|By PR Newswire||
|December 9, 2012 08:00 AM EST||
ATLANTA, Dec. 9, 2012 /PRNewswire-USNewswire/ -- Encouraging safety and efficacy data on novel and emerging therapies presented at the 54th Annual Meeting of the American Society of Hematology (ASH) signal an important step forward in the development of treatment strategies for patients with hard-to-treat leukemia, myeloma, and myelofibrosis.
Ongoing discoveries of critical molecular markers, pathways, and other drivers of some of the most difficult-to-treat forms of blood cancer have provided unprecedented opportunities for the development of new targeted therapies that attack, block, and silence the deadly genetic mutations that cause these disorders. These insights are revolutionizing how hematologists treat patients with resistant disease who otherwise had few options. Data presented today provide several examples of new targeted cancer therapies that have great potential to turn currently fatal disease subtypes into chronic conditions manageable with regular treatment.
"The significant drug discovery advances presented today represent our continued progress in fighting resistant disease, identifying and disabling cancer gene signaling, and improving outcomes in patients who struggle with poor prognoses and few treatment options," said Aaron Schimmer, MD, PhD, moderator of the press conference and Clinician Scientist at the Princess Margaret Cancer Centre, University Health Network in Toronto. "Considering the incredible progress we have made over just a few years, I am encouraged and excited to see what the next decade has in store, and how the next generation of therapies will further help us conquer blood cancers and save lives."
This press conference will take place on Sunday, December 9, 2012, at 8:00 a.m. EST.
Final Results of a Phase II Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation
Research suggests that a new targeted therapy, quizartinib, may be a safe and effective option to treat a subset of patients with treatment-resistant acute myeloid leukemia (AML).
AML is a fast-growing blood cancer in which patients produce an excessive amount of abnormal, immature white blood cells that are unable to adequately fight infection. Following AML diagnosis, leukemia cells from patients undergo genetic testing to identify the mutation driving the disease, which helps determine the appropriate treatment protocol. Of the many types of genetic mutations that can occur in AML, one of the most threatening is the FLT3-ITD (internal tandem duplication), which makes the leukemia even more aggressive and typically leads to failure of standard chemotherapy treatment response.
"The FLT3 mutation is essentially a power switch that leukemia cells use to spread more aggressively, which helps them to grow back immediately after chemotherapy," said Mark J. Levis, MD, PhD, lead author and Associate Professor of Oncology, Pharmacology, and Medicine at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore. "The only way to treat this type of mutation is to find a way to turn the switch off — a feat that has eluded researchers for far too long."
Patients with the FLT3-ITD mutation can achieve remission with standard chemotherapy but tend to relapse very quickly. An important treatment option is a stem cell transplant, but only if the patient is in some form of remission; otherwise, transplant failure rates are high. Given the barriers to treatment in this patient population, researchers have been examining the efficacy of the investigational oral agent quizartinib, which is designed to "turn off" the mutated FLT3 enzyme, thus forcing the immature cancer cells to either die immediately or undergo maturation (and eventually die). This eliminates enough leukemia cells to make it possible for patients to undergo stem cell transplants that can cure their disease.
In order to assess the efficacy and safety of quizartinib as a single agent (drug used alone in treatment) in AML patients with the FLT3-ITD mutation, researchers conducted a Phase II study among 333 patients that were divided into two treatment cohorts. Cohort 1 consisted of patients age 60 or over with the FLT3-ITD mutation who failed to achieve remission with standard chemotherapy, or who had recently relapsed for the first time. Cohort 2 consisted of patients over age 18 with the FLT3-ITD mutation who presented with relapsed or refractory AML and had been administered salvage chemotherapy after failing to respond to prior treatment, or had relapsed after a stem cell transplant. Most patients in this study had the FLT3-ITD mutation, but a small number in each cohort lacked the mutation.
Study results from Cohort 2 were based on an analysis of 137 patients (99 with mutation and 38 without) who received continuous treatment with quizartinib at a fixed dose during 28-day cycles. The primary endpoint of the study was the composite complete remission rate (CRc) of all patients, which includes complete remission (CR; no active disease), complete remission with incomplete platelet recovery (CRp, no active disease but abnormal platelet count), and complete remission with incomplete hematologic recovery (CRi, no active disease but abnormal red and white blood cell counts) of the patients following treatment with quizartinib.
