Cancer Consult - Cleveland Clinic · 2015. 8. 13. · CAnCer ConSult ASH 2008 edition Dear Colleagues and Friends: This issue of Cancer Consult is devoted to the Taussig Cancer Institute’s

Ta u s s i g C a n c e r I n s t i t u t e | A S H 2 0 0 8 E d i t i o n

Cancer Consult

Highlightsfrom the 2008American Society of HematologyAnnual Meeting

CAnCer ConSult ASH 2008 edition

Dear Colleagues and Friends:

This issue of Cancer Consult is devoted to the Taussig Cancer Institute’s

participation in the American Society of Hematology (ASH) Annual

Meeting, which took place in December 2008 in San Francisco.

This was a noteworthy meeting for ASH as it represented the 50th

anniversary of the society. This annual meeting has become our

department’s most important scientific meeting. It is a wonderful mix

of educational lectures, and offers a unique blend of basic, translational

and clinical research presentations. Twenty-four-thousand people

attended, with close to 6,000 abstracts submitted for consideration.

The Cleveland Clinic Taussig Cancer Institute sponsored our first Friday

Educational Symposium: “Bone Marrow Failure Syndromes: Optimizing

Outcomes Worldwide Through Disease Understanding.” These “Super

Friday” symposiums are competitively awarded by ASH, and we were

proud to be selected as a sponsor. Drs. Mikkael Sekeres and Jaroslaw

Maciejewski were the co-directors of this international symposium that

reached more than 400 participants.

The Taussig Cancer Institute presented 16 oral and 49 poster presen-

tations. Our Lymphoma Program co-authored an abstract that was

accepted for the Plenary Session. Dr. Yogen Saunthararajah presented

data concerning the genesis of cancer that was accepted as one of the

“Best of ASH” abstracts. In addition, Drs. Sekeres, Smith and I had the

privilege of serving as abstract reviewers for this year’s meeting.

I hope you find this edition of Cancer Consult valuable, as it highlights

many of theTaussig Cancer Institute’s presentations during the ASH

Annual Meeting. Our strong presence at this important event is indica-

tive of continued recognition of our research efforts and points to the

strength of the Department of Hematologic Oncology and Blood Disor-

ders. Our most important mission is to deliver outstanding care to our

patients and ultimately to win the war on cancer. I would like to thank

all of our colleagues and friends for your ongoing support. A directory of

our physicians is included with this newsletter. Please feel free to con-

tact any of us about your patients.

Sincerely yours,

Brian J. Bolwell, MD

Chairman, Department of Hematologic Oncology and Blood Disorders

ClevelAnd CliniC | tAuSSig CAnCer inStitute | CAnCer ConSult

clinical Trials 10

Bone Marrow Failure Syndromes:

Optimizing Outcomes Worldwide

Through Disease Understanding 1

Clinical Trials Under Way to

Improve Outcome in AML 4

Partnership Streamlines Drug

Development 5

Myeloma Program Expands with

Return of Researcher 6

Clinical Trial Shows Promise

in Some Non-Hodgkin’s

Lymphomas 7

Study Shows that Future Cancer

Treatments Could Be Less

Damaging, Toxic to Patients 8

Study Questions Timing of

Induction Therapy in Older AML

Patients 9

CLINICAL TRIALS 10

Fellow Highlights New

Technology at ASH 12

PUBLICATIONS 13

REFERRALS 14

S AT E L L I T E S Y M P O S I U M American Society of Hematology

Bone Marrow Failure Syndromes:

optimizing outcomes Worldwide through disease understanding


Understanding of the molecular underpinnings of

these disorders has exploded in the past decade,

and with it pathobiologically-driven therapies and

predictors of response to therapies, the availability

of which also vary across the world.

Cleveland Clinic hosted a well-attended satellite

symposium during the 50th ASH Annual Meeting

to share current understanding of bone marrow

failure syndromes, directed by Mikkael Sekeres,

MD, MS, Department of Hematologic Oncology

and Blood Disorders at Taussig Cancer Institute.

“This symposium evolved from the close collabora-

tion we have achieved at Taussig Cancer Institute

between clinical and translational researchers,”

says Dr. Sekeres, who co-designed the CME with

Jaroslaw Maciejewski, MD, PhD, Chairman of

the Department of Translational Hematologic

and Oncologic Research. “We included both the

basic and clinical aspects of these diseases, which

attracted each of us to devote our careers to their

study. We showcased the interplay between clinical

and translational research, and how it can result in

concrete changes. Some aspects of our collabora-

tion have earned international recognition.”

He pointed to both the recognition of the RARS-T

abnormality by the World Health Organization,

and upcoming revisions to the international

prognostic scoring system (IPSS) that have grown

out of Dr. Maciejewski’s application of innovative

technologies in translational research.

“In the past, we were able detect genetic abnor-

malities in about 50 percent of patients with bone

marrow failure syndromes,” says Dr. Sekeres. “But

by using SNP-Array technology, Dr. Maciejewski is

able to detect these abnormalities in 80 percent of

patients. These abnormalities are clandestine but

real, and they have prognostic implications.”

Several international experts joined the faculty

for the course, including Pierre Fennaux, MD,

PhD, from the University of Paris, France, who

addressed Preventing AML Transformation; and

Aristoteles A.N. Giagoudidid, MD, PhD, of St.

Johannes Hospital in Duisburg, Germany, who

shared his experience in Rationally Targeting the

Molecular Underpinnings of the Disease.

Dr. Sekeres says the international scope of the

symposium showcased the robust collaboration

among specialists from throughout the world

in studying and treating bone marrow failure

disorders. “We have strong relationships around

the U.S. and throughout the world,” he says. “We

recognize that there is strength in numbers.”

By including presentations from the Leukemia

& Lymphoma Society and the Aplastic Anemia

& Myelodysplastic Syndromes Foundation, Dr.

Sekeres says the event also addressed the need to

include patients in clinical trials.

