A series of studies presented at the 55th annual meeting of ASH?, the American Society of Hematology, being held in New Orleans, Louisiana, USA, from December 7 – 10, 2013, show promising efficacy and safety results for several unique compounds and combination treatments, each aimed at improving long-term outcomes for patients with blood disorders ranging from clots to cancer.
Recent advances have helped hematologists better understand the cellular activity of blood cancers and non-malignant blood disorders. These developments have paved the way for the development of new molecules that selectively target disease-causing mechanisms and, as a result, may improve treatment success. Furthermore, researchers are now identifying combinations of existing therapies, in addition to new targeted therapies, that can more effectively prevent disease progression while reducing the toxic side effects of current standard treatments.
Increasing patients? long-term survival
The encouraging efficacy of these novel therapies in patients has allowed researchers to focus on developing strategies that aim to increase patients? long-term survival while reducing toxicity. For example, several new investigational therapies being discussed in today?s press conference have been designed to target specific proteins on the cell surface that fuel cancer growth. Additional studies combine existing anti-cancer compounds in new ways to reduce toxicity and improve response rates among patients with disease that is resistant to current treatments. Yet another study harnesses the therapeutic value of clot-busting snake venom, translating it into a powerful new investigational therapy.
The concept that we can harness something potentially poisonous in nature and turn it into a beneficial therapy is very exciting…
?Our research efforts in hematology continue to focus on identifying ?next-generation? treatments that will make treatment easier and more tolerable for patients with blood disorders,? said Joseph Mikhael, MD, MEd, Associate Dean of the School of Graduate Medical Education, Deputy Director of Education at Mayo Clinic Cancer Center and Associate Professor of Medicine at Mayo Clinic College of Medicine in Scottsdale, Arizona, USA ?These clever approaches ? from selectively interfering with cancer-driving proteins to targeting mechanisms of abnormal cell growth to exploring the utility of purified snake venom as an anticoagulant ? exemplify the exciting progress we?re making in improving the treatment of hematologic cancers and blood diseases.?
Anfibatide, a Novel Glycoprotein Ib Antagonist
Using purified snake venom, a team of researchers developed a unique new anti-thrombotic compound known as anfibatide, which is designed to target a specific receptor on the surface of platelets that is instrumental to the formation of blood clots (glycoprotein Ib complex, or GPIb). Researchers initially assessed the investigational compound?s clot-busting effects in several in vitro laboratory tests, and then evaluated functional activity in mouse models. After reaching the conclusion that anfibatide may be effective as an anti-thrombotic drug, the team then evaluated its safety and efficacy in a Phase I clinical trial. When tested in 94 healthy volunteers, the compound effectively prevented platelets from sticking together specifically through the GPIb complex, but did not otherwise affect platelet count or significantly prolong bleeding. At the doses investigated, no anti-anfibatide antibodies were detected, and the treatment caused no serious adverse events or deaths among study participants. [1]
?The concept that we can harness something potentially poisonous in nature and turn it into a beneficial therapy is very exciting,? said one of the senior investigators Heyu Ni, MD, PhD, of St. Michael?s Hospital, the University of Toronto, and Canadian Blood Services. ?The fact that this compound only targets the platelet receptor involved in clotting and does not appear to have significant side effects makes it a particularly promising anti-thrombotic therapy.?
Blocking the function of IL-6
Drugs known as monoclonal antibodies, engineered to target disease-harboring proteins on the surface of cells or to block growth signals in the microenvironment, have demonstrated strong efficacy and safety, and have become more common treatments for blood cancers. Given this success, researchers are experimenting with the use of monoclonal antibodies in rare diseases with limited treatment options. One such disease is multicentric Castleman?s disease (MCD), a potentially fatal, incurable disorder with high morbidity believed to be partially mediated by the overproduction of a specific cell signaling molecule known as interleukin-6 (IL-6) that results in the dangerous overgrowth of cells in the lymph nodes.