Following one to three cycles of quizartinib treatment, researchers observed a CRc rate of 44 percent (4% CR, 0 CRp, and 40% CRi) in patients with the FLT3-ITD mutation with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. In patients without the mutation, researchers observed a 34 percent CRc rate (3% CR, 3% CRp, and 29% CRi) with a median duration of response of five weeks and median overall survival of 25.6 weeks. Of those patients in both cohorts who did not respond to their last AML therapy, 47 percent of those with FLT3-ITD and 31 percent of those without achieved a CRc with quizartinib. In both cohorts, 34 percent of patients were successfully bridged to a potentially curative allogeneic transplant.
Common adverse effects of treatment with quizartinib (observed in more than 20% of patients) included QT prolongation (26%), a heart complication associated with some medications and managed by reducing dosage, as well as nausea (38%), vomiting (26%), anemia (29%), fever (25%), diarrhea (20%), and fatigue (20%). These results demonstrate that quizartinib can produce a high treatment response rate in a group of very poor-prognosis AML patients with the FLT3-ITD mutation with manageable toxicity.
"Quizartinib is the first and only single-agent drug that has produced a clinical benefit in AML patients with this deadly mutation who have failed previous therapy," said Dr. Levis. "The number of patients bridged to a stem cell transplant was very significant. We plan on using these encouraging results to design and conduct additional randomized trials that will hopefully lead to the approval of quizartinib to make it accessible to those patients who previously had no hope for a cure."
Dr. Levis will present this study in an oral presentation on Monday, December 10, at 4:30 p.m. EST at the Georgia World Congress Center in Room A101, Level 1, Building A.
Combination Therapy Using JAK2 and HSP90 Inhibitors Increased Efficacy in Myelofibrosis in Vivo [Abstract 805]
Researchers have demonstrated that combination therapy with PU-H71 and ruxolitinib increases the durability and effectiveness of a treatment that had previously shown limited utility for patients with myelofibrosis.
Myelofibrosis is a chronic malignant blood disorder commonly caused by mutations in the JAK2 pathway (which normally signals the body to create blood cells), including most commonly the JAK2 V617F mutation. This mutation leads to the overproduction of scar tissue in the bone marrow and shifts red and white blood cells and platelets from the bone marrow into the spleen and liver, enlarging the organs and leading to anemia, infection, inflammation, and easy bleeding and bruising.
The first approved treatment for myelofibrosis is ruxolitinib, a therapy that targets the JAK2 mutation by blocking the action of all JAK-related genes in the body, including those from both healthy and diseased cells. However, clinical results have been modest to date. In particular, resistance to JAK inhibitors has been associated with an increase in JAK2 levels, which leads to continued JAK2 activity despite ruxolitinib treatment. This resistance can be reversed by inhibiting heat shock protein 90 (HSP 90), which destabilizes JAK2 and reduces JAK2 protein levels. Since cancer cells are continually dividing, they constantly burden the cell system and depend on HSP90 function to allow the JAK2 protein to maintain cancer cells' function and growth.
Recognizing HSPs as a potential target for treatment, researchers have recently explored the possibility of blocking HSP90 to treat blood cancers. Unlike ruxolitinib, which blocks the function of the abnormal JAK2 protein that maintains the function of the cancerous cell, HSP90 inhibitors block the function of HSP90 in the cells. This allows for the breakdown of the JAK2 protein and weakens the cell's ability to grow and divide, allowing it to become sensitive to treatment. PU-H71, a HSP90 inhibitor, previously shown to have efficacy in different cancer cells and animal models including myelofibrosis, is currently undergoing Phase I clinical trials.
One emerging hypothesis is that combining the JAK2 inhibitor ruxolitinib with HSP90 inhibitors may increase the efficacy of myelofibrosis treatment. To test this hypothesis, a team of investigators treated mice that had myelofibrosis with the investigational combination therapy, comparing their results to control groups treated with ruxolitinib alone or PU-H71 alone. They also assessed the effects of adding PU-H71 treatment as a second therapy to mice already being treated with ruxolitinib. Study endpoints included reduction in white blood cell count, platelet count, and spleen weight; reduction in JAK2 protein levels in the blood, spleen, and bone marrow; and presence of scar tissue in the bone marrow.
In this study, researchers observed that mice that had been treated with the combination therapy had a more significant reduction in white blood cell count, platelet count, and spleen weight after 14 days of therapy. The benefits of combination therapy versus ruxolitinib alone were even more significant after 29 days of treatment. The combination therapy was also associated with a reduction in bone marrow scar tissue and a reduction in the activity of the JAK2 pathway. Comparable effects were also observed in mice that were treated with PU-H71 plus ruxolitinib after initial monotherapy with ruxolitinib, further demonstrating the efficacy of combination treatment. Most importantly, in those mice treated with combination ruxolitinib and PU-H71 therapy, investigators observed a decrease in JAK2 levels, revealing that PU-H71 may prevent or reverse the increases in JAK2 protein levels seen with chronic ruxolitinib therapy. Of note, combination treatment was well tolerated and not associated with increased side effects compared to either therapy alone.
