Biomarkers recent-advances-in-their-application-to-the-treatment-of-hematologic-malignancies

WHITE PAPER
Executive Summary
Biomarkers hold promise in the diagnosis, prognosis and therapeutic stratification of hematopoietic malignancies.
These heterogeneous diseases – including multiple myeloma, lymphomas and leukemias – are frequently characterized
cytogenetically with diagnoses supported by genetic, immunohistochemical and flow cytometric analyses. Biomarkers
offer the hope of early detection as well as tracking disease progression and recurrence. Early detection may help improve
survival, as it could help identify individuals most at risk for disease development, distinguish aggressive from indolent
disease, and track disease progression. In therapeutic stratification, biomarkers potentially allow for patient-specific selection
of agents that are likely to be effective and not cause unnecessary toxicity. Notable clinical advances were reported at the
54th Annual American Society for Hematology Conference (December 7-11, 2012; Atlanta, GA), suggesting that through
innovative, biomarker-based approaches, better outcomes can be achieved with lower doses of drugs. Additionally,
recent progress in the characterization of the molecular genetics of various hematologic malignancies may form the basis
for improved patient stratification and future targeted/individualized therapies. Integration of clinical, cytogenetic and
molecular data will be indispensible in translating this progress into better outcomes for patients. There is also a need
for standardization of the technologies used for clinical assessment of minimal residual disease – enabling detection of
lingering disease burden after treatment – and their interpretation. In the future, for treatment of hematologic malignancies
to become affordable and value-driven, continued investment in biomarker discovery and the elucidation and application of
prognostic/predictive biomarkers will be needed. This has the potential to identify genetic associations and profiles that can
be drugged or targeted, ultimately putting the promise of personalized medicine within reach.
Biomarkers: Recent Advances in their Application to
the Treatment of Hematologic Malignancies
Harish Dave, M.D., MBA, Vice President, Global Medical Strategy Head, Hematology and Oncology, Oncology Therapeutic Area, Quintiles
Chris A. Learn, Ph.D., PMP, Senior Clinical Project Manager, Oncology Therapeutic Area, Therapeutic Delivery Unit, Quintiles
Ronald Lieberman, M.D., Senior Director, Hematology, Oncology and Transplantation, Oncology Therapeutic Area, Quintiles

www.quintiles.com | 2
table of contents
Myelomas 4
Lymphomas 5
Hodgkin and Non-Hodgkin Disease 5
Diffuse large B-cell Lymphoma 5
Other B cell Lymphomas 7
Chronic Lymphocytic Leukemia 7
Acute Myeloid Leukemia 8
Conclusion 9
References 11
About the Authors 14
table of contents

3 | www.quintiles.com
The use of biomarkers is becoming an increasing focus of hematology clinical research,
providing potential support for the diagnosis, prognosis and therapeutic stratification of
patients with hematopoietic malignancies. These uses are further supported by the fact
that most hematopoietic malignancies are widely disseminated even in their “early” stages,
and often do not have a well-defined localized phase, making them less amenable to
conventional early screening methods such as imaging and observation.
To this end, biomarkers offer the hope of early detection as well as for the tracking of
disease progression and recurrence of hematopoietic malignancies.1
Early detection may
help improve survival, as it would be particularly useful in (1) identifying individuals most
at risk for disease development, (2) distinguishing aggressive from indolent disease, and
(3) tracking disease progression from a benign or pre-neoplastic state. In therapeutic
stratification, biomarkers potentially allow for patient-specific selection of therapeutic agents
that are likely to be effective and not result in unnecessary toxicity.
Hematopoietic malignancies, which include a heterogeneous group of diseases such as
multiple myeloma, lymphomas and leukemias, are frequently characterized cytogenetically
with diagnoses supported by genetic, immunohistochemical and flow cytometric analyses.
To date, few biomarkers for the early detection, progression or risk assessment for such
malignancies have been identified or clinically validated.2
These standard diagnostics work
best in the setting of advanced disease. As a result, many patients are diagnosed at advanced
disease stages when therapies are less effective and typically result in higher mortality rates.
Furthermore, the vigorous interventions required for advanced disease also negatively affect
quality of life and impose a significant financial burden on both patients and payers. Given
that the diagnosis of these malignancies is still based largely on morphological criteria, as it
has been for decades, improving outcomes without more detailed genetic and mechanistic
information is a significant challenge, especially when trying to predict a given cancer’s
potential for progression and response to treatment. Thus, the need to identify and validate
clinically relevant biomarkers that yield informative associations with disease progression
and outcome in myeloma, lymphomas and leukemias remains urgent.
However, there are some reasons for optimism. At the 54th Annual American Society
for Hematology Conference held December 7-11, 2012 in Atlanta, Georgia, USA, notable
progress over the previous year was demonstrated regarding clinical advances in the
treatment of various hematologic malignancies. A unifying theme that arose from those
scientific presentations was that through innovative means, better outcomes with lower
doses of drugs can be achieved. As noted with each publishable finding resulting from these
studies, an improved understanding of underlying biology through biomarkers was the
foundation for these clinical advances, and for their potential future advancement.
Additionally, recent progress in the characterization of the molecular genetics of various
hematologic malignancies has validated recurrent cytogenetic and mutational changes
in leukemic blasts. These changes have been demonstrated to have high prognostic
significance, and may serve as a future opportunity for treatment. Yet, despite this progress,
the understanding of the mechanisms by which these changes influence cancer growth
and response to treatment is still limited, restricting the development of rationally targeted
therapies. The integration of clinical, cytogenetic and molecular data will therefore be
indispensable in translating this current progress into better outcomes for patients with
blood cancers.
Biomarkers offer the
hope of early detection,
which would be
particularly useful in:
• identifying individuals
most at risk for disease
development
• distinguishing
aggressive from
indolent disease, and
• tracking disease
progression from
a benign or pre-
neoplastic state.

