Hematology Pipeline: Baby Steps After a Giant Leap

Marie Rosenthal, MS
Published: Thursday, Jun 21, 2012

There are thousands of clinical studies in progress for hematologic malignancies, but many are in phase I or II trials, so it may be some time before the most promising compounds add new weapons to the hematology armamentarium, where they are sorely needed.

More than 1 million people suffer from a hematologic malignancy in the United States, and every year another 148,000 men, women, and children are diagnosed with lymphoma, leukemia, or myeloma.

Dr. Marshall A. Lichtman

Marshall A. Lichtman, MD

“We are still relying principally on the same two drug types to treat acute myeloid leukemia (AML) that we used 40 years ago: cytarabine and an anthracycline antibiotic such as daunomycin,” said Marshall A. Lichtman, MD, professor in the departments of Medicine, Hematology/Oncology, and Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry in New York. “This demonstrates the need for a broad and aggressive research program, new paradigms, and genius,” to find new therapies for these cancers.

The approval of imatinib (Gleevec, Novartis) in 2001 was a giant leap forward in the treatment of malignancies in which the ABL gene is mutated, resulting in a mutant tyrosine kinase (TK). This mutation occurs in chronic myeloid leukemia (CML) and acute leukemias. Imatinib’s clinical and financial success, as well as the success of the second-generation nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb), which target the mutant ABL TK to stop the proliferation of white cells in certain leukemias and permit restoration of normal blood cell production, encouraged pharmaceutical companies to invest in blood cancer research.

It is difficult to pinpoint exactly how much money companies are spending on developing therapies for hematologic malignancies, but several large companies, including Pfizer, Genentech, Novartis, and Bristol-Myers Squibb, have dedicated parts of their research and development budgets to finding treatments for blood cancers.

The National Cancer Institute (NCI) is also investing more than $425 million a year in hematologic malignancy research. The NCI reported that it earmarked another $81 million in FY2009-2010 in American Recovery and Reinvestment Act funds for blood cancer research.

However, Lichtman is concerned that many of the products are variations on a theme—tinkering with existing chemicals rather than finding new targets. He is also concerned that this approach decreases the potential market for a drug and may not provide a good business plan for pharmaceutical companies. The latter concern is mitigated in part by the ability of academic institutions with federal support to bear some of the early investment costs of drug development.

One example is tipifarnib (Zarnestra, Johnson & Johnson), a farnesyltransferase inhibitor being developed for older adults with newly diagnosed AML. “We have great difficulty treating older patients with cancer because they tend to have more resistant cancers, and they cannot tolerate harsh drug regimens for several reasons. Unfortunately, this time of life is when cancer incidence is greatest,” said Lichtman.

Dr. Joseph A. Bertino

Joseph A. Bertino, MD

“At first, tipifarnib didn’t do well because the percentage of remissions was low,” said Joseph A. Bertino, MD, professor of Medicine and Pharmacology, interim director of the Stem Cell Institute of New Jersey and The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School.

However, researchers learned that if the patient had a high RASGRP1 and a low APTX expression, they were most likely to benefit from tipifarnib-based therapies. “This just shows you how important it is to personalize some of the medicines that we are using,” Bertino said.

Lichtman said that the partnership of academia, the federal government, and industry is essential to encourage the development of personalized medicine for these small subsets of patients. Among the research currently under way, investigators are looking at ways to improve responses to stem cell transplantation, cytotoxic drugs such as thalidomide derivatives, as well as products that target various pathways, including tyrosine kinase, Aurora kinase, RAS, CD30, ABL, and JAK.

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Community Practice Connections™: Expert Insights on the Management of Myeloproliferative Neoplasms: Evidence-based Approaches and Emerging Strategies to Address Challenges in CareSep 29, 20181.5
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