“In adult oncology as a whole, less than 10 percent

of patients participate in clinical trials,” he says.

“Our speakers highlighted the resources avail-

able to patients through patient advocacy groups,

including direct economic support for travel and

participation in clinical trials.”

To discuss the sym-posium or to refer a patient to Dr. Sekeres, call 216.444.5385 or email [email protected]

Bone Marrow Failure Syndromes affect hundreds of thousands of people worldwide.

The epidemiology, risk factors, and molecular characterization of these diseases vary among

different countries, with incidence rates for aplastic anemia ranging from 2 per million in the U.S.,

Europe, and Israel to 7 per million in some Chinese provinces. Myelodysplastic syndromes are even

more prevalent, with an incidence ranging from 1 per 100,000 in Japan to 12 per 100,000 in

areas of the United Kingdom, and 3.4 per 100,000 in the U.S.

S Y M P O S I U M

( c o n t i n u e d )


“We showcased the interplay

between clinical and transla-

tional research, and how it can

result in concrete changes.”

2 | 3 | clevelandclinic.org/cancerconsult


The possibility of employing biological targeted

therapies with or without chemotherapy in

the treatment of hematological malignancies

has generated excitement over the last few

years. Members of the Taussig Cancer Institute

Department of Hematologic Oncology and Blood

Disorders are among investigators evaluating these

therapies in AML. A team led by Anjali Advani,

MD, presented results of a Phase I trial of imatinib

mesylate with daunorubicin and cytarabine for

patients with c-kit positive relapsed AML at the

2008 ASH Annual Meeting.

“Although AML is not associated with one specific

mutation, AML cells do share biological charac-

teristics that may allow the application of molecu-

lar targeted therapies,” says Dr. Advani. C-kit, a

tyrosine kinase receptor expressed on more than

90 percent of relapsed AMLs, mediates leukemic

proliferation and anti-apoptotic effects. Signaling

pathways including STAT3 and STAT5 may be acti-

vated downstream of c-kit. Higher c-kit expression

is associated with a shorter time to relapse and

shorter overall survival.

“Therefore, targeting the c-kit receptor in AML

may improve the outcome for patients,” says Dr.

Advani.

C-kit inhibitors are not active enough as single

agents in AML. However, it is possible that c-kit

inhibitors may be effective when used in combina-

tion with other therapies, including chemotherapy.

“Imatinib mesylate is a potent c-kit inhibitor that

has demonstrated some activity in relapsed/refrac-

tory AML,” says Dr. Advani. “In this trial, we com-

bined imatinib mesylate with standard induction

therapy for patients with c-kit+ relapsed AML.”

Twenty-one patients had enrolled at the time of the

presentation. “Eleven of the 19 evaluable patients

achieved complete remission (CR) or complete

remission with incomplete platelet recovery (CRp),

an encouraging result that merits evaluation in a

larger Phase II study,” says Dr. Advani.

Dr. Advani and her colleagues continue to open

clinical trials to improve the outcome for patients

with AML.

Acute myeloid leukemia (AML) is a difficult disease to treat. Although 65 percent of patients

achieve complete remission with chemotherapy, only 15 to 30 percent remain free of the disease

for five years. New treatment medications and approaches are desperately needed.

Clinical trials under Way to improve outcome in AMl

For more informa-tion or to contact Dr. Advani, call 216.445.9354or [email protected].

A Phase 1 Trial of Imatinib

Mesylate

with Daunorubicin

and Cytarabine

forPatients with C-Kit Positive Relapsed Acute Myeloid Leukemia

Anjali S Advani, MD1, Ed Copelan, MD1, Ronald Sobecks, MD1, Mikkael A Sekeres, MD, MS1, Jennifer Bates1, Mary Lynn Rush1, Barbara Tripp1, Elysa Noon, PhD2, Matthew Howard, MD3, Tao Jin4, Eric Hsi, MD3, Matt Kalaycio, MD11Hematologic Oncology and Blood Disorders, Taussig

Cancer Center, Cleveland Clinic, Cleveland, OH 44195, 2Novartis Pharmaceuticals, 180 Park Ave., Florham Park, NJ 07932,3Clinical Pathology, Cleveland Clinic, Cleveland, OH 44195, 4Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH 44195

Taussig Cancer Center

BackgroundTargeting the c-kit receptor in AML represents a potential therapeutic strategy. C-kit is expressed on more than 10% of blasts in 95% of patients with relapsed AML1. C-kit mediates proliferation and anti-apoptotic effects in AML2, 3. Signaling pathways, such as STAT3 and STAT5, may be activated downstream of c-kit.

Methods Results

ConclusionsThe MTD of imatinib

in combination with 7+3 was 300 mg. Since the hyperbilirubinemia

appeared to be reversible with discontinuation of imatinib, it may be possible to escalate imatinib

doses further and re-

challenge. The CR rate is encouraging and merits evaluation in a Phase 2 study. In particular, patients with no nuclear P-STAT3 had a high CR rate; whereas patients with nuclear P-STAT3 had a lower CR rate. STAT3 may be activated independently of c-kit; therefore, directly targeting STAT3 in this latter group of patients may potentially

improve prognosis.

References1.

Hans CP, Finn WG, Singleton TP, et al. Usefulness of anti-CD117 in the flow cytometric

analysis of acute leukemia. American Journal of Clinical Pathology 2002; 117: 301-5.

2.

Ikeda H, Kanakura

Y, Tamaki T, et al. Expression and functional role of the proto-oncogene c-kit in acute myeloblastic

leukemia cells. Blood 1991; 2962-8. 3.

Hassan H, Zander

A. Stem cell factor as a survival and growth factor in human normal and malignant hematopoiesis. Acta

Haematol

1996; 95: 257-62. 4.

Kindler T, Breitenbuecher

F, Marx A, et al. Efficacy and safety of imatinib

in adult patients with c-kit positive acute myeloid leukemia. Blood 2004; 103: 3644-54.

5.

