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Promising Results for Leukemia Patients With Novel Combinations

by Himabindu Venkatakrishnan on  December 8, 2014 at 1:55 PM Research News   - G J E 4
Leukemia cannot be conquered with a "one-size-fits-all" approach. Researchers are pursuing novel targeted therapies and combinations of existing treatment regimens with new agents.
 Promising Results for Leukemia Patients With Novel Combinations
Promising Results for Leukemia Patients With Novel Combinations
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These are beneficial for patient populations with historically poor prognoses, reveals the data presented today during the 56th American Society of Hematology (ASH) Annual Meeting and Exposition. In recent years, outcomes for patients with leukemia have steadily improved with the emergence of numerous therapies that target specific genetic drivers of disease, as well as potent combination regimens. While overall outcomes for patients with leukemia are improving as a result of these new therapies, some more vulnerable subgroups of patients, including elderly patients and patients with aggressive genetic mutations, have not experienced the same positive results.

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Studies presented today reflect dedicated efforts to better understand the course of disease among these higher-risk patients to enable the development of new treatments or more effective treatment combinations that will improve survival outcomes. Two studies suggest that combining new targeted agents with standard chemotherapy regimens may be effective in treating newly diagnosed young or elderly patients with acute leukemias. Further evidence suggests that adolescents and young adults may respond better to treatment with a chemotherapy regimen pioneered in pediatric patients rather than with standard adult regimens. Additional studies evaluate an investigational, targeted therapy for certain blood cancers fueled by a recently discovered genetic mutation and examine the use of a specific combination of chemotherapies to treat a rare type of pediatric leukemia.

"This group of studies represents important progress on our continued quest to develop new therapies and to maximize use of existing therapies to yield improved results for patients with leukemias, particularly those with aggressive disease that is resistant to current approaches," said David Steensma, MD, moderator of the press conference and faculty member in the adult leukemia program at Dana-Farber Cancer Institute in Boston. "Our challenge moving forward will be to better understand how distinct subtypes of these diseases can affect patients in different ways and to use that insight to tailor our treatment approaches to each biological type of leukemia, ultimately improving long-term outcomes."

This press briefing will take place at 9:30 a.m. PST on Sunday, December 7, in rooms 236-238 of Moscone South, East Mezzanine.

Children with Rare Leukemia Associated with Poor Prognosis Have Better-Than-Expected Outcomes After Tailored Treatment

T-Lymphoblastic Leukemia (T-ALL) Shows Excellent Outcome, Lack of Significance of the Early Thymic Precursor (ETP) Immunophenotype, and Validation of the Prognostic Value of End-Induction Minimal Residual Disease (MRD) in Children's Oncology Group (COG) Study AALL0434 [1]

Relapse after therapy is a major challenge for children and young adults with T-lymphocytic leukemia (T-ALL), a subset of leukemia sometimes associated with a poor prognosis. Previous research has indicated that patients with a specific protein signature of T-ALL, called the early thymic precursor (ETP) immunophenotype, have particularly poor outcomes. To better understand how the presence of this immunophenotype among pediatric T-ALL patients influences their response to therapy, researchers enrolled 1,144 T-ALL patients in this Phase III trial, the largest ever conducted among patients with this leukemia subtype. Included in the trial were children with the ETP immunophenotype (11.3%), children with a nearly identical type of T-ALL known as "near-ETP" (17%), and children without the ETP immunophenotype (71.6%).

After administering the same standard initial regimen to all children enrolled in the study, investigators measured levels of "minimal residual disease" (MRD - i.e., disease that is still detectable by sensitive techniques, but not by the pathologists' traditional light microscope) in each patient, placing children into groups at low-, intermediate-, and high-risk of relapse (low risk <0.1% MRD; intermediate risk <1% MRD; and high risk >1% MRD), and providing therapy tailored to patients' risk group.

