongoing research demonstrates even greater potential for new treatments, especially in adoptive cell therapy.

Leukemia is cancer of the bone marrow and lymphatic system, and affects both children and adults. In leukemia, abnormal cells, produced by the bone marrow, begin to overtake and replace the normal blood and marrow cells.

There are four main types of leukemia, each named for the rate at which the disease develops and worsens as well as the affected blood cell type.

• acute myeloid leukemia (AML): fast-growing cancer that starts in myeloid cells—the precursor to red blood cells, platelets (cells that clot the blood), or white blood cells known as granulocytes; also known as acute myelogenous or myeloblastic leukemia
• chronic myeloid leukemia (CML): slower-growing cancer that starts in myeloid cells—the precursor to red blood cells, platelets (cells that clot the blood), or white blood cells known as granulocytes; also known as chronic myelogenous or myeloblastic leukemia
• acute lymphocytic leukemia (ALL): fast-growing cancer that starts in lymphoid cells, which make different types of white blood cells; also known as acute lymphoblastic leukemia
• chronic lymphocytic leukemia (CLL): slower-growing cancer that starts in lymphoid cells, which make different types of white blood cells; also known as chronic lymphoblastic leukemia

Leukemia occurs most often in adults older than 55 years, but it is the most common cancer in children younger than 15 years. Among adults, the most common types are CLL (35%) and AML (32%). Among children and teens, ALL is the most common, accounting for 75% of pediatric leukemia cases.

Globally, an estimated 440,000 new cases of leukemia are diagnosed each year along with 310,000 deaths. There will be an estimated 60,000 new cases of leukemia in the United States in 2023, and more than 24,000 related deaths. Survival rates vary substantially by leukemia subtype, ranging from a current five-year relative survival rate of 27% for adults diagnosed with AML to 86% for those with CLL, and 66% for children, adolescents, and young adults diagnosed with AML to 92% for those with ALL. In 2018, there are an estimated 381,774 people living with or in remission from leukemia in the United States.

Leukemia Cancer Treatment Options

Treatment for leukemia depends on an individual’s age, cancer type, and the severity of the disease. In most cases, chemotherapy is the first line of treatment for this disease, though some patients require a stem cell transplant to eliminate the leukemia entirely.

Immunotherapy is class of treatments that take advantage of a person’s own immune system to help kill cancer cells. In addition to stem cell transplants, there are currently ten FDA-approved immunotherapy options for leukemia.

Targeted Antibodies

• Alemtuzumab (Campath®): a monoclonal antibody that targets the CD52 pathway; approved for subsets of patients with chronic lymphocytic leukemia (CLL)
• Blinatumomab (Blincyto®): a bispecific antibody that targets CD19 on tumor cells as well as CD3 on T cells; approved for subsets of patients with acute lymphoblastic leukemia (ALL)
• Gemtuzumab ozogamicin (MyloTarg®): an antibody-drug conjugate that targets the CD33 pathway and delivers toxic drugs to cancer cells; approved for subsets of adult and pediatric patients with CD33-positive acute lymphoblastic leukemia (ALL)
• Inotuzumab ozogamicin (Besponsa®): an antibody-drug conjugate that targets the CD22 pathway and delivers toxic drugs to cancer cells; approved for subsets of patients with advanced acute lymphoblastic leukemia (ALL)
• Obinutuzumab (Gazyva®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with CD20-positive chronic lymphocytic leukemia (CLL), including as a first-line therapy
• Ofatumumab (Arzerra®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with CD20-positive chronic lymphocytic leukemia (CLL), including as a first-line therapy
• Rituximab (Rituxan®): a monoclonal antibody that targets the CD20 pathway; approved for subsets of patients with chronic lymphocytic leukemia (CLL), including as a first-line therapy

Adoptive Cell Therapy

• Brexucabtagene autoleucel (Tecartus™): a CD19-targeting CAR T cell immunotherapy; approved for subsets of patients with acute lymphoblastic leukemia (ALL)
• Tisagenlecleucel (Kymriah®): a CD19-targeting CAR T cell immunotherapy; approved for subsets of children and young adult patients with acute lymphoblastic leukemia (ALL)

Immunomodulators

• Interferon alfa-2a (Roferin®-A): a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with hairy cell leukemia and Philadelphia chromosome positive chronic myeloid leukemia (CML)
• Interferon alfa-2b (Intron A®): a cytokine that targets the IFNAR1/2 pathway; approved for subsets of patients with hairy cell leukemia and aggressive follicular non-Hodgkin lymphoma

New immunotherapies are currently being tested in leukemia clinical trials.