Fang C, Kim C, Perkins C, et al. CGP57148B (STI-571) induces differentiation and apoptosis and sensitizes Bcr-Abl-

positive

leukemia cells to apoptosis due to antileukemic

drugs. Blood 2000; 96: 2246-53.

Table 3 Patient Characteristics

Median Age

47 years (range 24-75

)Sex

48% maleMedian time from CR to relapse

439 days (range 216-1100)CG risk group

Poor

14%

Intermediate

71%

Good

14%Median percentage of c-kit + blasts

89% (range 52-98)

Imatinib

mesylate, a c-kit inhibitor, has demonstrated complete and partial hematologic responses in relapsed/ refractory AML in

a Phase 2 study4. In vitro, co-treatment with imatinib

significantly increases cytarabine

or doxorubicin induced apoptosis of Bcr-Abl

positive leukemia cell lines5. This apoptosis is accompanied by downregulation

of anti-apoptotic proteins5. Thus, combining imatinib

with chemotherapeutic agents such as cytarabine

and daunorubicin

may be synergistic in the apoptosis of AML cells. This Phase 1 trial evaluated the safety and efficacy of combining imatinib

mesylate

with daunorubicin

and cytarabine

in patients with c-kit positive AML.

Cell survivalProliferation

AdhesionChemotaxis

Signalingproteins

CellSurface

Stem cell factor

P

P

P

P

P

P

P

P

P C-KITC-KIT

All patients were treated at the Cleveland Clinic from 2003-2008. Cytogenetic (CG) risk was defined by CALGB criteria. Phosphorylated

(P) activated STAT3 (nuclear and cytoplasmic) was assessed by immunohistochemistry

(IHC) on pre-treatment samples. IHC studies for P-STAT5 are ongoing.

Table 1 Eligibility Criteria

Relapsed AML (excluding APL)Relapse more than 6 months from induction therapyECOG performance status 0-2≥20% c-kit+ blasts (CD117+ by flow cytometry)Age ≥

18 yearsNot pregnant or lactatingCreatinine

≤

2 mg/dLAST and ALT ≤

2 x upper limits of normal, bilirubin

≤

2 mg/dL.

Treatment Plan: All patients received daunorubicin

45 mg/m2

IV for 3 days, and cytarabine

100 mg/m2/d continuous IV infusion for 7 days (7+3). Imatinib

dose was escalated using a standard 3 x 3 design. Dose levels are listed in Table 2.

Table 2 Dose Levels of Imatinib

Mesylate

-1 (300 mg)1 (400 mg)

Imatinib

mesylate

was administered with the first dose of chemotherapy and continued daily until disease progression, intolerance, removal from study for another treatment (including

alloBMT), or dose-limiting toxicity (DLT). DLT was defined as any non-hematologic toxicity ≥

Grade 3 excluding alopecia/ constitutional symptoms; any treatment-related death; and greater than 45 days to recover an absolute neutrophil

count of 500/ μL.

21 patients have been enrolled.

STAT3 expressionIn patients expressing nuclear P-STAT3, 2-6% of the blasts stained positiveEleven patients had no nuclear P-STAT3No patients had cytoplasmic

P-STAT3

Because there were 2 DLTs, subsequent patients were treated at dose level -1. One DLT was seen (bilirubin

5.5 mg/ dL) out of 6 patients, making 300 mg/ d the MTD. Enrollment to the expanded cohort at the MTD is currently complete. One patient died during induction and was not evaluable for response. Response data for

the other 20 patients is shown in Figure 1.

Patients received imatinib

mesylate

for a median 23 days (range 9-574+). Three discontinued imatinib

to proceed to alloBMT. Two patients continue on imatinib

and remain in a remission at 52+ and 574+ days.

2 (600 mg)3 (800 mg)

% o

f Pat

ient

s

Figure 1.Responses

Anjali Advani received research support from Novartis. Matt Kalaycio

is on the Speakers Bureau for Novartis. Elyssa

Noon is an employee of Novartis.

Nine patients were treated at dose level 1 (400 mg) because 3 patients discontinued imatinib

before DLT could be evaluated (2 due to nausea, 1 due to persistent leukemia on a Day 14 bone marrow). Of the 6 evaluable patients, 2 patients had a DLT. Both of these were > Grade 3 hepatotoxicity.

Predictors of ResponseC-kit expression did not correlate with achievement of CR. However, patients with no nuclear P-STAT3 had a higher CR rate (82%) than patients with P-STAT3 nuclear expression (33%) (p=0.18).

Dose Escalation

Disclosures

CR/ CRp0

20

40

60

No CR


The partnership, designed under the guidance of

John Sweetenham, MD, Brad Pohlman, MD, and

Chairman Brian Bolwell, MD, of the Department

of Hematologic Oncology and Blood Disorders,

streamlines the complex processes involved in

developing and advancing new anticancer treat-

ments through clinical studies. The goal is to

accelerate the development of successful therapies

for hematologic malignancies.

While most national clinical trials are conducted

by cooperative groups — vast networks of physi-

cians, researchers, medical centers and universi-

ties across the country — the Clinical Trial Center

for Hematologic Malignancies will expedite the ad-

vancement of new drugs, since the trials will all be

conducted by a single clinical center with access to

a large volume of patients. The partnership plans

to undertake more than six clinical trials over the

next three years, enrolling 100 to 150 patients,

increasing the number of trials typically completed

for these types of cancers in this timeframe.

Investigator Stephen Smith, MD, Associate Staff

in the Department of Hematologic Oncology

and Blood Disorders, says the Taussig Cancer

Institute brings a team of highly capable clinical

researchers and a strong research infrastructure to

the partnership, while the Leukemia & Lymphoma

Society has a long history of involvement in major

breakthroughs in treating hematologic cancers

nationwide. Since its launch, the center has

opened one study for treating lymphoma, and

expects to launch another this spring.

