Studies Assess Role of Genetics, Modified Treatment Strategies to Improve Outcomes and Reduce Toxicity for Patients with Blood

  Studies Assess Role of Genetics, Modified Treatment Strategies to Improve
         Outcomes and Reduce Toxicity for Patients with Blood Cancers

PR Newswire

ATLANTA, Dec. 8, 2012

ATLANTA, Dec. 8, 2012 /PRNewswire-USNewswire/ -- Research identifying genetic
factors that affect survival of patients with blood cancers and evaluating the
effectiveness of modified treatment strategies to improve outcomes while
reducing toxicity will be presented today at the 54th Annual Meeting of the
American Society of Hematology (ASH).

While the cancer research community has seen many significant therapeutic
advances over the last decade, only recently have investigators identified how
patients' individual genetic makeup influences their short- and long-term
response to therapy, demonstrating that while the disease may respond
positively to therapy, the patient may not. Current studies take these
insights a step further, examining specific patient subpopulations to
determine their risk for negative outcomes and whether early preventive
interventions or treatment adjustments may help avoid treatment-related
toxicity.

"Data presented today offer important insights into how and why patients
respond to blood cancer treatment," said William G. Woods, MD, moderator of
the press conference, Pediatric Hematology/Oncology Director, and the Daniel
P. Amos Children's Chair of the Aflac Cancer Center and Blood Disorders
Service at Children's Healthcare of Atlanta. "Findings from these studies help
further support the notion of one day personalizing cancer treatment to the
individual, rather than to the disease, to improve survival and reduce
toxicity."

This press conference will take place on Saturday, December 8, 2012, at 10:00
a.m. EST.

WT1 SNP rs16754 Genotype Predicts Treatment Related Mortality (TRM) in
African-American and Asian Pediatric AML Patients: A Report From the
Children's Oncology Group [Abstract 1385]

New research suggests that the presence of a specific genetic marker, known as
WT1  SNP rs16754, may be associated with reduced toxicity from chemotherapy in
African-American and Asian children with acute myeloid leukemia (AML).

AML, the second most common form of leukemia in children, is a blood cancer in
which the bone marrow makes a large number of abnormal white blood cells that
crowd out other healthy blood cells over time, leading to infection, anemia,
or excessive bleeding. Although 60 to 70 percent of children with AML achieve
long-term remission after treatment with multi-agent chemotherapy, the
treatment-related mortality (TRM) associated with this intensive treatment
regimen remains a major concern for this patient population. Recently,
researchers have developed models that use sophisticated genome sequencing
techniques to better understand how patients' genetic makeup may influence
their risk of TRM.

The WT1 gene, a tumor suppressor that regulates cell growth, can be subject to
"loss-of-function" mutations that lead to the development of AML. Unlike
genetic mutations, single-nucleotide polymorphisms (SNPs, naturally occurring
variations in the DNA that determine an individual's unique genetic makeup)
are not typically thought to play a role in leukemia development or treatment
response. However, researchers recently discovered that the presence of SNP
rs16754 in the WT1 gene is correlated with improved outcomes in pediatric
patients with AML. Based on the fact that the frequency of SNP rs16754 varies
by race, researchers assessed the effect of this SNP on outcomes in specific
ethnic patient groups.

To determine if the presence of SNP rs16754 affected survival, remission,
relapse risk, and TRM in pediatric AML patients of different ethnicities, a
team of investigators analyzed the DNA of 492 children with AML enrolled in
the CCG-2961 protocol, a Phase III Children's Cancer Group trial. The
intensive treatment regimen delivered to patients during CCG-2961 allowed
researchers to study the effects of ethnicity on patient outcome, while
minimizing non-biological influences such as access to care or oral medication
compliance. Of the 492 patients, 138 (28%) had the SNP rs16754 (SNP+). After
stratifying the patients by ethnicity, the investigators found that the
presence of SNP rs16754 varied by race, with 53 percent of Asians, 34 percent
of Hispanics, 25 percent of Caucasians, and 21 percent of African Americans
carrying the genetic variation. The SNP+ patients had higher five-year overall
survival rates than those without the variation (SNP-) (61% vs. 44%). Within
each racial subgroup, the five-year overall survival rate was higher in the
SNP+ patients.