Intermediate- and high-risk patients received additional radiation therapy and had the opportunity to be randomized to receive additional chemotherapy with nelarabine. When researchers evaluated overall responses of all T-ALL patients enrolled in the trial, they observed that children with the ETP subset and near-ETP immunophenotypic signatures of T-ALL had a higher incidence of residual disease after initial treatment and most commonly fit into the higher-risk groups. While ETP and near-ETP patients were more likely to fail initial treatment than those without these genetic signatures, all patients appeared to benefit from the tailored treatment regimen and experienced improvements in overall survival (OS; 93% OS among ETP patients; 91.6% OS among near-ETP patients; and 92% OS among non-ETP patients).

"When we looked at the overall outcomes among children with and without this form of T-ALL, we noticed that the children with the more aggressive subtypes had the same outcomes as other children with T-ALL, despite having a higher incidence of residual disease early after therapy," said lead study author Brent Wood, MD, PhD, of the University of Washington in Seattle. "This study represents the first large trial to demonstrate that patients with ETP T-ALL may have an outcome similar to that of other patients with this disease."

Dr. Wood will present this study during the Plenary Scientific Session at 2:00 p.m. PST on Sunday, December 7, in Hall D of Moscone North.

Pediatric Leukemia Treatment Regimens Lead to Improved Outcomes in Adolescents, Young Adults

Favorable Outcomes for Older Adolescents and Young Adults (AYA) with Acute Lymphoblastic Leukemia (ALL): Early Results of U.S. Intergroup Trial C10403 [796]

Children and young adults with acute lymphocytic leukemia (ALL) typically have better treatment outcomes than adults, due in part to differences in the disease, but also to higher-intensity pediatric treatment protocols. While research indicates that more intensive pediatric regimens may be more effective, patients characterized as "adolescent" or "young adult" (patients aged 16-39) most often receive adult regimens.

To determine whether adolescent and young adult ALL patients would have better outcomes with pediatric regimens, 296 adolescent and young adult ALL patients participating in a large, prospective U.S. Intergroup clinical trial received the standard pediatric ALL treatment protocol, including four intensive courses of chemotherapy. After two years of follow up, 78 percent of the patients had achieved overall survival and 66 percent of patients had maintained event-free survival (EFS). Factors linked to poor outcomes include high initial white blood cell counts as well as presence of minimal residual disease following completion of the first month of therapy. The nearly 30 percent of patients enrolled in the trial with a Ph-like gene expression signature indicating aggressive disease experienced markedly worse outcomes (52% two-year EFS vs. 81% EFS among those without the genetic alteration). Five patients died due to treatment-related reasons during therapy.

"Our results illustrate a clear opportunity to improve care by treating adolescents and young adults with an intensive pediatric regimen, which resulted in low treatment-related mortality and achieved promising disease-free and overall survival," said lead study author Wendy Stock, MD, of the University of Chicago Medical Center. "It is important to note that these results reflect a significant improvement from historical control studies, in which event-free survival was only 39 percent. With these new insights, we can now focus additional research on evaluating novel treatment combinations to reduce minimal residual disease in these patients to further improve their duration of response and long-term survival."

Dr. Stock will present this study during an oral presentation at 7:30 a.m. PST on Tuesday, December 9, in rooms 3009-3011-3022-3024, of Moscone West.

Study Presents First Randomized Evidence for Benefit From Adding a Tyrosine Kinase Inhibitor in Acute Myeloid Leukemia

Sorafenib Versus Placebo in Addition to Standard Therapy in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia: Results from 267 Patients Treated in the Randomized Placebo-Controlled SAL-Soraml Trial [6]

The emergence of targeted therapies known as tyrosine kinase inhibitors (TKIs) has improved prognoses for certain leukemia patients. Despite the success of TKIs in some forms of the disease such as chronic myeloid leukemia and a small subset of patients with acute lymphocytic leukemia, until now a TKI had yet to clearly demonstrate improved outcomes in acute myeloid leukemia (AML). Insights into the variety of mutations that drive AML have led researchers to study sorafenib, an oral tyrosine kinase inhibitor currently approved for kidney and liver cancer that blocks the activity of several mutated enzymes that can drive growth of AML.