“The first study combines two new drugs — consid-

ered ‘targeted therapies’ due to the specific manner

they affect tumor cells — to find out if they are safe

and effective together in patients with relapsed

B-cell lymphoma,” says Dr. Smith. “This study

builds upon recent advances in understanding the

complex processes that keep tumor cells alive.”

Dr. Smith says that research has shown that

lymphoma cells live and grow in a precarious

state, relying on a delicate balance of proteins that

perform the tasks that keep tumor cells alive.

The two medications are known for disrupting

the cell’s handling of proteins, which offsets

this balance and pushes cancerous cells toward

self-destruction. This study is the first to use

these specific medications together (even though

each has shown promise against lymphoma

alone), to determine the combination’s safety and

effectiveness.

The second trial, beginning enrollment this

spring, is slated to start at the Cleveland Clinic

main campus as well as regional Cleveland Clinic

Cancer Centers at Hillcrest and Fairview hospitals.

“This study is designed to test one of the most

specific types of anticancer therapies ever

developed — a drug that blocks a particular

genetic ‘message’ telling a lymphoma cell to pro-

duce a cancer-stimulating protein. By blocking

this message, the drug removes a major impetus

for tumor cell growth,” says Dr. Smith. “We’ll be

enrolling patients with certain non-Hodgkin’s

lymphomas that have relapsed after initial

treatment.”

He says news of the partnership generated excite-

ment at this year’s ASH meeting, where he served

as a reviewer of abstracts in the category of chemo-

therapy treatments for lymphoma. “ASH is fertile

ground for the development of promising new

therapies for lymphoma,” he says.

Partnership Streamlines drug development

In 2008, the Leukemia & Lymphoma Society and the Cleveland Clinic Taussig Cancer Institute

launched a groundbreaking partnership, the Clinical Trial Center for Hematologic Malignancies,

aimed at increasing access and participation in clinical trials among adult cancer patients.

For more information on the Clinical Trial Center for Hematologic Malignancies or to discuss patient enroll-ment, please call 866.246.5937, or email Dr. Smith at [email protected].



Dr. Reu graduated from the Eberhard-Karls Univer-

sitat Tubingen in Tubingen, BW, Germany, before

completing his internship, residency and fellow-

ship training at Cleveland Clinic. He returned to

Germany for two years to head the AML Task Force

at the University of Heidelberg, but welcomed the

opportunity to return to Cleveland Clinic.

“I like the way medicine is practiced at Cleveland

Clinic,” says Dr. Reu. “This environment provides

a unique setting to pursue my epigenetic research

and continue to deliver high quality patient care.”

Dr. Reu is leading basic and clinical research in

myeloma. His lab in the Taussig Cancer Institute

focuses on DNA methylation, regarded as one of

the most significant epigenetic events. Cytosine-

phosphate-guanine (CpG) methylation in the

promoter region of certain genes may be the

earliest alteration in some cancers. It is correlated

with silencing of genes.

“Medications that can inhibit the shutdown of

these tumor suppressor genes are already FDA ap-

proved for myelodysplastic syndomes (MDS), and

they’re being tested for other cancers,” says Dr.

Reu. “They are incorporated into the DNA and bind

the enzyme that is responsible for methylation,

thereby inactivating it.”

Taussig Cancer Institute is pleased to announce the return of Frederic Reu, MD, to the Chronic

Leukemia and Myeloma Program in the Department of Hematologic Oncology and Blood Disorders.

Myeloma Program expands with return of researcher

But cell division in myeloma is significantly slower

than in MDS, which suggests that dosing schedules

would need to be altered to get the same effect. Dr.

Reu has approval to open a clinical trial of a prom-

ising epigenetic drug in multiple myeloma.

In his lab, Dr. Reu is involved in basic research to

uncover agents that reactivate specific genes.

“Currently available drugs will reactivate any gene

that is silenced by DNA methylation,” he explains.

“I’m working to find the pathways necessary for

reactivation of only the genes that we want to reac-

tivate. Ultimately, this could lead to the develop-

ment of agents that are far more specific.”

In addition to his work in cancer research, Dr. Reu

is collaborating with colleagues in cardiology to

establish an amyloid center.

“Amyloidosis is a disease where abnormal proteins

are deposited in the tissue between cells, thereby

disrupting organ function,” says Dr. Reu. “The

most common form, AL amyloidosis, is very simi-

lar to multiple myeloma because it is caused by the

same cells.”

Dr. Reu and Mazen Hanna, MD, a cardiologist with

advanced training in heart failure, plan to incor-

porate multiple disciplines and offer treatment

approaches that include novel systemic therapies,

heart and stem cell transplantation.

For more information on Dr. Reu’s studies or to refer a patient, call 216.636.0200 or email [email protected].


While he cautions that the data are preliminary,

Dr. Sweetenham says that the fact that this is

an orally available molecule with a new target is

generating excitement.

The drug, fostamatinib, targets a new pathway

known as Syk (spleen tyrosine kinase), which is

tumor specific and may selectively kill tumor cells

while decreasing potential side effects.

“The results were particularly impressive in chron-

ic lymphocytic leukemia (CLL) and diffuse large

B-cell lymphoma (DLBCL), which in many ways

are on opposite ends of the spectrum. Patients can

live with CLL for a very long time before it becomes

resistant to chemotherapy, whereas DLBCL is rela-

tively aggressive and fast-growing,” he says.

“Normally in these very preliminary studies, we’re

looking to determine toxicity of the treatment rath-

er than necessarily seeing responses to the drug.

But there were a significant number of responses

in these two groups.”

In a heavily pretreated population with few thera-

peutic options, the overall response rate was 55

percent in CLL and 22 percent in DLBCL.

Besides the encouraging results, Dr. Sweetenham

says that the fact that it can be offered as a pill is

very attractive to patients and favorably impacts

compliance. “With so many of the new agents

being intravenous treatments that carry problems

with drug delivery, this is a welcome alternative,”

he says.

However, he describes himself as naturally

cautious.

