Zosia Chustecka

December 03, 2013

The upcoming American Society of Hematology (ASH) 55th Annual Meeting will feature "fantastic science in all aspects of hematology," said ASH secretary Stephanie Lee, MD, MPH. She is also professor of medicine at the University of Washington, and a member of the Fred Hutchinson Cancer Research Center in Seattle.

Dr. Lee was speaking at a preview press call with selected journalists ahead of the meeting, which begins in New Orleans on December 6.

She said that several of the practice-changing studies being presented at the meeting have been conducted in patients who are too old and/or too ill for some of the new aggressive therapies. These sorts of cases actually make up the bulk of the patients that are seen in clinic, she said.

A case in point is the presentation at the plenary session of a phase 3 trial in multiple myeloma patients who are not eligible for stem cell transplant (abstract 2). The standard approach for such patients is melphalan, prednisone, and thalidomide, according to the researchers, but they set out to see how it compared with a newer option of using lenalidomide (Revlimid) with low-dose dexamethasone.

Another study was conducted in patients with chronic lymphocytic leukemia (CLL) who have comorbidities and so cannot tolerate aggressive chemotherapy, Dr. Lee noted. This study directly compared the new agent obinutuzumab (Gazyva) against the standard therapy rituximab (Rituxan), and both were administered in combination with chlorambucil (abstract 6). Top-line results from this trial recently released by the company (Genentech/Roche) show significantly improved progression-free survival with obinutuzumab, and the drug has just recently been approved in the United States.

For both of these studies, the median age of the patients was 73 years, which is quite a bit older than patients usually taking part in clinical trials, but this is actually consistent with the median age at diagnosis for these diseases, Dr. Less commented.

"So it is representative of the patients that need to be treated, and this helps to identify the best treatments for them," she said.

Also in CLL, but this time in heavily pretreated patients, is a phase 3 placebo-controlled study evaluating the novel first-in-class drug idelalisib in combination with rituximab (abstract LBA-6). "This is an important study, as it showed improved overall survival," Dr. Lee commented, noting that the median age of this patient population was 70 years.

Idelalisib (under development by Gilead) is currently awaiting approval from the US Food and Drug Administration for use in the treatment of refractory indolent non-Hodgkin's lymphoma, but the company is also planning to file for use in CLL on the basis of this trial.

More pointers on the clinical trials to watch out for were discussed by Bruce Cheson, MD, head of hematology at Georgetown University in Washington, DC, in his Medscape videoblog preview of the meeting. He highlighted a number of studies in lymphoma, including 2 trials with lenalidomide (abstracts 850 and 248); this could be a new indication for the drug, which is currently marketed for multiple myeloma.

Dr. Cheson also highlighted "a very important study" in CLL, which compares regimens of fludarabine, cyclophosphamide, and rituximab vs bendamustine and rituximab (abstract 526).

In addition, Dr. Cheson drew attention to a number of studies that will be reporting on the novel agent ibrutinib (Ibruvica), which has recently been approved in the United States for the treatment of mantle cell lymphoma. At the meeting, results with ibrutinib in diffuse large B-cell lymphoma (abstract 251) and in CLL (abstracts 525 and 675) will be reported.

Better Understanding of Disease

Some of the new research to be presented at the meeting offers new understanding of diseases, said ASH president Janis Abkowitz, MD, who is hematology division head, professor of medicine, and adjunct professor of genome sciences at the University of Washington. She also directs the hematology clinic at Seattle Cancer Care Alliance, and was speaking on the premeeting press call.

She highlighted a report of whole-exome sequencing of multiple myeloma (abstract 399), which has revealed heterogenous clonal architecture and genomic evolution. "These researchers found a huge degree of clonal heterogeneity and many genes that had not previously been identified as important for clonal expansion in myeloma," Dr. Abkowitz said.

In addition, some of these myeloma patients were found to have recurrent genetic signatures that were similar to those found in breast cancer, and others had signatures that have been associated with ageing. So as well as providing new insights into myeloma, these data also address the fundamental processes involved in how cells age and become neoplastic, she said.

Dr. Abkowitz also highlighted research showing frequent mutations in the calreticulin gene CALR in myeloproliferative neoplasms (MPN) (abstract LBA-1), and a related study that found somatic mutations in CALR in the majority of patients with JAK2 wild-type (unmutated) MPN (abstract LBA-2).

These 2 abstracts are critically important contributions to hematology.                 Dr. Janis Abkowitz

"These 2 abstracts are critically important contributions to hematology," Dr. Abkowitz commented. Using 2 different approaches, they have identified a previously unknown gene (CALR) and shown that it is a major driver in MPN patients who are negative for JAK2 and MPL mutations — this comprises about 68% of patients with essential thrombocythemia and 88% of patients with primary myelofibrosis.

"So this is a huge contribution to the understanding of pathogenesis," she said.

The study authors suggest that this research could help to simplify the diagnosis of patients with MPN, and also identify new targets for developing new treatments for these disorders.

Another scientific first will be reported at the plenary session: "The first clear example of an epigenetic mechanism that causes lymphoma," Dr. Abkowitz said. This study focused on diffuse large B-cell lymphoma and follicular lymphoma, and found that disease progression and initiation involves oncogenic co-operation between 2 proteins (abstract 1). The researchers comment that this finding provides "a rational epigenetic-based and molecular-targeted therapeutic approach with the potential to eradicate lymphomas without harming normal tissues."

Novel Cellular Therapies

Several abstracts show progress being made with novel cellular therapies using chimeric antigen-receptor engineering approaches (abstracts 67, 151, 163, 168). This involves taking cells from patients (or from a stem cell transplant) and then engineering these cells so that they  can more precisely kill the leukemia or other types of malignancies, Dr. Lee explained. Although these are early studies in a small number of patients, the results look "very promising, and I think we will be hearing more about this approach in the future," she said.

Progress in Hematology

The ASH officers also highlighted a number of presentations that show progress being made in other hematologic conditions.

One of these focused on the D-dimer test, which is used to rule out pulmonary embolism (PE) without imaging in about a third of patients. However, this test becomes less useful in older patients because of a lower specificity with increasing age, the researchers comment. They devised an aged-adjusted cut-off for the D-dimer test, and now report the results of a multinational management outcome study in 3377 patients (of whom 789 were aged 75 years or more). "Our study demonstrates that the age-adjusted D-dimer may now be used in clinical practice in emergency rooms patients with suspected PE," they conclude (abstract LBA-4).

Finally, there is the discovery of new hormone, provisionally named erythroferrone (abstract 4), which "has answered a longstanding clinical mystery," Dr. Abkowitz commented. This may be the long-sought hormone that is made by the bone marrow and says to the liver, 'I need iron,' so the liver suppresses hepcidin, and more iron is absorbed from the gastrointestinal tract, she explained. The researchers suggest that the factor may contribute to the pathogenesis of iron-loading anemias including beta-thalassemia.


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