To better determine the safety and efficacy of sorafenib in combination with standard chemotherapy, researchers enrolled 267 AML patients ages 18-60 in a Phase II study and randomized them to receive either sorafenib (134 patients) or placebo (133 patients) in addition to a standard protocol. After three years of follow up, sorafenib-treated patients had a median event-free survival of 20.5 months and a three-year relapse-free survival rate of 56 percent. By comparison, patients receiving placebo had a median event-free survival of 9.2 months and a three-year relapse-free survival rate of 38 percent. The treatment combination was generally well tolerated; however, the sorafenib-treated patients experienced higher rates of certain events such as fever and bleeding. Sorafenib did not lead to improved overall survival in the treatment group when compared to those patients receiving placebo.

"The positive, lasting responses we observed in AML patients receiving sorafenib represent the first randomized evidence for a clinical benefit of a tyrosine kinase inhibitor in this type of leukemia," said lead study author Christoph Röllig, MD, of University Hospital Dresden in Germany. "In addition to validating these promising results in a larger trial, it will be useful to further evaluate the genetic markers that may predispose some patients to respond better than others to this treatment to fully maximize its potential."

Dr. Röllig will present this study during the Plenary Scientific Session at 2 p.m. PST on Sunday, December 7, in Hall D of Moscone North.

Targeted Therapy Effective in Elderly Patients with Philadelphia-Positive Acute Lymphocytic Leukemia

Nilotinib (Tasigna®) and Chemotherapy for First-Line Treatment in Elderly Patients with De Novo Philadelphia Chromosome/BCR-ABL1 Positive Acute Lymphoblastic Leukemia (ALL): A Trial of the European Working Group for Adult ALL (EWALL-PH-02) [798]

While rates of remission among elderly patients with leukemia continue to improve, the outlook remains poor among those with a disease subtype present in nearly one-third of adults with acute lymphocytic leukemia known as Philadelphia-positive ALL (Ph+ ALL).

This Phase II study evaluated the efficacy of the tyrosine kinase inhibitor nilotinib in combination with a low-intensity chemotherapy regimen to treat patients 55 or older with newly diagnosed Ph+ ALL. Patients received 400 mg of nilotinib twice daily with initial chemotherapy and then continuously during subsequent phases of chemotherapy for up to two years. Of 36 evaluable patients, 35 (97%) experienced complete responses, with 31 of 35 patients remaining in complete remission. Four patients relapsed after a median follow up of 211 days. Complete molecular remission, defined as the absence of mutations in the blood, was reached in 30 percent of patients after initial therapy and 42 percent during a subsequent phase known as consolidation. No patients died during initial therapy, though there were 34 reports of serious adverse events, including infections and neutropenic fever. "Our results strongly support adding this targeted therapy to standard chemotherapy to help elderly ALL patients achieve remission without significant toxicity," said lead study author Oliver G. Ottmann, MD, of Goethe University in Frankfurt, Germany. "This study, which joins several others evaluating treatments for elderly patients with Ph+ ALL, offers physicians valuable information to improve outcomes among these patients. We hope that additional study will further illuminate this drug's positive effects and lead to its eventual approval as a treatment in this setting."

Dr. Ottmann will present this study during an oral presentation at 7:30 a.m. PST on Tuesday, December 9, in rooms 3009-3011-3022-3024, of Moscone West.

Chemo-Free Treatment Approach Demonstrates Positive Responses in Leukemia Patients

AG-221, an Oral, Selective, First-in-Class, Potent Inhibitor of the IDH2 Mutant Metabolic Enzyme, Induces Durable Remissions in a Phase I Study in Patients with IDH2 Mutation Positive Advanced Hematologic Malignancies [115]

Approximately 15 percent of acute myeloid leukemia (AML) patients harbor a mutation of the IDH2 gene, a genetic abnormality that leads to increased production of an oncometabolite known as 2-hydroxyglutarate (2-HG) that prevents immature white blood cells from developing into healthy adult infection-fighting white cells. This allows immature leukemic white cells to accumulate and crowd out normal red cells (causing anemia) and platelets, leading to the development of AML. By inhibiting this mutated IDH2 enzyme, AG-221 has shown efficacy in treating IDH-2 positive AML and myelodysplastic syndromes.