“There’s no such thing as a free lunch and it did

have side effects, including quite marked fatigue

and diarrhea,” he says. “And what we don’t know

yet is how easy it is going to be to combine this

drug with other types of chemotherapy, which cer-

tainly is where its future impact is going to be.”

Dr. Sweetenham expects that larger studies will

help experts determine the future applications

of fostamatinib. But, he says, the most important

thing may not be the drug itself, but its concept.

“We’re now in a position where we are assessing

drugs that have been designed to work in a par-

ticular way, so this is no longer chance observation

that something works. These are designer drugs,”

he says. “It’s an important step on the way to indi-

vidualized therapy.”

Results of the study also point to the importance of

enrolling patients in clinical trials.

“Patients who participated in this study truly ben-

efited from this drug, which they couldn’t have got-

ten without being part of a clinical trial,” he says.

Clinical trial Shows Promise inSome non-Hodgkin’s lymphomas

A Phase II clinical trial of a novel drug for relapsed/refractory Non-Hodgkin’s Lympoma presented during a

plenary session at the ASH Annual Meeting showed promising results according to study co-investigator

John Sweetenham, MD, Department of Hematologic Oncology and Blood Disorders.

To refer a patient to Dr. Sweetenham, or to dis-cuss this or another trial, call 216.445.6707 or email [email protected].


“These are designer drugs. It’s

an important step on the way

to individualized therapy.”


The researchers found that they could alter an

existing chemotherapy drug to stop the growth of

cancer cells and encourage the growth of healthy

cells. Current treatments kill both cancer cells and

healthy cells, which leads to numerous side effects.

The results of the studies suggest that the mecha-

nisms that cause cancer cells to divide and grow

uncontrollably are often different from the mecha-

nisms that drive the growth of healthy stem-cells.

This difference can be exploited to selectively stop

the growth of the cancer cells without stopping the

growth of healthy stem-cells.

“Today, most cancer chemotherapy works the

margins — the chemotherapy is marginally more

poisonous to cancer cells than normal cells,” said

lead investigator Yogen Saunthararajah, MD, of

Taussig Cancer Institute. “Therefore, treatment is

Study Shows that Future Cancer treatments Could Be less damaging, toxic to Patients

Cleveland Clinic researchers presented findings at the 50th Annual ASH Meeting that

suggest cancer could be treated in a novel way that is much less toxic.

difficult and risky for patients and can only be given

for a few days at a time, with long periods without

treatment during which the cancer can regrow.

“Using this alternative approach, which in the

test-tube has opposite effects on cancer cells

versus healthy stem cells, perhaps therapy can be

given regularly and for longer periods, to get the

maximum benefits of treatment. We are excited

that we can modify the use of existing drugs to

produce this effect, which will allow us to start

clinical trials soon.”

The research team studied bone marrow samples

of myelodysplastic syndrome (MDS) and leuke-

mia patients as well as healthy blood stem cells to

discover that the enzyme known as DNMT1 plays

opposite roles in the healthy stem cells versus the

cancerous cells. Therefore, inhibiting the function

of this enzyme produced opposite effects on the

healthy cells versus the cancerous cells. The drug

used to inhibit this enzyme, decitabine, is already

available for clinical use, allowing for clinical stud-

ies to be conducted in the next year to determine if

using decitabine in this new method can repro-

duce the effects seen in the test tube in patients.

The research team emphasized that this work

needs to undergo the peer review process and

publication, and that clinical trials must be

conducted to further test this approach in

patients. This study was highlighted as a “Best

of ASH” presentation by the American Society

of Hematology, the world’s largest professional

association of blood specialists.

The U.S. Department of Defense has agreed to fund

further preclinical studies to continue to improve

this approach as a treatment of cancer.

To reach Dr. Sauntha-rarajah, please call 216.444-8170 or email [email protected].

DNMT1 depletion, using non-DNA damaging levels of the nucleoside analogue decitabine (DAC), has opposite effects on acute myeloid leukemia and normal stem cell self-renewal.


The study included more than 1,300 patients with

acute myeloid leukemia (AML) and showed that

every day of delay from diagnosis to the start of

therapy worsens survival in younger adults, while

delay does not impact survival in the elderly.

“In an ideal patient, who is younger than 60 with

a core binding factor cytogenetic abnormality,

standard induction chemotherapy will achieve

complete remission (CR) nearly 85 percent of

the time,” says Dr. Sekeres. “But most patients

are older, with other cytogenetic abnormalities

or secondary AML. In this group, outcome from

standard therapy is much worse, with CR rates less

than 50 percent and treatment mortality rates that

approach 25 percent.”

The combined database from Cleveland Clinic and

M.D. Anderson included 1,660 AML patients treat-

ed from 1994 to 2005. Excluded patients included

those with promyelocytic leukemia, those under

age 17, those with white blood cell counts more

than 50,000/mm³, those diagnosed more than

three months before therapy, those who began

therapy immediately on the date of diagnosis, and

those with incomplete data. The final dataset con-

sisted of 1,317 patients who were all treated with a

remission induction regimen that included cytara-

bine. These patients were typical of other large

AML studies in the distribution of pretreatment

covariates, the rates of CR and overall survival (OS),

and the effect of covariates on outcome.

Cytogenetics were determined using metaphase

karyotyping based on analysis of 20 or more cells.

Patients with complex cytogenetics or -7 abnor-

malities were classified as “unfavorable”; those

with core binding abnormalities were classified

as “favorable”; and remaining patients, including

those with insufficient metaphase to determine

cytogenetic abnormalities, were placed in the

“intermediate risk” category. Both univariate and

multivariate analyses were completed.

“Our data suggest that in younger patients with

WBC less than 50,000/mm³, AML should continue

to be considered an oncologic emergency. Out-

comes were worse in the 41 percent of younger

patients whose treatment was delayed for five or

more days,” says Dr. Sekeres. “The findings raise

the question of whether it is prudent to delay

therapy in younger patients to determine eligibility

for clinical trials that may or may not offer better

outcomes.”