"Now that we have found a way to combat the treatment resistance commonly seen in myelofibrosis, we are continuing these trials with the hope that these results will one day provide a treatment option superior to what is currently available for these patients," said Priya Koppikar, PhD, second author and research scholar in the Human Oncology and Pathogenesis Program (HOPP) at Memorial Sloan-Kettering Cancer Center in New York.
"We believe these results provide the impetus for the first studies combining ruxolitinib with HSP90 inhibitors in myelofibrosis patients, and we are working to begin these trials as soon as possible to improve their outcomes," added Ross Levine, MD, lead author and Associate Attending Physician in the HOPP and Leukemia Service at Memorial Sloan-Kettering Cancer Center in New York.
Dr. Koppikar will present this study in an oral presentation on Monday, December 10, at 6:15 p.m. EST at the Georgia World Congress Center in Room B216-B217, Level 2, Building B.
A Pivotal Phase II Trial of Ponatinib in Patients with Chronic Myeloid Leukemia (CML) and Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Resistant or Intolerant to Dasatinib or Nilotinib, or with the T315I BCR-ABL Mutation: 12-Month Follow-up of the PACE Trial [Abstract 163]
Researchers have discovered that ponatinib, a new oral tyrosine-kinase inhibitor (TKI), can silence a deadly mutation in chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphocytic leukemia (Ph+ALL).
CML and Ph+ALL are leukemias caused by an abnormality known as the Philadelphia chromosome that produces the cancer-causing gene BCR-ABL. This gene provides the DNA code to produce the BCR-ABL tyrosine-kinase, a protein found on the leukemia cell surface critical to its development. TKIs such as imatinib, dasatinib, and nilotinib, which bind to the protein and "turn off" its signal, have been revolutionary in the treatment of leukemia and have quickly become standard first-line therapies for CML and Ph+ALL.
Despite this success, no targeted treatment option exists for approximately5 to 20 percent of CML and Ph+ALL patients with the "gatekeeper" T3151 BCR-ABL mutation, which makes them resistant to available TKIs. The only treatment alternative is a hematopoietic stem cell transplant which has toxic side effects. Ponatinib, the first targeted therapy that has emerged for these hard-to-treat patients, has demonstrated excellent activity against the T3151 mutation in early clinical trials. High levels of response have also been observed in patients with other mutations or with no mutations who have experienced resistance or intolerance to two or all three available TKIs. Given these promising results, researchers conducted a pivotal Phase II trial assessing the drug.
A team of researchers from the United States and Europe enrolled 449 patients with CML and Ph+ALL who were either resistant or intolerant (R/I) to dasatinib or nilotinib or had the T3151 mutation. Patients were assigned into six cohorts based on their disease resistance or genetic profile and then treated with ponatinib. Nearly all of the patients were previously treated with two of the available TKIs (imatinib, dasatinib, and/or nilotinib) or with all three TKIs. The primary endpoint of the study was major cytogenetic response (>65% of cells are normal) within 12 months of treatment for those with chronic phase CML and major hematologic response (normal white blood cell counts) within six months after treatment for those with advanced-phase CML or Ph+ALL.
Major cytogenetic response was observed in 55 percent of all chronic-phase CML patients (50% of R/I patients and 70% with T3151 mutation), and major hematologic response was observed in 58 percent of patients with accelerated-phase CML (57% of R/I patients and 50% with T3151 mutation) and 34 percent of those with blast-phase CML/ Ph+ALL (35% of R/I patients and 33% with T3151 mutation). The similar response rates observed in patients with and without the T3151 mutation build on previous evidence and imply that ponatinib is a TKI that may work across a wide range of mutations associated with TKI resistance and also in instances where mutations are not detected.
Remarkably, complete cytogenetic response (no Ph+ cells measured in the body) was achieved in 46 percent of patients with chronic phase CML, with higher response rates observed in patients who were exposed to fewer prior TKIs and those with shorter disease duration. The therapy was also well tolerated in all cohorts, as evidenced by the minimal toxicities observed. The most common adverse events observed were skin toxicity (including rash or dry skin), elevation of pancreatic enzymes and/or pancreatitis, and myelosuppression (a side effect of cancer treatment that lowers blood cell count). At the time of analysis, 52 percent of patients remained on the therapy. These results demonstrate ponatinib's efficacy in CML and Ph+ALL patients with no other viable treatment options.
