The Leukemia Program at the Johns Hopkins Kimmel Cancer Center
The internationally-recognized Leukemia Program at the Kimmel Cancer Center is directed by Judith Karp, M.D., professor of oncology. Dr. Karp leads a team of clinicians and scientists making discoveries in the laboratory that are translating to new treatments for patients.
Below are the latest advances we offer patients. If you would like to schedule a consultation with one of our leukemia experts to discuss treatment options, please call 410-955-8964 and choose option #2 when prompted. We also have a updated list of open clinical trials for leukemias.
Preventing Cell Division
Flavopiridol and Chemotherapy Based on Cell Growth Kinetics: Flavopiridol is a leukemia drug that leads to cell cycle arrest, causing cancer cells to die. Leukemia program director Judith Karp is a leading expert on the drug, having studied it for more than a decade. She has used a “timed sequential therapy” approach , giving Flavopiridol to kill leukemia cells and then recruit the remaining leukemia cells into a growth phase, where they become more sensitive to traditional chemotherapy drugs Ara-C and Mitoxantrone. This “FLAM” regimen has yielded promising results in patients with poor-risk acute leukemias. Dr. Karp and her team will be leading a multi-institutional randomized Pase II clinical trial to compare the effectiveness of FLAM with standard chemotherapy.
Blocking Leukemia Cells: Drs. Karp, Douglas Smith and Keith Pratz are leading clinical trials on several new cancer targets that promise to improve the effectiveness of leukemia therapies. Chk-1 inhibitors, block a checkpoint that repairs DNA damage caused by chemotherapy. Drs. Karp, Smith, and Pratz are combining the inhibitor with the classic antileukemia drug Ara-C, or Cytarabine, which disrupts the cell cycle and prevents cell division. Another agent, called a Parp inhibitor, blocks an enzyme, in a similar pathway, that helps cancer cells repair damage to DNA. Our team is combining these inhibitors with specific antileukemia drugs in order to prevent the leukemia cells from repairing chemotherapy-induced damage, to thwart cancer cell division, shut off checkpoints that protect cancer cells, and then prevent them from repairing damage, which they hope will increase the effectiveness of anti-leukemia drugs.
Taking on the FLT3 Gene in AML: Mutations to the FLT3 gene have been linked to a poor prognosis in acute myeloid leukemia (AML). Early trials of FLT3 inhibitors—agents that block FLT3 gene signaling—have provided proof-of-principle. As a result, researchers Mark Levis and Keith Pratz are working on the next generation of FLT3 inhibitors. The new drugs are more potent and selective for FLT3. Levis and team are working with several cooperative groups around the world, developing a series of clinical trials to incorporate FLT3 inhibitors into conventional treatment regimens for AML. Most exciting, perhaps, is the development of a new FLT3 inhibitor, AC220, which is showing remarkable activity in patients with highly resistant leukemia. The AC220 trial is currently accruing patients at the Kimmel Cancer Center and other academic medical centers around the world. The team plans to open a trial of AC220 combined with chemotherapy in early 2011.
Helping to Guarantee Long-Lasting Responses to Therapy: Signal transduction inhibitors are drugs that prevent cancer cells from multiplying quickly by blocking specific enzymes and cell growth factor receptors. Several of these drugs have already demonstrated effectiveness against leukemia. Keith Pratz and team are examining their effectiveness as part of maintenance therapy to sustain remissions in patients treated for Acute Myelocytic Leukemia (AML) as well as prior to and following bone marrow transplant.
Focus on Histone Deactylase Inhibitors (HDI)
Altering Gene Expression: Myelodysplastic syndrome (MDS) is a pre-leukemia condition that disrupts the orderly and controlled production of blood cells. Clinician-scientist Steven Gore was among the first to reverse the suppression of a gene in a pioneering trial of the demethylating agent, 5-azacytidine in conjunction with a histone deactylase inhibitor. Regions of genes can have increased amounts of methylation, a biochemical process that acts like an off switch for different types of genes including key tumor suppressor genes. Histones, which are critical to DNA structure and gene expression, are also known to control to the expression of key tumor suppressor genes. When histones are in a “deacetylated” state, the expressions of affected genes are silenced. The combined approach of 5-Azacytidine and HDI appears to reprogram cells to behave more like normal cells. Promising results in an earlier trial led to the FDA-approval of a demethylating drug for the treatment of MDS. Gore and team are continuing to work on ways to alter gene expression to reverse MDS and prevent it from developing into leukemia.
A Combined Approach: Clofarabine, like Ara-C, is among the anticancer agents known as antimetabolites that work by hampering cancer cell division. In earlier studies, the drug was effective in certain Acute Lymphocytic Leukemia (ALL) patients who did not respond to standard therapy or whose leukemia returned following treatment. Researcher Hetty Carraway and team are now studying a combined approach using Clofarabine with histone deacetylase inhibitors.
Making Leukemia Cells Die
Retinoids and AML and ALL: Research by B. Douglas Smith and team has found that leukemia cells often become locked in a primitive, embryonic cell-like state, in which they continue to produce new cells but do not have any cell death. This overproduction and overabundance of a particular blood cell, crowds out normal blood cells. Smith is working to return these cells to state in which they can mature and die. He is studying cell differentiation in Acute Myeloid Leukemia (AML) and Acute Lymphocytic Leukemia (ALL). Retinoids come from vitamin A and are known to play a role in the regulation of cell differentiation; for instance, determining whether a blood stem cell will become a red cell, white cell, or platelet.
Making Progress Against a Rare Leukemia: Researcher Michael McDevitt has initiated landmark studies dissecting the genetics of Chronic Myelomonocytic Leukemia (CMML), and unusual type of leukemia that is currently not well understood. There is no standard therapy for this type of leukemia. McDevitt’s much-needed research, which has already revealed abnormal expression of a specific gene, is expected to lead to a better understanding of the disease and, as a result, the development of more effective treatments.
Vaccine Clears Out Leukemia Cells
A leukemia vaccine developed by Kimmel Cancer Center researchers Douglas Smith, M.D., and Hy Levitsky, M.D., appears to get rid of cancer cells left behind after treatment with the drug Gleevec. While the findings are preliminary, the investigators are cautiously optimistic that the vaccine could improve treatment outcomes and reduce toxic side effects for patients with chronic myeloid leukemia (CML).
The researchers are now conducting additional studies to confirm that the favorable responses were solely due to the vaccine.
"We want to get rid of every last cancer cell in the body, and using cancer vaccines may be a good way to mop up residual disease," says cancer immunology expert Hyam Levitsky, M.D., who collaborated with Dr. Smith to developed the experimental vaccine.
While most patients with CML will need to remain on Gleevec therapy for the rest of their lives to remain cancer free, about 10 to 15 percent of patients cannot tolerate the drug long term.
"Ultimately, should this vaccine approach prove to be successful, the ability to get patients off lifelong Gleevec therapy would be a significant advance," says B. Douglas Smith, M.D.
Gleevec was introduced about a decade ago as one of the first targeted therapies in cancer and widely celebrated for its ability to specifically destroy malignant cells in patients with CML. While the drug has led to very good responses in many patients, it does not kill all of the cells leaving some patients at risk for relapse, particularly if they stop Gleevec therapy.
The vaccine developed by Dr. Smith and Dr. Levitsky is made from CML cells irradiated to halt their cancerous potential and genetically altered to stimulate an immune response against other CML cells. In the initial trial, it was given to 19 patients whose cancer was no longer responding to Gleevec therapy. After an average of six years of follow up, 13 patients saw declining numbers of cancer cells, seven of whom had no measurable evidence of disease.