However, in patients 60 or older, the time from

diagnosis to treatment did not appear to affect

complete remission or overall survival rates.

“Since indirect data suggest that older patients

derive very little benefit from standard induction

therapy, waiting until cytogenetic or molecular

results become known and offering individualized,

investigational therapy to this group is probably

beneficial,” says Dr. Sekeres.

Study Questions timing of inductiontherapy in older AMl Patients

Research completed by Mikkael Sekeres, MD, MS, Department of Hematologic

Oncology and Blood Disorders, and investigators from M.D. Anderson was

featured in the Jan. 1, 2009 issue of Blood.

To refer a patient to Dr. Sekeres, call 216.444.5385 or email [email protected].



Acute Myeloid Leukemia (AML)

A Phase II Study of Imatinib Mesylate (Gleevec) as Maintenance Therapy after Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed C-kit Postitive AML Less than 60 Years of Age

PI: Anjali Advani, MD

A Phase IIB, Randomized, Double-Blinded, Placebo-Controlled Study of Low Dose Cytara-bine and Lintuzumab Compared to Low Dose Cytarabine and Placebo in Patients 60 Years of Age and Older with Previously Untreated AML

PI: Mikkael Sekeres, MD, MS

Acute Lymphocytic Leukemia (ALL)

An Intergroup Phase II Clinical Trial for Adoles-cents and Young Adults with Untreated Acute Lymphoblastic Leukemia (ALL)


Bone Marrow Transplant

Multiple Unit Unrelated Donor Umbilical Cord Blood Transplantation for Patients with Hema-tologic Diseases

PI: Ronald Sobecks, MD

A Study of Outcomes and Toxicity of Busulfex as Part of a High Dose Chemotherapy Prepara-tive Regimen in Autologous Hematopoietic Stem Cell Transplantation for Patients with Plasma Cell Myeloma

PI: Ronald Sobecks, MD

A Phase II Trial Evaluating Modified High Dose Melphalan (100 mg/m2) and Autologous Pe-ripheral Blood Stem Cell Supported Transplan-tation (SCT) for Patients with AL Amyloidosis or High Risk (greater than or equal to Age 70 or Poor Renal Function) Patients With Multiple Myeloma (A BMT Study)

SWOG study

Chronic Lymphocytic Leukemia (CLL)

A Phase I/II, Multi-Center, Open-Label Study of the Safety and Efficacy of a Stepwise Dose-Escalation Schedule of Lenalidomide Monotherapy in Subjects with Relapsed or Re-fractory B-Cell Chronic Lymphocytic Leukemia


A Phase I Trial of Bendamustine plus Alem-tuzumab for the Treatment of Fludarabine Refractory Chronic Lymphocytic Leukemia

PI: Matt Kalaycio, MD

Myelodysplastic Syndromes (MDS)

A Phase I/II Study of Revlimid in Combination with Azacitidine in Patients with Advanced MDS


A Phase II Trial of RAD001 in Low and Inter-mediate-1 Risk Myelodysplastic Syndrome


A Phase IIa, Open-Label, Dose Confirmation Study of Oral Clofarabine in Previously Treated Adult Patients with Myelodysplastic Syndromes (MDS)


Cleveland Clinic Taussig Cancer Institute is at the forefront of the cancer

drug discovery and development revolution. Through our cancer research

projects led by some of the world’s leading scientists, we have identified new

molecules with anti-tumor effect, which may lead to new drug therapies.

Key collaborative relationships with the world’s top biotech firms, university

research labs, renowned scientists, and major health organizations enhance

our research initiatives.

Hematologic Oncology and Blood Disorders

Cancer Consult provides information from Cleveland Clinic Taussig Cancer Institute specialists about innovative research and diagnostic and management techniques.

Please direct correspondence to Brian Bolwell, MD, Medical Editor [email protected]

Taussig Cancer Institute/R35 Cleveland Clinic 9500 Euclid Avenue Cleveland, OH 44195

Cleveland Clinic Taussig Cancer Institute annually serves more than 26,000 cancer patients. More than 250 cancer specialists are committed to researching and applying the latest, most effective techniques for diagnosis and treatment to achieve long-term survival and improved quality of life for all cancer patients. Taussig Cancer Institute is part of Cleveland Clinic, an independent, not-for-profit, multispe-cialty academic medical center.

Cancer Consult Medical EditorBrian Bolwell, MD, Chairman, Hematologic Oncology and Blood Disorders

Cancer Consult Editorial Board

Derek Raghavan, MD, PhD, Chairman, Taussig Cancer Institute

Robert Dreicer, MD, Chairman, Solid Tumor Oncology

Brian Rini, MD Solid Tumor Oncology

Timothy Spiro, MD, Chairman, Regional Oncology

John Suh, MD, Chairman, Radiation Oncology

Gene Barnett, MD, Director, Brain Tumor and Neuro-Oncology Center

Eric Klein, MD, Head, Urologic Oncology,Glickman Urological & Kidney Institute

Managing Editor Marjie Heines

DesignerAmy Buskey-Wood

PhotographyRussell Lee, Tom Merce, Don Gerda

Marketing

Lori Schmitt, RN, Andrew Kraynak,Melissa Raines

Cancer Consult is written for physicians and should be relied upon for medical education purposes only. It does not provide a complete overview of the topics covered and should not replace the independent judgment of a physician about the appropriateness or risks of a procedure for a given patient.