"This therapy may be able to transform highly fatal forms of leukemia into a curable disease in these patients – we have simply never had any treatment produce such high rates of durable response in such a heavily treated group of patients," said Jorge Cortes, MD, lead author, Professor of Medicine, Deputy Chair of the Department of Leukemia, and Chief of the CML and AML Sections at The University of Texas MD Anderson Cancer Center in Houston. "Our next step is to test ponatinib's potential as an initial therapy in an attempt to prevent the occurrence of relapse that may decrease the prospects of a normal lifespan for patients."
Dr. Cortes will present this study in an oral presentation on Sunday, December 9, at 4:30 p.m. EST at the Georgia World Congress Center in Room A411-A412, Level 4, Building A.
Phase I/II Study of Weekly MLN9708, an Investigational Oral Proteasome Inhibitor, in Combination with Lenalidomide and Dexamethasone in Patients with Previously Untreated Multiple Myeloma (MM) [Abstract 332]
Early-stage research suggests that when added to standard multiple myeloma therapy, an investigational oral proteasome inhibitor known as MLN9708 increases the efficacy of treatment with few side effects.
The last decade has seen an explosion of new therapies for myeloma, a disease that causes the plasma cells found in the bone marrow to grow uncontrollably and form tumors. These tumor cells can destroy bones, damage kidneys, and make it difficult for the bone marrow to produce healthy blood cells and platelets, which puts patients at higher risk of infection and abnormal bleeding. One therapy for myeloma is bortezomib, a drug classified as a proteasome inhibitor for its activity blocking the proteasome (a cell structure that regulates the proteins involved in cell replication and survival), which prevents the function of proteins essential for myeloma cell survival. Another myeloma treatment strategy involves immunomodulatory agents, such as lenalidomide, which bolster the immune system's response to myeloma and alter the tumor microenvironment that sustains cancer cell growth. While each therapy is individually effective, when combined they offer improved response rates and lead to longer duration of response.
While immunomodulatory agents are produced in convenient oral pill form, bortezomib must be administered via injection and carries a risk of nerve damage, which can deter patient adherence to treatment regimens. MLN9708, the first oral proteasome inhibitor to enter clinical trials for the treatment of myeloma, may offer a more convenient and tolerable form of treatment that limits the risk of nerve damage.
In order to assess the efficacy, safety, and proper dose of MLN9708 in previously untreated myeloma patients, researchers enrolled 65 patients in a Phase I/II study and administered an oral dose of the proteasome inhibitor combined with lenalidomide and dexamethasone for up to 12, 28-day cycles, followed by maintenance therapy with MLN9708 every 28 days until disease progression. Primary objectives in Phase I included safety, maximum tolerated dose, and recommended Phase II dose. In Phase II, primary objectives included complete remission and very good partial response (VGPR, measured by a 90% or greater reduction in abnormal myeloma proteins in the blood).
In Phase I, the maximum tolerated dose was determined as 2.97 mg/m2 and recommended Phase II dose was selected as 2.23 mg/m2, which was later converted to a 4.0 mg/m2 dose based on encouraging results related to the body's ability to tolerate the drug. In Phase II, the investigators observed an overall response rate of 92 percent with 55 percent of patients reaching VGPR or better, including 23 percent with a complete remission. As the treatment cycles progressed, the rate and depth of response increased.
Minor adverse events, such as fatigue, nausea, and rash, were noted in approximately 40 percent of patients. Serious adverse events were minimal and primarily consisted of decreased blood counts, nausea and vomiting, diarrhea, rash, and electrolyte disturbances. One patient died from pneumonia while on treatment, and seven patients discontinued treatment due to different side effects.
"As targeted therapies continue to evolve, we are now shifting our efforts to focus on making them safer and producing them in more convenient forms for patients. MLN9708 is a great example of how to accomplish this goal," said Shaji K. Kumar, MD, lead author and Professor of Medicine and Consultant in Hematology at the Mayo Clinic in Rochester, Minn. "We are now planning ongoing studies to examine this drug in combination with other myeloma drugs in Phase II and Phase III clinical trials. Once approved for treatment of myeloma, this drug will allow patients the convenience of a completely oral, highly effective regimen for treatment of multiple myeloma."
Dr. Kumar will present this study in an oral presentation on Monday, December 10, at 7:15 a.m. EST at the Georgia World Congress Center in the Thomas Murphy Ballroom 2-3, Level 5, Building B.
Pomalidomide in Combination with Low-Dose Dexamethasone: Demonstrates a Significant Progression Free Survival and Overall Survival Advantage, in Relapsed/Refractory MM: A Phase III, Multicenter, Randomized, Open-Label Study [LBA 6]
An advanced trial comparing therapeutic options for refractory multiple myeloma finds that combination treatment with pomalidomide and low-dose dexamethasone may be superior to high-dose dexamethasone alone for patients with resistant and relapsed disease.