This paper examines the potential of recent biomarker-related technological advances and
applications for several key hematopoietic malignancies for the purpose of improving the
current clinical picture of disease management and outcome.
Myelomas
Advances in genomics and proteomics have improved the understanding of myeloma
pathogenesis, identifying novel mediators of the disease process, and potential therapeutic
targets.3
These developments have allowed for molecular classification of the disease,
yielding new diagnostic tools for myeloma, and better monitoring of disease status.
Recent advances in investigative techniques that have refined the diagnostic work-up for
myeloma include serum-free light chain ratios,4
use of MRI and PET scans in diagnosis
and managing bone disease, and use of cytogenetics and fluorescent in situ hybridization
(FISH) to assess prognosis. Newer risk stratification protocols include international staging
systems and chromosomal changes detected using FISH. Given the application of these
techniques, predictive risk stratification models are now used to guide treatment algorithms,
and response categories are also being redefined as novel therapies have achieved
complete responses in a significant number of patients. Recent studies have confirmed the
importance of achieving complete remission in extending overall survival.5,6
Interrogation
methods for cancer cell DNA, such as high-throughput expression profiling, high-density
single nucleotide polymorphism (SNP) arrays and array-based comparative hybridization
(aCGH), are now increasingly utilized to better understand myeloma pathobiology.7,8
Such
efforts have also been applied to gene discovery, biomarker identification, and delineation
of patient subgroups with the goal of offering individualized therapy. Novel biomarkers
recently identified for myeloma include circulating progenitor endothelial cells,9
circulating
micoRNAs,10
angiopoietins,11
and serum B-cell activating factor,12
all of which have
demonstrated an association with worsened prognosis in patients.
Multiple myeloma (MM) is the second most prevalent hematological malignancy in the
U.S. (after non-Hodgkin lymphoma) and develops in 1–4 per 100,000 people per year
in adults, and despite extensive information on its molecular biology and significant
advances in therapeutics, this disease retains a high mortality.13
The identification of novel
biomarkers, especially through the use of mass spectrometry, is expected to help in the
diagnosis, prognosis and therapeutic stratification of MM. Mass spectral analysis has been
used to identify new serum biomarkers that may distinguish between MM patients and
normal individuals. Additionally, this technique has enabled the identification of biomarkers
indicating resistance to several chemotherapeutic drugs used for the treatment of MM.
It has also been used to investigate the signaling networks involved with the disease, the
results of which are expected to guide future studies of MM pathogenesis.
Perhaps one of the greatest promises of mass spectrometry will be its use in helping direct
therapy.13
“Since current ‘one size fits all’ therapy is complicated by serious toxicities and
may be unnecessary in some good prognosis patients, it is critical to introduce risk-adapted
therapy,” write Micallef and Dharsee in a 2010 Journal of Hematology & Oncology paper.13
This approach will require better prognostic markers, since current prognostic models are
inadequate for predicting disease outcome in individual patients. Protein expression profiling
by mass spectrometry holds promise in identifying biomarkers for improving the diagnosis
and prognosis of MM. As such, this will also help advance understanding of the mechanisms
of drug resistance, which will invariably aid in directing therapeutic strategies.
Multiple myeloma
is the second most
prevalent hematological
malignancy in the U.S.
(after non-Hodgkin
lymphoma).