In an ongoing Phase I study to evaluate the safety and maximum tolerated dose of the IDH2 inhibitor AG-221, 45 patients with IDH2 mutant AML or pre-leukemia (including myelodysplastic syndromes, chronic myelomonocytic leukemia, and myeloproliferative neoplasms) received the agent once or twice daily at escalating doses up to 150 mg and 200 mg, respectively and were evaluable for efficacy; as of the most recent safety and efficacy analysis of trial data the maximum tolerated dose had not yet been reached. Responses were observed in 25 patients (56%), including complete remissions in 15, and partial remission in 10 additional patients. Further, responses have been durable, as participants have experienced complete remissions lasting as long as eight cycles of treatment to date, and many patients continue to be treated with AG-221. Overall, this agent has been better tolerated than conventional chemotherapy for relapsed leukemia.

"These early results in this hard-to-treat population demonstrate that when we inhibit mutant IDH2, we can transform leukemia cells into healthy, normal adult white blood cells and eradicate disease without the use of traditional chemotherapy," said lead study author Eytan M. Stein, MD, of Memorial Sloan Kettering Cancer Center in New York. "This approach to treat leukemia is revolutionary and represents the future of treatment for hematologic diseases. Our goal is to treat patients with therapy that is targeted to the specific genotype of their disease, thereby increasing efficacy, extending patients' life spans, and minimizing toxicity."

Dr. Stein will present this study during an oral presentation at 4:30 p.m. PST on Sunday, December 7, in rooms 2001-2003-2014-2016, of Moscone West.

Compound Improves Survival in Aggressive AML with Manageable Added Toxicity in Phase III Trial

Improved Survival in Patients with First Relapsed or Refractory Acute Myeloid Leukemia (AML) Treated with Vosaroxin Plus Cytarabine Versus Placebo Plus Cytarabine: Results of a Phase 3 Double-Blind Randomized Controlled Multinational Study (VALOR) [LBA-6]

Effective and safe therapies are critically needed for patients with relapsed or treatment-resistant acute myeloid leukemia (AML), a disease for which there is currently no standard of care or approved treatments. The chemotherapy agent cytabarine has been used since the 1960s either alone or in combination with other agents to treat aggressive AML; however these cytarabine-based treatment approaches are associated with substantial adverse effects and are not effective for many patients. By combining cytabarine with new agents, researchers hope to develop an effective treatment for AML that does not cause significant additional toxicity. One such agent is vosaroxin, a therapy that can induce cancer cell death by causing site-specific DNA damage. Researchers have investigated this compound in a Phase III randomized trial to evaluate its ability to overcome the limitations of current therapies without the cardiotoxicities commonly observed with other treatments.

In the trial, 711 adult AML patients at 124 sites worldwide with relapsed disease or disease unresponsive to other therapies were randomized to receive cytarabine together with either vosaroxin or placebo. Patients treated with vosaroxin achieved longer overall survival compared to those treated with placebo (7.5 months vs. 6.1 months), but this difference did not achieve statistical significance (p=0.06). When censoring for transplantation, however, the survival benefit was statistically significant (p= 0.02). Patients who received vosaroxin were also more likely to achieve complete responses (CR) to the treatment (30.1% experiencing CR in the vosaroxin arm vs. 16.3% in the placebo arm). Patients 60 or older and those experiencing early relapse experienced the greatest overall survival benefit from the treatment. Early mortality was similar in the two arms, and the most common adverse events in both groups included neutropenia, sepsis, infection, and mouth sores. "In this study, one of the largest randomized trials conducted in the setting of relapsed/refractory AML, the combination of vosaroxin and cytarbine demonstrated longer survival time and almost double the complete response rates compared to cytarabine alone. The benefit was particularly visible in older patients, who experienced manageable added toxicity," said lead study author Farhad Ravandi, MD, of The University of Texas MD Anderson Cancer Center in Houston. "Although it is clear that we still have a long way to go to improve outcomes for such patients, these data provide support that the vosaroxin/cytarabine combination is the most effective approach to date for treatment of older patients with this challenging condition."

Dr. Ravandi will present this study during the Late-Breaking Abstracts Session at 7:30 a.m. PST on Tuesday, December 9, in Hall D of Moscone North.



Source: Eurekalert
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