Multiple myeloma (MM) causes abnormal plasma cells to accumulate in the bone marrow, interfering with normal blood cell production and increasing the risk of infection and abnormal bleeding. Current treatments include combinations of steroid therapies like dexamethasone, which reduces inflammation and manages the immune response with targeted therapies like bortezomib and lenalidomide that inhibit tumor growth and reproduction. However, many patients eventually become resistant to these standard therapies and therefore have a poor prognosis. Since there are few treatment options available for these difficult-to-treat patients, research has aimed to identify new therapy combinations and disease targets that may lead to better results.
Early trials of a novel immunomodulatory drug called pomalidomide have shown some evidence of activity in these relapsed and treatment-resistant patients. Pomalidomide offers an effective mechanism against resistant myeloma because it directly targets the disease in multiple ways. It not only encourages the immune system to attack and destroy myeloma cells, but also prevents the growth of new blood vessels and inhibits myeloma cell growth by reducing the supply of oxygen and nutrients to the myeloma cells. To evaluate whether a combination regimen with pomalidomide plus low-dose dexamethasone therapy might offer relapsed multiple myeloma patients better progression-free and overall survival than high-dose dexamethasone alone, researchers conducted a study in a population of patients with refractory or relapsed and refractory disease.
The open-label, multicenter, Phase III trial evaluated the safety and efficacy of pomalidomide and low-dose dexamethasone (LoDEX) combination as compared to high-dose dexamethasone (HiDEX) alone. A total of 455 patients were enrolled and randomized to receive regimens of either pomalidomide with LoDEX (Arm A, 302 patients) or HiDEX (Arm B, 153 patients) in a 28-day cycle until disease progression or severe toxicity. The primary endpoint was progression-free survival (PFS), while secondary endpoints included measures of safety, overall survival, and quality of life.
After a median follow-up of 18 weeks, patients who received the pomalidomide and LoDEX combination experienced significantly longer PFS compared with those who received HiDEX alone (15.7 vs. 8 weeks), and overall survival was also longer in the combination treatment arm. After an independent review committee concluded that the combination regimen offered survival advantage, the study's Data Safety Monitoring Board recommended that patients from Arm B be switched to Arm A to receive the combination treatment.
The combination regimen was well tolerated among the study participants, although some expected toxicities were reported in both groups, including low neutrophil count (42% in Arm A vs. 15% in Arm B), low platelet count (21% vs. 24%), and fever (7% vs. 0%). At the time of analysis, 45 percent of patients in Arm A and 25 percent of patients in Arm B remained in the study. The primary reason cited for discontinuation was progressive disease, which occurred in 35 percent of patients in Arm A and 49 percent in Arm B. One-fourth (25%) of patients in Arm A and 38 percent in Arm B died during the study, primarily from advanced disease and infections.
"We are excited about these results, as they show that a combination approach with pomalidomide and low-dose dexamethasone offers superior results than current treatment options for hard-to-treat myeloma patients," said Meletios Dimopoulos, MD, lead author and Professor and Chairman of the Department of Clinical Therapeutics at Alexandra Hospital in Athens, Greece. "We believe this study provides the basis to consider this combination as a new standard of care for patients who have exhausted most standard treatments to treat their refractory disease and may even offer greater benefit if studied among less heavily treated patients as a first-line therapy for the disease."
Dr. Dimopoulos will present this study during the Late Breaking Abstracts session on Tuesday, December 11, at 7:30 a.m. EST at the Georgia World Congress Center in Hall B5, Level 1, Building B.
American Society of Hematology 54th Annual Meeting
The study authors and moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new targeted treatment for chronic lymphocytic leukemia (CLL), efforts to reduce toxicity and improve survival for blood cancer therapy, strategies to increase the efficacy and safety of treatments for clotting disorders, and advances in stem cell technology and transplant strategies. For the complete annual meeting program and abstracts, visit www.hematology.org/2012abstracts. Follow ASH (@ASH_hematology) on Twitter (use the hashtag #ASH12 when posting tweets about the meeting) and on Facebook at www.facebook.com/AmericanSocietyofHematology for the most up-to-date information about the 2012 ASH Annual Meeting.
The American Society of Hematology (ASH) (www.hematology.org) is the world's largest professional society of hematologists dedicated to furthering the understanding, diagnosis, treatment, and prevention of disorders affecting the blood. For more than 50 years, the Society has led the development of hematology as a discipline by promoting research, patient care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.
SOURCE American Society of Hematology
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