Lymphomas
Hodgkin and Non-Hodgkin Disease
Lymphoma is actually a name covering a set of diseases associated with lymphocytes and
may include acute, aggressive and indolent forms, each with its own set of problems. Non-
Hodgkin lymphoma (NHL) is the most prevalent hematologic malignancy in the U.S. with
an estimated incidence of 69,760 cases in 2013.14
Prediction of outcomes in patients with
lymphoma is a major challenge for clinicians.15
Recently, gene-expression profiling has enabled identification of specific gene expression
signatures that are associated with distinct genetic alterations and differing survival rates in
various lymphomas. From these studies, signatures that included increased expression of
MCL1, BCL6 and/or CFLAR demonstrated a decreased chance of achieving stable disease or
better, while those gene profiles that experience decreased expression of CDKN1B correlated
with lower progression survival16
in patients with relapsed/refractory NHL.
The importance of the tumor microenvironment has been demonstrated in classical
Hodgkin Lymphoma (cHL). Multiple reports now support the value of enumerating tumor-
associated macrophages in pretreatment biopsies for outcome prediction in cHL. Kamper
et al. used immunohistochemistry to investigate a large number (n = 288) of pretreatment
biopsies from patients with cHL and found a significant correlation between tumor-
associated macrophages and adverse treatment outcome. Furthermore, these investigators
demonstrated a previously unrecognized association of CD68+ macrophages with latent
Epstein-Barr virus (EBV) infection of the tumor cells.17
This study, together with others,18,19
strongly suggests that the number of CD68+ macrophages can be used as a reliable
biomarker in cHL and NHL.
Diffuse large B-cell lymphoma
Significant progress was made in the mid-1990s when an international group set up the
International Prognostic Index (IPI) for diffuse large B-cell lymphoma (DLBCL). DLBCL is
the most common type of non-Hodgkin lymphoma among adults with an annual incidence
of 7-8 cases per 100,000 people per year in the U.S. Many studies now suggest that cases
of DLBCL can be separated into two groups on the basis of their gene expression profiles
(GEP); these groups are known as germinal centre B-cell-like (GCB) and non-GCB or
activated B-cell-like (ABC). Risk stratification for DLBCL is important since the GCB subtype
has a better prognosis and more favorable response to current standard of care therapy with
RCHOP compared to the ABC subtype.20
While GEP is recognized as the gold standard for
the molecular classification of DLBCL subtypes, considerable progress has been made in
developing less technically complex classification algorithms with immunostains such as the
Choi algorithm. Using highly specific antibody-based immunostains of GCET1, CD10, BCL6,
MUM1, and FOXP1 proteins, this new algorithm closely approximated the GEP classification
of DLBCL into GCB and ABC subtypes with 93% concordance.21
These new immunostain
based algorithms are being used increasingly in clinical trials of novel agents for risk
stratification of DLBCL.
Diffuse large B-cell
lymphoma is the most
common type of non-
Hodgkin lymphoma
among adults.

In addition, various genetic features, such as IRF4 translocations, gains in 1q21, 18q21, 7p22,
and 7q21, as well as changes in 3q27, including gains and translocations affecting the BCL6
locus, are significantly associated with increased patient age and worsened prognosis in
DLBCL.22
Clearly, an improved understanding of the biology of biomarkers such as these and
their specific contribution to prognosis and outcome will be paramount. Another notable
finding of recent gene expression studies is the importance of the cells and microscopic
structures interspersed between the malignant B cells within the DLBCL tumor, an area
commonly known as the tumor microenvironment. The presence of gene expression
signatures commonly associated with macrophages, T cells, and remodelling of the
extracellular matrix seems to be associated with an improved prognosis and better overall
survival. In contrast, expression of genes coding for pro-angiogenic factors is correlated with
poorer survival.23
The LLBC study concluded that variations in biologic features are largely overshadowed by
the IPI for prognostic impact, and that biomarkers only allow subtle refinements of the IPI.
Attempts to build an index using biomarkers alone, or the combination of biomarkers with
IPI individual factors (instead of IPI categories) did not result in an improved model fit or
discrimination, the authors note.15
The inability of biomarkers to further stratify outcomes
“may reflect the importance of patient characteristics over biologic characteristics of
tumor cells in this patient subset.” However, biomarkers may contribute to defining more
homogeneous biologic subsets of DLBCL for which targeted therapies can be investigated.
The study also concluded that attempts to validate immunohistochemical (IHC) biomarkers
for prognostic stratification of patients “clearly require large cohorts and reproducible
methodology that allows for the control of cofactor interactions. In this regard, stratification
based on biomarkers for guiding treatment options should be viewed cautiously.” The
authors conclude that the IPI remains the best available index in patients with DLBCL treated
with rituximab and chemotherapy.15
Some progress may be possible with more reliable IHC,
cytogenetic or molecular markers, but their assessment as prognostic factors will require
careful evaluation before they can be routinely used in clinical practice.
Other B cell Lymphomas
Several lymphoma types, such as follicular lymphoma (FL), mantle cell lymphoma (MCL),
and Burkitt lymphoma (BL), are linked with hallmark translocations due to errors when the
physiologic mechanisms involved in generating immunologic diversity go awry.24
However,
the associations are not absolute and none is completely diagnostically specific or sensitive,
leading to the absence of clinically relevant biomarkers for these indications. In a 2011
Hematology paper, Bagg also writes that it is not necessary to perform any kind of genetic
testing to render a diagnosis, but it is clear that genetic factors and/or cell-of-origin data
are key determinants of prognosis as well as of specific subtypes. Nonetheless, in spite of
a decade of investigation, none of the interesting data from gene expression profiling and
other technologies has translated into routine clinical practice. “For now, unless a patient is
not a candidate for aggressive therapy, it might be appropriate to consider screening all such
lymphomas for not only MYC translocations, but also BCL2 and BCL6 translocations, as
well,” concludes the author.

Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in the western world;
it is estimated there will be 15,680 new cases and 4,580 deaths from CLL in the USA in
2013.25
The clinical course of this disease is remarkably heterogeneous. As such, some
patients have relatively aggressive disease requiring early treatment, while others have highly
indolent disease that does not require treatment for decades.26
Current staging systems
have not been able to predict which patients in early or intermediate risk stages will undergo
disease progression and which will undergo an indolent course. Universal treatment of
all patients with early stage disease has been shown to be more harmful than beneficial.
As such, early identification of patients who will have more aggressive disease soon after
diagnosis has been a major goal in CLL research. However, several clinical parameters
have been identified that are predictive of the clinical course. As mentioned below, there
are a number of molecular biomarkers that have been identified and verified as providing
prognostic information, most involving cytogenetics by FISH, immunoglobulin heavy chain
(IgH) mutational status and expression of ZAP70. Regarding ZAP70, researchers have
utilized quantitative DNA methylation analysis to discover a single CpG dinucleotide that
plays an important role for ZAP70 expression, which has shown significant correlation with
prognosis status in CLL, so much so that it is likely to be incorporated as part of the clinical
staging of this disease going forward. A remaining challenge is to understand how to use
this information in clinical practice, and whether to alter treatment based on the detection of
“high-risk” features.
Of note, recent investigations into B-cell activation via the PI3K signaling pathway in
CLL have elucidated important biomarkers that have led to clinical advances with the
investigational drug ibrutinib. A primary focus of ASH 2012, ibrutinib has received
considerable attention given its ability to selectively inhibit Bruton’s tyrosine kinase (Btk),
a key component to B-cell activation and further intracellular signaling. To this end,
ibrutinib has been shown to decrease tumor cell chemotaxis towards chemokines, as well
as inhibit cellular adhesion following B-cell receptor (BCR) activation.27, 28
Thus, ibrutinib’s
purported mechanism of action is through the blockage of BCR signaling, resulting in
cellular apoptosis. Ibrutinib is currently under development for CLL, but is also being actively
investigated in mantle cell lymphoma, DLBCL, and MM.
While ibrutinib has clearly shown the clinical importance of specifically targeting Btk in
CLL, additional biomarkers in CLL are also under investigation and merit consideration
here. CD38+,29
miRNAs,30
and BCL-231
have all been shown to have significant associations
with clinical disease management and outcome in CLL. These studies also suggest, and as
mentioned earlier, the definition of predictive medicine and predictive tests is now being
expanded to include the risk-stratification of patients with early forms of a disease such
as CLL using biomarkers. For example, the overproduction of CD38+ and ZAP70 proteins
identifies those patients who will go on to develop the more aggressive form of the disease.
Rather than waiting until such patients develop more aggressive disease and require
treatment with both chemotherapy and monoclonal antibodies, treatment decisions can be
made earlier and with more confidence given the context of greater information and how to
more effectively target biomarkers such as these.
Chronic lymphocytic
leukemia is the most
prevalent leukemia
in the western world.
Some patients have
relatively aggressive
disease requiring early
treatment, while others
have highly indolent
disease that does not
require treatment for
decades.

Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a disease in particular need of relevant biomarkers to
improve decision-making. Like CLL, AML is a highly heterogeneous disease, lacking well-
defined biomarkers for clinical staging. As with other hematologic malignancies, there is
clear need for the ability to stratify patients with AML according to current disease status,
as well as for assigning patients with certain subtypes of this disease to available molecular
targeted therapies. Further complicating matters is the fact that many AML patients do not
feature any known molecular markers and therefore cannot be stratified. Given this lack
of information and knowledge on how best to treat, the clinical outcome for AML patients
remains poor.
At this time, approximately 12,000 adults are diagnosed with AML in the United States
annually, the majority of whom die from their disease32
, with 5-year survival for less than
25%.33
Currently, the worldwide standard of care for initial treatment, cytosine arabinoside
combined with an anthracycline, was developed approximately 40 years ago; further, as the
epidemiology of AML is biased towards older patients, a large fraction of patients are really
not candidates for this standard therapy. AML is a genetically heterogeneous disease, and
many patients can be categorized into clinicopathologic subgroups based on the underlying
molecular genetic defects. Greater specificity of diagnostic classification would be expected
to lead to more effective application of targeted agents and an ability to create personalized
treatment strategies. Roboz32
concludes that several strategies may accelerate the availability
of new drugs or treatment regimens in the clinic:
• Development of existing drugs in addition to searching for new ones – In pediatric acute
lymphoblastic leukemia, major improvements in outcomes have been achieved by
optimizing the combination, schedule, and duration of treatment using existing,
potentially outdated drugs.
• Increased accrual to clinical trials – Currently, fewer than 5% of adults with cancer in
the United States participate in clinical trials, while 60% of pediatric cancer patients
participate in trials.34
• Change the paradigm for drug development – For AML, there is growing realization
that the traditional phase 1-3 drug development paradigm is ineffective. Phase 1
trials typically provide novel agents to patients with relapsed and refractory disease,
a setting where non-cytotoxic, molecularly targeted agents have little chance of
success, and where signals of their true biologic efficacy may be missed. Some of
these agents should be considered instead for trials aimed at prolonging response
duration and survival in AML patients who have already achieved remission. Phase 2
trials in AML are often small and may also give misleading efficacy signals. “Given the
heterogeneity of the disease, subgroup analyses based at least on age, performance
status, cytogenetics, and molecular features are essential, yet these are meaningless
when the total cohort includes only 20-50 patients,” notes Roboz. “There is increasing
support for randomized phase 2 trials, including adaptive randomization and ‘pick-
the-winner’ strategies aimed at rapidly comparing new treatments with existing
standards of care, using as few patients as possible and to continue only with those
that meet predetermined efficacy benchmarks. Phase 3 trials in AML are described as
being “often unbearably slow and expensive to complete and, unfortunately, for the
Like chronic lymphocytic
leukemia, acute myeloid
leukemia is a highly
heterogeneous disease,
lacking well-defined
biomarkers for clinical
staging.

most part have resulted in only small improvements in outcome.” Also, as the number
of molecularly and clinically defined subgroups increases, it is ever more challenging
to determine a reasonable control arm for new Phase 3 trials. Roboz concludes: “It is
hoped that further refinements in the molecular characterization of AML will allow the
identification of more homogeneous treatment groups and tailored therapeutics.”32
In current clinical practice, a relatively small number of genetic abnormalities are used
to predict outcome and to direct therapy in AML. These include CBF translocations and
translocations associated with acute promyelocytic leukemia, which predict for favorable
outcome with induction/consolidation and for sensitivity to all-trans retinoic acid and
arsenic trioxide, respectively. Schlenk et al. have shown that mutational analysis of FLT3
in combination with NPM1 or CEBPA mutations can be used to predict outcome in
cytogenetically normal AML and to identify patients who will benefit from allogeneic
stem cell transplantation.35
However, a large number of AML patients lack any of these
abnormalities, so there remains significant heterogeneity in clinical outcome within currently
classified prognostic groups. These observations suggest there are additional biomarkers
that can predict outcome in AML. Recently, genetic studies have identified an increasing
number of recurrent somatic mutations in AML patients, including mutations in TET2,36,37
ASXL1,38,39
IDH140
and IDH2,41,42
DNMT3A43,44,45
and PHF6.46
In addition, several of these
newly identified genetic abnormalities have been shown to have prognostic importance in
AML.47
Haferlach48
notes that in AML, a diverse range of new compounds is under preclinical and
clinical investigation. A goal is to develop targeted treatment concepts that are based on
interference with molecular genetic or epigenetic mechanisms. The author writes that “future
therapy in AML will hopefully be based more on genetic and epigenetic targets that will be
individually defined for each patient.” Haferlach suggests that the search for new diagnostics
and therapeutic targets “should be conceived as integral parts, as only their perfect
interaction will be able to pave the way to targeted treatment for patients with AML.”48
Conclusion
Recent advances in understanding the pathogenesis of hematopoietic malignancies and the
advent of high-throughput technologies have the potential to facilitate rigorous translational
research toward the discovery, development, and clinical validation of novel biomarkers for
the early detection as well as for disease progression and recurrence.49
There is also a need
for the development and improvement of specific technologies and methods for quantitative
detection of novel biomarkers associated with these hematopoietic malignancies. Such
biomarkers – for early stage detection or for identification and stratification of groups at
risk for aggressive disease or for detection of minimal residual disease50
– may improve
overall survival rates by reducing the high levels of morbidity and mortality associated with
late stage diagnosis. To this end, careful clinical assessment of minimal residual disease
enables detection of lingering leukemia burden following treatment with improved sensitivity
compared to morphological analyses alone. Detection of residual burden following therapy
supports the notion that there is a clinically relevant value to treatment decisions based on
this type of analysis. Thus, the need for standardization of minimal technologies and their
interpretations must be emphasized.
In the future, the
investment in
biomarker discovery,
elucidation and
application will remain
necessary, if not
indispensable.