© 2009 The Cleveland Clinic Foundation

07-CNR-042


S E L EC T E D C L IN I C A L T R I A L S


Multiple Myeloma

An Open-Label, Single-arm, Phase II Study of Carfilzomib in Patients with Relapsed and Refractory Multiple Myeloma

PI: Fred Reu, MD

Non-Hodgkin’s Lymphoma

A Phase I/II Study of CMC-544 Administered in Combination with Rituximab in Subjects with Follicular or Diffuse Large B-Cell Non-Hodgkin’s Lymphoma


A Phase I Trial of the Combination of Everoli-mus (RAD001) and Bortezomib (Velcade) for Relapsed or Refractory Indolent and Mantle Cell Non-Hodgkin’s Lymphoma

PI: Stephen Smith, MD

A Phase I/II Study of Clofarabine in Patients with Relapsed T-cell and NK-Cell Lymphomas

PI: Brad Pohlman, MD

A Phase I/II, Multicenter, Open-Label Study of the X-Linked Inhibitor Apoptosis (XIAP) Anti-sense AEG35156 in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia and B-cell Lymphomas

PI: John Sweetenham, MD

A Randomized Phase IIB Placebo-controlled Study of R-ICE Chemotherapy (Rituximab, Ifosfamide, Carboplatin and Etoposide) with and without SGN-40 (anti CD-40 human-ized monoclonal antibody) for Second-Line Treatment of Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

PI: Brad Pohlman, MD

For more information on clinical

trials or to refer a patient, call

216.444.7923 or 866.223.8100.


Dr. Tiu works under the tutelage of Jaroslaw P.

Maciejewski, MD, PhD, Chairman of the Depart-

ment of Translational Hematologic and Oncologic

Research. The primary focus of his research has

been on advancing cytogenetic diagnosis in AML

and MDS using SNP-A.

“What we have found is that we’re not just detect-

ing new abnormalities using SNP-A, but that these

new abnormalities are important clinically in

patient prognosis,” says Dr. Tiu.

SNP-A is a novel molecular tool initially intended

to detect changes in the human genome that can

help define specific predispositions to certain

types of diseases. “But what we have found is that

in addition to being a genotyping tool, SNP-A is a

good karyotyping tool that allows us to see specific

defects in the chromosomes that may be impor-

tant in disease pathogenesis. We found a group of

patients who had normal findings using standard

metaphase cytogenetics, but who actually had hid-

den chromosomal abnormalities,” says Dr. Tiu.

Two of Dr. Tiu’s abstracts were selected for oral

presentations at the ASH Annual Meeting.

Dr. Tiu’s presentation on “Chromosomal Defects

Detected by SNP-Array-Based Karyotyping Are In-

dependent Predictors of Survival in Acute Myeloid

Leukemia,” showcased research comparing stan-

dard metaphase cytogenetics to SNP-A.

In his second presentation, “SNP-Array Based

Karyotyping Complements Routine Cytogenetics

For second-year hematology/oncology fellow Ramon Tiu, MD, the ASH meeting provided a rare

opportunity to showcase his role in promising research using the latest technology, SNP-Array

(SNP-A) karyotyping, in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).

Fellow Highlights new technology at ASH

in Diagnosis and Risk Stratification Schemes of

MDS,” Dr. Tiu showed the benefits of using both

standard and new technology in improving cytoge-

netic diagnosis and prognostication in MDS.

“There has been a lot of uncertainty in myelodys-

plastic syndromes, since they are highly heterog-

enous,” says Dr. Tiu. “For many years, it has sort

of been a wastebasket diagnosis for patients with

bone marrow failures issues that could not fit in a

specific nosologic category. But there has been a

recent move to try to modify the current prognostic

system in these diseases.

“As much as SNP-A is very good at detecting un-

balanced abnormalities, there are conventional

abnormalities that you can’t detect,” he says, “such

as balanced abnormalities exemplified by certain

types of translocations or rearrangements. So both

technologies have a place in the correct diagnosis

and risk stratification of AML and MDS patients.”

Dr. Tiu says his experience at ASH confirmed his

decision to pursue a career in cancer research.

As a young investigator, he sees the breadth and

depth of ongoing work in the field and the vast

opportunities ahead.

“It was a great honor to represent Cleveland Clinic

and the Taussig Cancer Institute in front of the

most prominent experts in the field and to have

them be pleased with our work,” says Dr. Tiu. “It’s

a testament to the commitment of my mentor who

has been so instrumental in my career and to the

hard work of everyone in the laboratory.”



Advani AS, Rodriguez C, Jin T, Jawde RA, Saber W, Baz R, Kalaycio M, Sobecks R, Sekeres M, Tripp B, Hsi E. Increased C-kit intensity is a poor prognostic factor for progression-free and overall survival in patients with newly diagnosed AML. Leuk Res. 2008 Jun;32(6):913-918. [PM:17928050].

Advani AS, Jin T, Ramsingh G, Tiu R, Saber W, Theil K, Sobecks R, Sekeres M, Copelan E, Sungren S, Tripp B, Kalaycio M. Time to post-remission therapy is an independent prognostic factor in adults with acute lymphoblastic leukemia. Leuk Lymphoma. 2008 Aug;49(8):1560-1566. [PM:18766970].

Dean RM, Fry T, Mackall C, Steinberg SM, Hakim F, Fowler D, Odom J, Foley J, Gress R, Bishop MR. Association of serum interleukin-7 levels with the development of acute graft-versus-host disease. J Clin Oncol. 2008 Dec 10;26(35):5735-5741. [PM:19001329].

Dunbar AJ, Gondek LP, O’Keefe CL, Makishima H, Rataul MS, Szpurka H, Sekeres MA, Wang XF, McDevitt MA, Maciejewski JP. 250K single nucleotide polymorphism array karyotyping identifies acquired uniparental disomy and homozygous mutations, including novel missense substitutions of c-Cbl, in myeloid malignancies. Cancer Res. 2008 Dec 15;68(24):10349-10357. [PM:19074904].

Kalaycio M, Advani A, Pohlman B, Sekeres M, Tripp B, Rybicki L, Sobecks R. Timed sequential induction chemotherapy and risk-adapted postremission therapy for acute myelogenous leukemia. Am J Hematol. 2008 Nov;83(11):831-834. [PM:18756545].