Although survival improvements in leukemia clinical trials are often
attributed to increased remission rates or decreased relapse, remission and
relapse rates did not differ significantly between SNP+ and SNP- patients in
this study. The investigators examined whether the SNP had any association
with TRM and found that TRM rates did not differ by SNP rs16754 genotype when
all ethnicities were considered together. However, TRM rates in SNP+
African-American and Asian patients, when taken together, were significantly
lower than in SNP- patients of those two ethnicities. African-American and
Asian patients without SNP rs16754 had significantly higher rates of
treatment-related toxic death compared to SNP+ patients (African-American: 25%
vs. 0%; Asian: 43% vs. 0%). These results suggest that the protective effect
of the presence of SNP rs16754 in reducing chemotherapy-related toxicity in
pediatric AML patients is more pronounced in those of African-American and
Asian descent.

"Identifying the patient-specific factors that can affect responses to
treatment in different patients with the same disease brings us closer to our
goal of designing personalized treatments that provide the most therapeutic
benefit with the least amount of toxicity to these children," said Phoenix Ho,
MD, lead author and Attending Physician at Seattle Children's Hospital in the
Division of Pediatric Hematology/Oncology at the University of Washington
School of Medicine and Research Associate at the Fred Hutchinson Cancer
Research Center in Seattle. "Our analysis was conducted on a trial completed
in 2002, and treatment protocols for pediatric AML have evolved since that
time. Our next step is to validate our findings by studying this same
association in contemporary trials. We are also designing studies to uncover
the mechanism behind the association between the SNP and reduced toxicity,
with the hope of translating these findings into improved treatments for
pediatric AML."

Dr. Ho will present this study in a poster presentation on Saturday, December
8, at 5:30 p.m. EST at the Georgia World Congress Center in Hall B1-B2, Level
1, Building B.

Genetic Susceptibility to Anthracycline-Related Congestive Heart Failure (CHF)
in Survivors of Hematopoietic Cell Transplantation (HCT) [Abstract 589]

Researchers have identified specific genetic factors that are associated with
heart failure in patients who have undergone hematopoietic stem cell
transplantation (HCT) for blood cancer.

The transplantation of blood-forming stem cells from the bone marrow,
circulating blood, or umbilical cord blood is the primary treatment option for
many patients with blood cancer who relapse after receiving standard
front-line therapies. During the transplant, healthy stem cells replace
damaged cells that caused the illness, effectively curing patients of their
disease. Advances in transplant strategies have led to a growing number of
long-term survivors of HCT. However, this growing population of survivors is
at risk for developing life-threatening complications such as congestive heart
failure, due in large part to their exposure to pre-HCT treatments with a
class of chemotherapy drugs called anthracyclines. Transplant survivors tend
to develop heart failure earlier than the general population, and the overall
survival rate following diagnosis is less than 50 percent.

By analyzing transplant patient demographics such as age and gender, treatment
strategy (i.e., pre-HCT chemotherapy and chest radiation), and presence of
cardiovascular risk factors such as high blood pressure, diabetes, and high
cholesterol, researchers have been able to create a clinical profile to
determine which patients are likely to develop heart failure after transplant.
However, this current profile is limiting, as it fails to accurately explain
the wide variability in the risk of heart failure between individual patients.
Importantly, it does not account for how individuals' genetic makeup can
exacerbate their risk of developing heart failure.

Seeking additional insight into how genetics can influence the risk for
developing heart failure later in life, researchers conducted a case-control
study to identify the genetic pathways that may make certain transplant
survivors more sensitive to the toxicities of pre-transplant chemotherapy and
subsequently increase their risk of heart failure. In this study, the
investigators evaluated specific genes responsible for the breakdown of
anthracyclines into toxic byproducts (CBR1, CBR3, NQO1, MRP1, and MRP2),
defense from oxidative stress, a condition that causes damage to healthy heart
cells (NCF4, RAC2, CYBA, SOD), iron overload (HFE), and blood pressure and
heart rate regulation (AGT, AGTR1, ACE and ADRB1, ADRB2) in 77 patients with
leukemia, lymphoma, and myeloma who underwent a transplant at City of Hope
between 1988 and 2007 and later developed congestive heart failure.
Investigators matched the survivors with 178 controls (transplant survivors
who did not experience heart failure).

After comparing the genetic makeup of the transplant survivors who developed
heart failure to their controls, researchers found that patients who had
variations in the MRP2, RAC2, and HFE genes had up to a three-fold higher risk
of developing heart failure after transplant; these genes are responsible for
key proteins that regulate the metabolism of anthracyclines and defense
against oxidative stress. Females with two or more genetic variations were at
the highest risk of developing the conditions when compared to males with one
or none of these variations. The discovery of these genetic variations
supplements previously identified clinical variables known to affect a
transplant survivor's heart health.