The challenges of patient stratification and treatment optimization through specific
biomarkers are inherently grounded in understanding the biology of those markers and
how to best utilize them in the clinic. Given the considerable complexity of the hematologic
malignancies we are dealing with, the discovery of determinant biomarkers is a critical
exercise. However, researchers will also have to effectively negotiate the full range of
difficulties of prospective verification and clinical validation for the most promising factors.
In the future, to make treatment of hematologic malignancies affordable and value-driven,
the investment in biomarker discovery, elucidation and application will remain necessary, if
not indispensable.
In summary, if the application of the aforementioned techniques continues to progress
genetic associations and profiles that can be either effectively drugged or targeted, then
efficacious personalized medicine for numerous hematologic malignancies is potentially
within reach.

References
1 http://grants.nih.gov/grants/guide/pa-files/PA-12-220.html
3 Munshi NC. Investigative Tools for Diagnosis and Management.
Hematology 2008;298-305
4 Larsen JT, Kumar SK, Dispenzieri A, Kyle RA, Katzmann JA, Rajkumar SV. Serum free
light chain ratio as a biomarker for high-risk smoldering multiple myeloma.Leukemia,
October 16, 2012.
5 Asher Chanan-Khan A, Giralt S. Importance of Achieving a Complete Response in
Multiple Myeloma, and the Impact of Novel Agents. JCO May 20, 2010 vol. 28 no. 15
2612-2624.
6 Hoering A, Crowley C, Shaughnessy JD, Hollmig K, Alsayed Y, Szymonifka J, Waheed
S, Nair B, van Rhee F, Anaissie E, Barlogie B. Complete remission in multiple myeloma
examined as time-dependent variable in terms of both onset and duration in Total
Therapy protocols. Blood, August 13, 2009 vol. 114 no. 7 1299-1305.
7 Sawyer JR. The prognostic significance of cytogenetics and molecular profiling in
multiple myeloma. Cancer Genetics, Volume 204, Issue 1, January 2011, Pages 3–12.
8 Monaghan, S.A., Dai, L., Mapara, M.Y., Normolle, D.P., Gollin, S.M., and Lentzsch, S.
Longitudinal bone marrow evaluations for myelodysplasia in patients with myeloma
before and after treatment with lenalidomide. Posted online on January
28, 2013. (doi:10.3109/10428194.2012.755177).
9 Circulating endothelial progenitor cells as potential prognostic biomarker in
multiple myeloma. Leukemia & Lymphoma. April 2012, Vol. 53, No. 4 , Pages 635-640
10 Jones CI, Zabolotskaya MV, King AJ, et al. British Journal of Cancer (2012) 107, 1987–1996.
11 Posted online on November 26, 2012, Leukemia & Lymphoma
12 Fragioudaki M, Tsirakis G, Pappa CA, et al. Leukemia Research, Volume 36, Issue 8,
August 2012, Pages 1004–1008.
13 Micallef J, Dharsee M, Chen J, Ackloo S, Evans K, Qiu L, Chang H. Applying mass
spectrometry based proteomic technology to advance the understanding of multiple
myeloma. Journal of Hematology & Oncology 2010, 3:13. http://www.jhoonline.org/
content/3/1/13
14 National Cancer Institute web page, Non-Hodgkin Lymphoma. http://www.cancer.gov/
cancertopics/types/non-hodgkin
15 Salles G, de Jong D, Xie W, Rosenwald A, Chhanabhai M, Gaulard P, Klapper W,
Calaminici M, Sander B, Thorns C, Campo E, Molina T, Lee A, PfreundschuhM,
Horning S, Lister A, Sehn LH, Raemaekers J, Hagenbeek A, Gascoyne RD, Weller E.
Prognostic significance of immunohistochemical biomarkers in diffuse large B-cell
lymphoma: a study from the Lunenburg Lymphoma Biomarker Consortium. Blood (June
2011);117(26):7070-78.
16 British Journal of Haematology, July 2012, Volume 158, Issue 2, Pages 153–296.