This study evaluated the safety and efficacy of siltuximab (also known as CNTO 328; Janssen Research & Development), an investigational monoclonal antibody designed to block the function of IL-6 in an attempt to ameliorate uncontrolled cell growth and control other inflammatory disease symptoms. Investigators enrolled 79 MCD patients in a Phase II trial who were randomized to receive either siltuximab or placebo, in combination with best supportive care, to assess rates of remission and improvement in symptoms. Roughly one-third of patients treated with siltuximab achieved a durable tumor and symptom response whereas none of the placebo-treated patients showed a response. While disease symptoms completely resolved in one-quarter of the siltuximab-treated patients for a median of 1.3 years, this was never observed in patients treated with placebo, indicating that siltuximab led to prolonged duration of disease control. Rates of adverse events were similar between the treatment and placebo groups, despite a two-fold longer duration of treatment in the siltuximab group.[2]
?Based on these promising results, it appears that patients treated with this highly targeted monoclonal antibody approach can potentially experience far superior and equally safe responses than those observed with current conventional treatments,? noted study author Raymond S. Wong, MBChB, MD, of the Prince of Wales Hospital and the Chinese University of Hong Kong. ?If siltuximab gains regulatory approval, this experimental therapy could become the first globally approved treatment for this incurable disease and could potentially transform how patients are treated in the future.?
Less likely to experience disease progression
During the annual meeting, the initial phase III results of the first (Frontline Investigation of Revlimid + Dexamethasone Versus Standard Thalidomide) Trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients who are ineligible for stem cell transplantation (SCT), designed to compare the efficacy and safety of a combination of two oral drugs, lenalidomide (Revlimid?; Celgene)and low-dose dexamethasone (Rd), to a standard combination therapy including melphalan, prednisone, and thalidomide (MPT) used worldwide to treat patients with newly diagnosed multiple myeloma (NDMM) were presented.[3]
A total of 1,623 NDMM patients ineligible for stem cell transplant due to age or other factors were randomized into three treatment arms: continuous Rd until disease progression, Rd for 72 weeks, or MPT for 72 weeks. After a median follow-up period of 37 months, the study met its primary endpoint by demonstra
ting that those patients treated with continuous Rd were more than a quarter (28%) less likely to experience disease progression or death than those patients treated with MPT. Further, patients in both Rd treatment arms showed improvements in overall survival, overall response rate, and duration of response. While the safety profiles of the two treatment regimens were similar, patients treated with Rd showed fewer secondary hematologic malignancies than those treated with MPT.
?Traditionally, newly diagnosed patients have received initial, short bursts of treatment, while continuous treatment was reserved for relapsed patients. However, we believe that these new results will help encourage more research on the efficacy and safety of continuous treatment for newly diagnosed patients to help maximize their chances for overall long-term survival,? said study author Thierry Facon, MD, of Service des Maladies du Sang, H?pital Claude Huriez, and CHRU Lille in France. ?For some patients with low-risk myeloma, this continuous regimen could make this disease a manageable, chronic condition.?
Post-treatment relapse rate
For children diagnosed with cancer, their post-treatment relapse rate is one of the major indicators of their potential for long-term survival. Results from a randomized phase III Children?s Oncology Group (COG) trial shows that Gemtuzumab Ozogamicin (Mylotarg?; Pfizer), an antibody-drug conjugate, in children with de novoacute myeloid leukemia (AML) improves Event-Free Survivalor EFS by reducing relapse risk.* This research program evaluated whether adding the monoclonal antibody-drug conjugate gemtuzumab ozogamicin(GO) to standard chemotherapy might improve event-free survival without causing excessive toxicity and mortality in children with acute myeloid leukemia or AML. In this Phase III trial, more than 1,000 children (10 years old on average) were treated with GO or a standard treatment regimen, followed by additional chemotherapy for low-risk patients and stem cell transplants for high-risk patients. Overall, compared with standard regimens, the addition of GO was associated with better disease-free survival (61 vs. 55%) and reduced relapse risk (33 vs. 41%), though it did not significantly improve overall survival (74 vs. 70%). [4]
?These results are encouraging. Combining gemtuzumab with chemotherapy appears to reduce the risk of disease relapse, which translates to an improved event-free survival in children with AML,? noted study author Alan S. Gamis, MD, MPH, of Children’s Mercy Hospital and Clinics in Kansas City, Mo, USA. ?Importantly, the therapy seemed to have a particularly lasting effect among those patients who achieved remission in the course of treatment. Though gemtuzumab was previously removed from the market due to lack of clinical value in earlier trials, this growing body of positive data in populations of critical need may be sufficient to bring it back as a commercial treatment option.?