"Following this study we now have a much better profile of those transplant
survivors who are likely to develop heart failure," said Saro Armenian, DO,
MPH, lead author and Assistant Professor in the Division of Outcomes Research
and Medical Director of the Pediatric Survivorship Clinic in the Childhood
Cancer Survivorship Program at City of Hope in Duarte, Calif. "Armed with
these insights, we can now create better screening measures and perhaps even
tailor intervention strategies based on a patients' genetic makeup, minimizing
long-term transplant-related toxicity and making a tremendous difference in
the long-term health of these patients."

Dr. Armenian will present this study in an oral presentation on Monday,
December 10, at 2:45 p.m. EST at the Georgia World Congress Center in Room
C108-C109, Level 1, Building C.

Daunorubicin or Not During the Induction Treatment of Childhood Standard-Risk
B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): The Randomized
Fralle 2000-A Protocol [Abstract 135]

New data demonstrate that omitting the chemotherapy drug daunorubicin from an
initial treatment regimen for children with standard-risk acute lymphocytic
leukemia (ALL) does not reduce survival outcomes, suggesting that these
children may be able to achieve positive outcomes without having to endure a
treatment associated with both short- and long-term toxicities.

ALL, the most common form of leukemia in children, is a fast-growing cancer of
the white blood cells in which the bone marrow makes a large number of
abnormal white blood cells that are unable to develop and fight infection.
Important developments over the past 20 years have led to seminal insights
about ALL in children, and today nearly 90 percent of children diagnosed with
standard-risk ALL are cured. Some treatment regimens for standard-risk ALL
include initial infusions of daunorubicin, a type of anthracycline. While
effective, continual use of this therapy is associated with potential
long-term heart damage, leading researchers to assess whether eliminating or
reducing the dosage of daunorubicin during the initial one-month induction
therapy period might provide the same level of efficacy as the standard
treatment protocol with reduced long-term risk.

In order to assess the efficacy of ALL treatment without daunorubicin during
induction therapy, a team of researchers from 20 centers across France and one
center in Belgium initiated a multicenter Phase III clinical trial in which
1,128 pediatric patients with standard-risk B-cell ALL were randomized into
two treatment arms. Arm A included 560 patients who received a standard dose
of daunorubicin during induction therapy, while Arm B included 568 patients
who did not receive initial therapy with daunorubicin. Both groups received
doxorubicin during delayed intensification (last treatment phase before
reaching maintenance) and a standard protocol of 24-month maintenance therapy
from December 2000 to June 2010, during which five-year event-free survival
(EFS) and overall survival (OS) were assessed.

For those patients treated with daunorubicin, the five-year EFS rate was 92.9
percent, compared to 93.3 percent in the non-daunorubicin arm. Overall
survival rates were 97.2 percent and 98.2 percent in the daunorubicin and
non-daunorubicin arms, respectively. Measurements of minimal residual disease,
in which a small number of leukemic cells remain during treatment, were also
equivalent in the two study arms. These results demonstrate similar efficacy
rates of treatment strategies for standard-risk ALL that do or do not include
induction treatment with daunorubicin.

"Our study data have the potential to benefit children with ALL in two
important ways," said Andre Baruchel, MD, lead author and Head of the
Department of Pediatric Hematology at the Robert Debré University Hospital
(Assistance Publique Hôpitaux de Paris) in Paris. "First, we now have strong
evidence that reducing the amount of chemotherapy initially administered to
these children, who constitute the majority of ALL patients, does not
negatively affect their immediate outcome. Perhaps more importantly, we know
and anticipate that removing harmful chemotherapy from their treatment can
help minimize their risk of experiencing heart damage later in life."

Dr. Baruchel will present this study in an oral presentation on Sunday,
December 9, at 5:00 p.m. EST at the Georgia World Congress Center in Room
A103, Level 1, Building A.

ATRA and Arsenic Trioxide (ATO) Versus ATRA and Idarubicin (AIDA) for Newly
Diagnosed, Non High-Risk Acute Promyelocytic Leukemia (APL): Results of the
Phase III, Prospective, Randomized, Intergroup APL0406 Study by the
Italian-German Cooperative Groups Gimema-SAL-AMLSG [Abstract 6]

New research demonstrates the efficacy of the first curative treatment for
acute promyelocytic leukemia (APL) that does not include chemotherapy, marking
an important step toward front-line use of targeted therapies for acute
leukemia.

