Zosia Chustecka

December 02, 2011

December 2, 2011 — This year's annual meeting of the American Society of Hematology (ASH), which starts next week in San Diego, California, will feature some new drugs, some findings that might breathe new life into an old drug, and also some long-term data that might end a fierce debate.

"We are really building on the foundation of high-throughput genomic sequencing and the discovery of new targets for the development of new drugs," said ASH president J. Evan Sadler, MD, PhD, professor of medicine in the division of hematology at Washington University, in St. Louis, Missouri. "We have, on the one hand, new targeted therapies; on the other hand, we have so much information about individual patients that we can say which targeted therapies may be specifically useful for them."

Speaking at a premeeting conference call with journalists, Dr. Sadler highlighted several abstracts as being particularly newsworthy.

One of the new targeted therapies that holds great promise, although the research is still in the early stages, is the first drug that has been designed to home in on Bruton's tyrosine kinase, he noted. This enzyme plays a central role in B cell development, and has been implicated in chronic lymphocytic leukemia. The new drug, currently known as PCI-32765 (Pharmacyclics), is an oral irreversible inhibitor of the enzyme. The results of a phase 2 study of 61 patients suggest efficacy, and will be presented at the meeting (abstract 983). A larger phase 3 study is now planned.

I don't want to hype this, but we are hoping for a repeat of the success that was enjoyed by the poster child of targeted therapy, imatanib.

"I don't want to hype this, but we are hoping for a repeat of the success that was enjoyed by the poster child of targeted therapy, imatanib (Gleevec), for the treatment of chronic myeloid leukemia," Dr. Sadler said. Subsequent tyrosine kinase inhibitors have not shown such spectacular results, he noted, "but this one looks encouraging. There have been some striking responses described."

"This is the way of the future, where scientists first understand the molecular defect of the disease, and then drugs are designed to specifically target those diseases," explained ASH secretary and coordinator of the abstracts review, Charles Abrams, MD, associate chief of the division of hematology/oncology at the University of Pennsylvania in Philadelphia. The defect of Bruton's tyrosine kinase was first identified in children with an inherited blood disorder, X-gammaglobulinemia; this story goes "all the way from the patient to the laboratory bench and then back to the patient," he said.

Another example of how observations in patients have resulted in new therapies is that of thalidomide and related drugs, said Dr. Sadler. Studies of how thalidomide produced birth defects led to its use in the treatment of multiple myeloma, and resulted in the development of related next-generation agents, such as lenalidomide (Revlimid, Celgene) and the investigational agent pomalidomide (under development by Celgene). Exactly how these drugs exert their antitumor effects has been unclear. New research to be presented at the meeting (abstract 127) outlines the central role played by the recently identified protein cereblon. It appears to be "absolutely required" for a response to these drugs, say the authors, and preliminary data suggest that low levels of cereblon in a patient with multiple myeloma predicts a poor response to these drugs.

Breathing New Life Into an Old Drug

Featured in the plenary session will be research that could breathe fresh life into an old drug — gemtuzumab (Mylotarg, Wyeth) (abstract 6). This product was voluntarily withdrawn from the American market last year. It had been available for a decade, after the US Food and Drug Administration (FDA) granted it accelerated approval in 2000 for the treatment of relapsed acute myeloid leukemia (AML). However, subsequent clinical trials and years of postmarketing experience did not show evidence of clinical benefit in patients with AML, according to the FDA, and revealed toxicity that was highlighted in a black box warning.

Gemtuzumab is a monoclonal antibody directed against CD33 on white blood cells; it was used to supplement the treatment of AML, particularly in older patients, Dr. Abrams explained. It was then tested in the initial treatment of AML, but the results were inconclusive and some alarming toxicities emerged, he said. "In one trial in younger patients, mortality actually increased in patients who received the drug," he explained, so the drug was withdrawn.

In the study to be presented, gemtuzumab was used upfront in older patients, around 60 to 70 years of age, who were newly diagnosed with AML. The results show that "not only was there a benefit in the initial treatment of the disease, there was also a survival benefit," Dr. Abrams explained. "This study is really quite tantalizing," he said. There will now be a resurgence of interest in gemtuzumab, he predicted, adding that "this is a drug that wasn't studied fully enough."

Novel Cell-Based Approach

A novel cell-based approach to therapy is highlighted in a study in which genetic engineering was used to program some lymphocytes to attack other lymphocytes (abstract 167), noted Dr. Sadler. "This is instructing the T cells in what they should attack, rather than leaving it up to our immune system," he added. In this research, T cells were genetically engineered to express chimeric antigen receptors that specifically recognize the B cell antigen CD19, and were tested in patients with B cell malignancies. The clinical trial has so far enrolled 4 patients with chronic lymphocytic leukemia and 4 with B cell lymphoma.

Stem-cell transplantation offers a curative therapy for some hematologic malignancies, and a whole press conference at the meeting will focus on developments in this approach. One abstract describes an emerging methodology for preventing chronic graft-vs-host disease (GvHD) (abstract 817); another reports an increased incidence of chronic GvHD and no survival advantage with peripheral blood stem cells, compared with bone marrow transplantation (abstract 1). In addition, there are now long-term data (10+ years) on survivors of hematopoietic cell transplantation (abstract 841).

Answer to Longstanding Question?

An answer to a longstanding question about how best to treat patients with limited-stage Hodgkin's lymphoma comes from a final analysis of a trial now with a median follow-up of 11.3 years (abstract 590). There has been fierce debate about whether the initial treatment of these patients should include radiotherapy or whether they should be treated with chemotherapy alone; proponents of chemotherapy alone argue that adding radiation increases the risk for late toxicities without providing any clear benefit.

However, when radiotherapy was added to chemotherapy, the short-term results do look better, said Dr. Sadler. "Now, looking at the very long-term data, the morbidity and mortality associated with late complications from radiotherapy may well trump this short-term effectiveness," he added.

"I interpret this study as evidence that the long-term complications of radiotherapy are not necessarily worth the short-term efficacy," Dr. Sadler said. It appears that treating initially with chemotherapy alone will give sufficient benefit; if the patient relapses, they can be given radiotherapy, he explained. This approach would spare a number of people the toxicity of radiation, he noted. Dr. Abrams added that this is a very well-designed study with very long-term follow-up. In answer to the question of whether this is a final answer, he said: "I doubt that there will be another trial like this."

Other Hematology News

In addition to news on the hematologic malignancies front, which we will be focusing on here at Medscape Medical News, other newsworthy abstracts to be presented include a new gene therapy for hemophilia B (abstract 5), and research on the use of antiplatelet agents to decrease the recurrence of venous thromboembolism (abstract 543).

Several presentations will focus on sickle-cell disease, which is a fairly common and at times a morbid condition, said Dr. Abrams. It has long been known that these patients have a mutation in hemoglobin, but although they all have the same mutation, some patients have relatively mild disease and others have severe forms and die in childhood. "It has always been extremely perplexing as to why," he said. Metabolomic studies that have looked beyond hemoglobin are starting to provide some answers for the variability in this disease (abstract LBA-3).

Hydroxyurea is a standard treatment for sickle cell disease, but there has always been some discomfort about using such chemotherapy, particularly in children, Dr. Abrams noted. However, a large trial of children provides reassuring data on the safety and efficacy of hydroxyurea in the pediatric population (abstract 7 and abstract 8), which is "good news for our patients," he said. Another trial highlighted in the press program explores the use of preoperative blood transfusions to prevent complications in patients with sickle cell disease who undergo low- or moderate-risk surgery (abstract 9).

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