Focused on cellular protein activity
While lenalidomide is an effective treatment commonly used for multiple myeloma and certain B-cell lymphomas, research has yet to fully explain how it works. Using a combination of experiments focused on cellular protein activity, investigators discovered that lenalidomide has a unique mechanism of action for a drug. Specifically, investigators concluded that the drug promotes binding of two lymphoid transcription factors, IKZF1 and IKZF3, to the CRBN-DDB1 ubiquitin ligase. This interaction leads to the selective degradation of these transcription factors, which are essential for multiple myeloma cells. Consistent with this mechanism, the researchers also observed that lenalidomide decreased IKZF1 and IKZF3 levels in human T-cells, leading to activation of IL-2 expression, a known effect of the drug.
?Lenalidomide is a unique tool in our treatment arsenal, as we have used it effectively for many years but have not yet fully understood its mechanisms. This research offers a clear illustration of its specific activity in multiple myeloma,? said study author Jan Kr?nke, MD, of Brigham and Women?s Hospital in Boston. ?Based on these mechanisms, we may be able to design new drugs in our efforts to improve patient outcomes in lymphomas or even in other diseases.?
Notes:
* In 2000, gemtuzumab ozogamicin, an antibody-drug conjugate with calicheamicin as the active agent,was granted accelerated approval by the US Food and Drug Administration (FDA). The approval was based on promising phase II trial data in relapsed older adults with acute myeloid leukemiaor AML.At that time, the researchers believed that gemtuzumab ozogamicinheld promise as a new, powerful, agent that, withacceptable toxicity, could be efficacious in newly diagnosed AML. Several phase III studies were designed to test gemtuzumab ozogamicinin this setting. However, results of a randomized study by the Southwest Oncology Group led – in the summer of 2010 – to Pfizer’s voluntary withdrawal of this agent after improved efficacy could not be demonstrated and toxicity appeared excessive. Remarkably, since the withdrawal of the drug, 4 randomized clinical studies have been completed that, in aggregate, offer strong support for the efficacy of gemtuzumab ozogamicinin newly diagnosed AML with acceptable toxicity. According to a number of researchers, there is a very plausible explanation for this discrepancy. According to a number of researchers, the current trial results make a compelling case for re-approval of gemtuzumab ozogamicinin AML. [6][7]
For more information:
[1]The first in vitro and in vivoassessment of anfibatide, a novel glycoprotein Ib antagonist, in mice and in a phase I human clinical trial. Hou Y, Lei Xi, Li BX, Dai X, Yang Z, Qian F, et al. [Abstract]
[2]Multicenter, randomized, double-blind, placebo-controlled study of the efficacy and safety of siltuximab, an anti-interleukin-6 monoclonal antibody, in patients with multicentric Castleman?s disease. Wong RS, Casper C, Munshi N, Ke X, Foss? A, Simpson D, et al [Abstract]
[3] Initial phase 3 results of the first (frontline investigation of lenalidomide + dexamethasone versus standard thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma (NDMM) patients (Pts) ineligible for stem cell transplantation (SCT). Facon T, Dimopoulos MA, Dispenzieri A, Catalano JV, Belch AR, Hulin C, Cavo M, Pinto A, et al.[Abstract]
[4]Gemtuzumab Ozogamicin (GO) in children with de novoacute myeloid leukemia (AML) improves event-free survival (EFS) by reducing relapse risk ? results from the randomized phase III children?s oncology group (COG) trial, AAML0531. Gamis AS, Aplenc R, Alonzo TA, Sung L, Meshinchi S, Gerbing RB, Raimondi SC et al. [Abstract]
[5]Lenalidomide promotes CRBN-mediated ubiquitination and degradation of IKZF1 and IKZF3. Kr?nke J, Udeshi N, Narla A, Grauman P, Hurst S, McConkey M, Svinkina T et al. [Abstract]
[6]Cytotoxic Agents – ADC Review/Journal of Antibody-drug Conjugates [Article]
[7] Rowe JM, L?wenberg B Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug. Blood. 2013 Jun 13;121(24):4838-41. doi: 10.1182/blood-2013-03-490482. Epub 2013 Apr 16 [Article][PubMed]
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