APL is an uncommon, yet aggressive, subtype of acute myeloid leukemia (AML) in
which there are too many immature white blood cells in the bone marrow,
leading to a shortage of normal white and red blood cells and platelets in the
blood, which is associated with clotting defects that can cause serious
bleeding. Without prompt diagnosis and treatment, APL can be fatal in a matter
of hours or days.

Early treatment regimens for APL relied heavily on anthracycline-based
chemotherapy with daunorubicin or idarubicin. In the early 1990s, research
supported the addition of a non-chemotherapeutic agent, all-trans-retinoic
acid (ATRA, a vitamin A derivative developed from ancient Chinese herbal
medicine), to standard regimens. ATRA causes cancer cells to develop fully
into mature blood cells, which progress through full differentiation and
eventually die (unlike leukemia cells that are unable to fully mature). The
combination regimen of chemotherapy and ATRA dramatically improved the
survival outlook for those with APL and made the disease curable in up to 80
percent of patients. More recently, another natural compound, arsenic trioxide
(ATO), was integrated into APL treatment, showing higher efficacy and better
tolerability when compared with conventional chemotherapy. Today, as
investigators continue to report the success of targeted cancer therapies
(best exemplified by imatinib for chronic myeloid leukemia), researchers have
questioned whether traditional toxic chemotherapy is still necessary to
achieve high cure rates for patients with APL.

To investigate whether a combination of ATO+ATRA could provide the same
therapeutic benefit as conventional treatment including chemotherapy,
researchers from the Italian-German cooperative teams Gruppo Italiano Malattie
EMatologiche dell'Adulto (GIMEMA), Study Alliance Leukemia (SAL) group, and
German-Austrian AML Study Group (AMSLG) designed a multicenter, international
Phase III trial in which 162 patients with standard-risk APL were divided into
two treatment arms. Patients in Arm A received a regimen of ATO+ATRA, while
patients in Arm B received the standard ATRA+idarubicin (AIDA) treatment
regimen. The primary study objective was event-free survival (EFS) at two
years, with secondary objectives including overall survival (OS), disease-free
survival (DFS), cumulative incidence of relapse (CIR) rates, molecular
response, and safety.

Results suggest that the targeted ATO+ATRA therapy strategy might offer
similar efficacy to the chemotherapy-based regimen. In the 154 patients who
were evaluable for response, complete remission was achieved in all patients
(100%) in the ATO+ATRA arm and 95 percent in the AIDA arm. EFS was observed in
97 percent in the ATO+ATRA arm, with one death and two relapses, compared to
86.7 percent in the AIDA arm, in which seven deaths and four relapses were
observed. Overall survival, DFS, and CIR rates were 98.7 percent, 97 percent,
and 1.6 percent, respectively, in the ATO+ATRA arm, versus 91.1 percent, 91.6
percent, and 4.3 percent, respectively, in the AIDA arm. Additionally, fewer
side effects (fever, low neutrophil and platelet counts) were observed in the
ATO+ATRA arm.

"This is one of the first times that we can report the success of a treatment
strategy for an acute leukemia that relies solely on targeted molecular
therapy," said Francesco Lo-Coco, MD, lead author and Chairman of the APL
subcommittee of the Italian GIMEMA group and Professor of Hematology at
University Tor Vergata in Rome, Italy. "Our results are an important step
toward the further utilization of targeted therapies for other types of
leukemia, as we begin to focus on improving the overall treatment experience
for patients by offering new strategies that deliver the same efficacy as
traditional options with considerably lower toxicity."

Dr. Lo-Coco will present this study during the Plenary Scientific Session on
Sunday, December 9, at 3:45 p.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) and hard-to-treat blood disorders, 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, visitwww.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

Website: http://www.hematology.org
Contact: Amanda Hesse, +1-609-529-8980, amanda.hesse@fleishman.com, for
Fleishman-Hillard; or Andrea Slesinski, +1-614-352-5096,
aslesinski@hematology.org, for ASH; or Georgia World Congress Center (Dec.
8-11), +1-404-222-5936; if you need to reach Andrea after hours, call her at
+1-614-352-5096
 
Press spacebar to pause and continue. Press esc to stop.