17 Kamper P, Bendix K, Hamilton-Dutoit S, et al. Tumor-infiltrating macrophages correlate
with adverse prognosis and Epstein-Barr virus status in classical Hodgkin’s lymphoma.
Haematologica February 2011 96: 269-276.
18 Panico L, Ronconi F, Lepore M, Tenneriello V, Cantore N, Carmela Dell’Angelo A, Ferbo
U, Ferrara F. Prognostic role of tumor-associated macrophages and angiogenesis in
classical Hodgkin lymphoma. Leukemia & Lymphoma. (doi:10.3109/10428194.2013.7784
05)
19 Gaslain S, Stolbrink M, Jones M, Soilleux E. CD68+
cell numbers and dendritic cell
numbers and phenotype fail to predict the presence of a MYC rearrangement in
aggressive B-cell lymphomas. Journal of Hematopathology, December 2012, Volume 5,
Issue 4, p. 291-296.
20 Lenz G, Wright G, Dave SS, Xiao W, Powell J, Zhao H, Xu W, Tan B et al. (2008).Stromal
Gene Signatures in Large-B-Cell Lymphomas. New England Journal of Medicine 359 (22):
2313–2323.
21 Choi WW, Weisenburger DD, Griner TC, et al. Clin Cancer Res. 2009 Sep 1;15(17):5494-
5502
22 Klapper W, Kreuz M, Kohler CW, et al., Molecular Mechanisms in Malignant Lymphomas
Network Project of the Deutsche Krebshilfe, Blood February 23, 2012 vol. 119 no. 8 1882-
1887.
23 Linderoth J, Edén P, Ehinger M, Valcich J, Jerkeman M, Bendahl PRO, Berglund M,
Enblad G et al. (2008). Genes associated with the tumour microenvironment are
differentially expressed in cured versus primary chemotherapy-refractory diffuse large
B-cell lymphoma. British Journal of Haematology 141 (4): 423–432.
24 Bagg A. B Cells Behaving Badly: A Better Basis to Behold Belligerence in B-Cell
Lymphomas. Hematology 2011; 330-35.
25 National Cancer Institute web site, General Information About Chronic Lymphocytic
Leukemia. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/healthprofessional/
page1/AllPages
26 Gribben JG. Molecular Profiling in CLL. Hematology 2008; 444-49.
27 Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, Keating MJ,
O’Brien S, Chiorazzi N, Burger JA. (2012) The Bruton tyrosine kinase inhibitor PCI-32765
thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in
vivo. Blood 119: 1182-1189.
28 de Rooij MF, Kuil A, Geest CR, Eldering E, Chang BY, Buggy JJ, Pals ST, Spaargaren M.
(2012) The clinically active BTK inhibitor PCI-32765 targets B-cell receptor (BCR)- and
chemokine-controlled adhesion and migration in chronic lymphocytic leukemia. Blood
119: 2590-2594.
29 Ann Oncol (2012) 23 (suppl 5): v12-v22.
30 Moussay E, Wang K, Cho JH, et al. Proc Natl Acad Sci US A. 2011 Apr 19; 108(16):6573-8.
31 Clin Oncol 30:488-496, 2011.
32 Roboz GJ. Novel Approaches to the Treatment of Acute Myeloid Leukemia. Hematology

2011;43-50.
33 http://seer.cancer.gov/statfacts/html/amyl.html#survival
34 Transforming Clinical Research in the United States: Challenges and Opportunities:
Workshop Summary. Institute of Medicine (US) Forum on Drug Discovery, Development,
and Translation. Washington (DC): National Academies Press (US); 2010.
35 Schlenk RF, Dohner K, Krauter J, et al. Mutations and treatment outcomes in
cytogenetically normal acute myeloid leukemia. N Engl J Med 2008; 358 (18): 1909-1918.
36 Delhommeau F, Dupont S, Della Valle V, et al. Mutation in TET2 in myeloid cancers. N
Engl J Med. 2009;360(22):2289-2301.
37 Abdel-Wahab O, Mullally A, Hedvat C, et al. Genetic characterization of TET1, TET2, and
TET3 alterations in myeloid malignancies. Blood. 2009;114(1):144-147.
38 Gelsi-Boyer V, Trouplin V, Adelaide J, et al. Mutations of polycomb-associated gene
ASXL1 in myelodysplastic syndromes and chronic myelomonocytic leukaemia. Br J
Haematol. 2009;145(6):788-800.
39 Abdel-Wahab O, Manshouri T, Patel J, et al. Genetic analysis of transforming events that
convert chronic myeloproliferative neoplasms to leukemias. Cancer Res. 2010;70(2): 447-
452.
40 Mardis ER, Ding L, Dooling DJ, et al. Recurring mutations found by sequencing an acute
myeloid leukemia genome. N Engl J Med. 2009;361(11):1058-1066.
41 Marcucci G, Maharry K, Wu YZ, et al. IDH1 and IDH2 gene mutations identify novel
molecular subsets within de novo cytogenetically normal acute myeloid leukemia: a
Cancer and Leukemia Group B study. J Clin Oncol. 2010;28(14):2348-2355.
42 Ward PS, Patel J, Wise DR, et al. The common feature of leukemia-associated IDH1 and
IDH2 mutations is a neomorphic enzyme activity converting alpha- ketoglutarate to
2-hydroxyglutarate. Cancer Cell. 2010;17(3):225-234.
43 Yamashita Y, Yuan J, Suetake I, et al. Array-based genomic resequencing of human
leukemia. Oncogene. 2010;29:3723-3731.
44 Ley TJ, Ding L, Walter MJ, et al. DNMT3A mutations in acute myeloid leukemia. N Engl J
Med. 2010;363(25):2424-2433.
45 Yan XJ, Xu J, Gu ZH, et al. Exome sequencing identifies somatic mutations of
DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet.
2011;43(4):309-315.
46 Van Vlierberghe P, Patel J, Abdel-Wahab O, et al. PHF6 mutations in adult acute myeloid
leukemia. Leukemia. 2011; 25(4):130-134.
47 Patel JP and Levine RL. How do novel molecular genetic markers influence treatment
decisions in acute myeloid leukemia? Hematology 2012; 28-34.
48 Haferlach T. Molecular Genetic Pathways as Therapeutic Targets in Acute Myeloid
Leukemia. Hematology 2008; 400-11.
50 DiNardo CD, Luger SM. Beyond morphology: minimal residual disease detection in
acute myeloid leukemia. Curr Opin Hematol. 2012 Mar;19(2):82-8.