CRI’s Impact in Leukemia Cancer

Throughout our history, the Cancer Research Institute has funded numerous studies and clinical trials involving the treatment of leukemia with immunotherapy. Some of these studies have led to discoveries that have the potential to cure several subtypes of leukemia.

Current and past CRI-funded studies on immunotherapy for leukemia include:

• The first toxin-linked monoclonal antibody targeted toward CD33 on leukemic blasts for acute myeloid leukemia (gemtuzumab ozogamicin, or Mylotarg), was developed by Irving Bernstein, MD, a CRI postdoctoral fellow from 1972-1974, and was approved by the FDA in 2000.
• Paola Betancur, PhD, a CRI postdoctoral fellow from 2014-2016 in the laboratory of Irving L. Weissman, MD, at Stanford University School of Medicine, is working to validate and test therapeutic strategies targeting the CD47 protein a “don’t eat me” signal that stops macrophages, a type of immune cell that engulfs and destroys its targets) to treat cancer.
• Kristen E. Pauken, PhD, a CRI postdoctoral fellow at the University of Pennsylvania from 2013-2016, along with Michael A. Farrar, PhD, a former CRI postdoctoral fellow and investigator award recipient at the University of Minnesota, found BCR-ABL leukemia actively suppresses immune responses by converting leukemia-specific T cells into inhibitory, regulatory T cells, aiding leukemia’s progression.
• CRI investigator Hiroyoshi Nishikawa, MD, PhD, at Osaka University found that several cancer-testis antigens, including NY-ESO-1, were highly expressed in adult T cell leukemia/lymphoma (ATLL) and that they could be recognized by killer T cells, providing proof-of-principle that cancer-testis antigens are a promising target for ATLL immunotherapy.
• CRI investigator Ryan Teague, PhD, at Saint Louis University School of Medicine has shown that blockade of CTLA-4, PD-1, and LAG-3 could restore anti-tumor activity in adoptively transferred T cells and result in durable and more effective anti-tumor immunity in advanced leukemia.

Explore CRI’s current funding for leukemia research in our funding directory.

Leukemia Treatments

After reviewing your lab results and accurately diagnosing your stage of leukemia, Johns Hopkins Kimmel Cancer Center will design a treatment plan tailored for each patient, based on their age, symptoms and type of leukemia. People with acute leukemias need to be treated immediately, to destroy the disease and eliminate symptoms. Those with chronic leukemia may not need to start treatment right away; in some cases, doctors prefer to monitor patients’ health closely and start treatment after the onset of symptoms. Chemotherapy (drug treatment to destroy leukemia cells) is the mainstay of leukemia treatment, and may incorporate multiple types of drugs. Radiation and surgery are contemplated only for cases in which leukemia cells have collected in definitive areas.

Chemotherapy

Depending on the type of leukemia, you may receive a single drug or a combination of two or more drugs. The medications may be prescribed as pills, or as fluids administered through a needle or tube inserted into a vein; through a tube inserted in the chest; or through injection into the cerebrospinal fluid.

Chemotherapy is usually given in cycles, with patients receiving treatment either in a clinic or at home. Some patients may need to stay in the hospital for treatment. Side effects can depend on which drugs were given and how much, but include fatigue, hair loss, poor appetite, nausea or vomiting, diarrhea, or infertility.

Patients with CML and some with ALL may receive drugs called targeted therapy, that use drugs that block the growth of leukemia cells. Side effects include swelling, bloating, weight gain, nausea or vomiting, diarrhea, muscle cramps or a rash.

Some leukemia patients receive drugs called biological therapy – treatments that improve the body’s defenses against the disease. They may be substances that bind to or kill leukemia cells, that help the immune system destroy leukemia cells or that slow the growth of leukemia cells. Some therapies cause a rash or swelling where the drug was injected. Other side effects include headache, muscle aches, fever or weakness.