Harish Dave, MD, MBA
Vice President, Global Medical Strategy Head, Hematology and Oncology,
Quintiles
With fifteen years of academic hematology-oncology experience, Dr. Dave oversees a
number of hematology and oncology studies at all phases of drug development, and
provides strategy and guidance. His areas of therapeutic experience include cancers of
lung, breast, colorectal, brain, sarcoma, pancreas, prostate, melanoma and liquid tumors.
Dr. Dave has served as a P.I. on multiple studies, served as Chairman of an NIH Study
Section and chaired the Research and Development Committee at a major academic
medical institution. In the latter capacity, Dr. Dave oversaw all research and IRB-related
activity, reviewing and managing over 170 protocols annually.
He received his medical degree from the University of Sheffield Medical School, England
and his residency training at Royal Medical Postgraduate Medical School System,
University of London, England. He conducted basic research in gene regulation and gene
therapy at the NIH. He is board certified in internal medicine, medical oncology and
hematology and was previously Associate Professor of Medicine at George Washington
University and Assistant Chief of Hematology and Chief of Laboratory of Molecular
Hematology at the Veterans Affairs (VA) Medical Center in Washington, DC.
Chris Learn, Ph.D, PMP
Senior Clinical Project Manager, Oncology, Quintiles
Chris Learn, Ph.D, PMP, is Senior Clinical Program Manager, Oncology, Quintiles. He has
over 10 years of experience leading investigator led oncology trials in academic settings
and in industry. His expertise includes the development of molecular immunotherapies
for malignant glioma. Prior to joining Quintiles, he held senior positions in clinical
research at Surgical Review Corporation, The Hamner Institutes for Health Sciences and
Duke University Medical Center.
About the Authors
Ronald Lieberman, MD
Senior Medical Director, Oncology, Quintiles
Dr. Lieberman is a senior director in the medical and scientific services group in Quintiles’
Oncology therapeutic area. He is board certified in internal medicine, hematology/
oncology, clinical pharmacology and blood banking, and has served as the medical and
scientific advisor on clinical trials in the following hematology-oncology indications: solid
tumors (lung, prostate, breast, colon, bladder, gliomas, melanoma, kidney, ovary, head
and neck, stomach, esophagus, and liver) and hematologic malignancies (leukemia,
lymphoma, myeloma, and bone marrow/stem cell transplantation (GVHD). He has also
served as a global and regional medical advisor supporting multiple registrational Phase 3
trials for drugs and biologics. Dr. Lieberman’s special interests include early phase clinical
trials-translational oncology/biomarkers, PK and Bayesian guided clinical trial design,
immunotherapy and clinical development of new anticancer drugs and biologics.

Prior to joining Quintiles, Dr. Lieberman has had an active career in clinical development
with more than 30 years experience including leadership positions at the FDA (CDER);
National Institutes of Health/National Cancer Institute (NIH/NCI) and Biopharma
(MedImmune). At FDA, he served as a team leader in the Division of Oncology Drug
Products and Assistant Director of Clinical Pharmacology Training. At NIH/NCI, he served
as Program Director for Blood Diseases and Resources, Clinical Immunology, Acting Chief
of the Prostate and Urologic Cancer Group and Attending Physician in the NCI Oncology
Clinic. At MedImmune, he served as Medical Director for clinical development, translational
oncology and business development/due diligence. He has authored/coauthored
approximately 100 articles and serves on the Editorial Board/Expert Reviewer for several
journals.

Biomarkers recent-advances-in-their-application-to-the-treatment-of-hematologic-malignancies

Recommended

Recommended

More Related Content

What's hot

What's hot (19)

Similar to Biomarkers recent-advances-in-their-application-to-the-treatment-of-hematologic-malignancies

Similar to Biomarkers recent-advances-in-their-application-to-the-treatment-of-hematologic-malignancies (20)

More from Quintiles

More from Quintiles (7)

Recently uploaded

Recently uploaded (20)

Biomarkers recent-advances-in-their-application-to-the-treatment-of-hematologic-malignancies