Radiation Therapy

Radiation therapy uses high-energy rays to kill leukemia cells by damaging the genetic material they contain. This treatment can be used adjunctively to chemotherapy to control disease or eradicate local areas of disease. Some patients receive targeted radiation from a large machine aimed at the spleen, brain or other parts of the body where leukemia cells have collected. This type of therapy takes place five days a week for several weeks. Others may receive radiation directed to the whole body. These sessions are given once or twice a day for a few days, usually before a stem cell transplant.

The side effects of radiation therapy, including fatigue, can depend on the dose of radiation and the part of the body that is treated. For example, radiation to the abdomen can cause nausea, vomiting and diarrhea. In addition, skin in the area being treated may become red, dry, and tender. Hair loss in the treated area also may occur.

Surgery

Surgery usually is not an option for treating certain manifestations of leukemia when leukemia cells spread to organs via the blood stream and lymph vessels. In some cases of CLL, for example, doctors may recommend surgery to remove the spleen, an organ located in the abdomen behind the ribs that removes and destroys old red blood cells and helps fight infection. The procedure, called a splenectomy, is helpful if the spleen is destroying red blood cells and platelets.

Vaccine Treatment

Doctors at some medical centers including the Johns Hopkins Kimmel Cancer Center are conducting clinical trials to test novel vaccines for leukemia.

Research

New Leukemia Treatment Options

Read about the latest treatment options for leukemias.

B.Douglas Smith, M.D., leukemia expert

Our leukemia experts did much of the groundbreaking work in the treatment of acute myeloid leukemia (AML), developing an intensive and effective drug treatment for this otherwise fatal disease. In addition, our experts pioneered timed sequential therapy (TST), a treatment strategy that specifically use chemotherapy drugs at an optimal time to best treat leukemias and prevent them from growing back.

Among the pivotal research areas shaping leukemia treatment, Johns Hopkins experts have led the following research advances:

• Dose-intensive, curative chemotherapy for minimal residual leukemia
• Pioneered clinical trials of the drug tipifarnib, known by its trade name Zarnestra, which blocks an enzyme called farnesyltransferase, which modifies certain cellular proteins so that they can attach to cellular membranes or other structures. The drug was first tested in adults with relapsed or therapy-resistant acute leukemia, and was the first clinical trial of a signal transduction inhibitor in AML.
• Studies of gene silencing through a process called methylation, which tags DNA with tiny chemicals that regulate the on/off switch of genes, have led to new clinical trials of drugs that inhibit this process in combination with drugs that block enzymes controlling gene expression.
• Johns Hopkins researchers were the first to clone the FLT3 gene, now know to be mutated in certain patients with an aggressive form of acute myelogenous leukemia. The scientists have tested drugs that block the gene’s protein products in combination with chemotherapy agents.
• Supportive care improvements including ridding the GI tract of bacteria harmful to cancer patients with antibiotics called quinolones.

Treatment Approaches

The goal of the leukemia research program at the Johns Hopkins Kimmel Cancer Center is to develop new therapies based on the biologic and molecular aspects of the disease to improve cure rates and quality of life. Kimmel Cancer Center leukemia experts are leaders in developing new standards of care and directing clinical trials at the forefront of discovery in leukemia research.

Oncologist-researchers at Johns Hopkins continually seek new agents or new combinations of therapies to maximize success for each patient. Chemotherapy cycles offered to most patients with leukemias and MDS includes traditional cytotoxic chemicals plus other targeted therapies, such as drugs that block abnormal signals sent out by cancer genes, explains oncologist B. Douglas Smith, M.D., associate professor of oncology. Oncologists also are using growth factors to try to normalize how cancer cells grow, making them less resistant to chemotherapy, and they are studying and looking at agents to control cancer stem cells. Epigenetic agents, such as Vidaza or Decitabine (DNA methlyating agents) and histone deacetylase inhibitors, under development attempt to “unsilence” genes that have been silenced by acute leukemias and myelodysplastic syndrome (MDS). Scientists also are testing the KGEL vaccine alone and in combination with other agents in patients with CML and AML.