Lee SJ, Kukreja M, Wang T, Giralt SA, Szer J, Arora M, Woolfrey AE, Cervantes F, Champlin RE, Gale RP, Halter J, Keating A, Marks DI, McCarthy PL, Olavarria E, Stadtmauer EA, Abecasis M, Gupta V, Khoury HJ, George B, Hale GA, Liesveld JL, Rizzieri DA, Antin JH, Bolwell BJ, Carabasi MH, Copelan E, Ilhan O, Litzow MR, Schouten HC, Zander AR, Horowitz MM, Maziarz RT. Impact of prior imatinib mesylate on the outcome of hematopoietic cell transplantation for chronic myeloid leukemia. Blood. 2008 Oct 15;112(8):3500-3507. [PM:18664621].

Maciejewski JP, Mufti GJ. Whole genome scanning as a cytogenetic tool in hematologic malignancies. Blood. 2008 Aug 15;112(4):965-974. [PM:18505780].

Mahindra A, Bolwell B, Sobecks R, Rybicki L, Pohlman B, Dean R, Andresen S, Sweetenham J, Kalaycio M, Copelan E. Elevated ferritin is associated with relapse after autologous hematopoietic stem cell transplantation for lymphoma. Biol Blood Marrow Transplant. 2008 Nov;14(11):1239-1244. [PM:18940678].

Marks DI, Perez WS, He W, Zhang MJ, Bishop MR, Bolwell BJ, Bredeson CN, Copelan EA, Gale RP, Gupta V, Hale GA, Isola LM, Jakubowski AA, Keating A, Klumpp TR, Lazarus HM, Liesveld JL, Maziarz RT, McCarthy PL, Sabloff M, Schiller G, Sierra J, Tallman MS, Waller EK, Wiernik PH, Weisdorf DJ. Unrelated donor trans-plants in adults with Philadelphia-negative acute lymphoblastic leukemia in first complete remission. Blood. 2008 Jul 15;112(2):426-434. [PM:18398065].

Natkunam Y, Farinha P, Hsi ED, Hans CP, Tibshirani R, Sehn LH, Connors JM, Gratzinger D, Rosado M, Zhao S, Pohlman B, Wongcha-owart N, Bast M, Avigdor A, Schiby G, Nagler A, Byrne GE, Levy R,

Hematologic Oncology and Blood Disorders

A Sampling of 2008 Journal Publications

Gascoyne RD, Lossos IS. LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracy-cline-based chemotherapy with and without rituximab. J Clin Oncol. 2008 Jan 20;26(3):447-454. [PM:18086797].

Rizzo JD, Somerfield MR, Hagerty KL, Seidenfeld J, Bohlius J, Bennett CL, Cella DF, Djulbegovic B, Goode MJ, Jakubowski AA, Rarick MU, Regan DH, Lichtin AE. Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2008 Jan 1;26(1):132-149. [PM:17954713].

Rodriguez CP, Baz R, Jawde RA, Rybicki LA, Kalaycio ME, Advani A, Sobecks R, Sekeres MA. Impact of socioeconomic status and distance from treatment center on survival in patients receiving remission induction therapy for newly diagnosed acute myeloid leukemia. Leuk Res. 2008 Mar;32(3):413-420. [PM:17727945].

Sekeres MA, List AF. Active treatment strategies improving outcomes in patients with myelodysplastic syndromes with the deletion 5q abnormality. Clinical Leukemia. 2008 Feb;2(1):28-33.

Sekeres MA, Schoonen WM, Kantarjian H, List A, Fryzek J, Paquette R, Maciejewski JP. Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst. 2008 Nov 5;100(21):1542-1551. [PM:18957672].

Sekeres MA, Maciejewski JP, Giagounidis AA, Wride K, Knight R, Raza A, List AF. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2008 Dec 20;26(36):5943-5949. [PM:19018091].

Sobecks RM, Dean R, Rybicki LA, Chan J, Theil KS, Macklis R, Andresen S, Kalaycio M, Pohlman B, Ferraro C, Cherni K, Sweeten-ham J, Copelan E, Bolwell BJ. 400 cGy TBI with fludarabine for reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008 Dec;42(11):715-722. [PM:18711346].

Sobecks RM, Ball EJ, Askar M, Theil KS, Rybicki LA, Thomas D, Brown S, Kalaycio M, Andresen S, Pohlman B, Dean R, Sweetenham J, Macklis R, Bernhard L, Cherni K, Copelan E, Maciejewski JP, Bolwell BJ. Influence of killer immunoglobulin-like receptor/HLA ligand matching on achievement of T-cell complete donor chimerism in related donor nonmyeloablative allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2008 Apr;41(8):709-714. [PM:18195688].

Sweetenham JW. Minimizing late effects in children and adults with Hodgkin lymphoma - the beginning of the end for radiation therapy. Leuk Lymphoma. 2008 May;49(5):839-840. [PM:18464101].

Thakkar SG, Fu AZ, Sweetenham JW, McIver ZA, Mohan SR, Ramsingh G, Advani AS, Sobecks R, Rybicki L, Kalaycio M, Sekeres MA. Survival and predictors of outcome in patients with acute leukemia admitted to the intensive care unit. Cancer. 2008 May 15;112(10):2233-2240. [PM:18348307].

Tiu RV, Sekeres MA. The role of AMG-531 in the treatment of thrombocytopenia in idiopathic thrombocytopenic purpura and myelodysplastic syndromes. Expert Opin Biol Ther. 2008 Jul;8(7):1021-1030. [PM:18549331].

Viny AD, Lichtin A, Pohlman B, Loughran T, Maciejewski J. Chronic B-cell dyscrasias are an important clinical feature of T-LGL leukemia. Leuk Lymphoma. 2008 May;49(5):932-938. [PM:18452068].

7th Annual

innovation SummitImproving the Prognosis:Cancer Cures Through Innovation

October 5-7, 2009Cleveland, Ohio

Join top CEOs, venture investors, medical leaders

and journalists as they highlight new technologies,

economics and the newest innovations in cancer

therapeutics, diagnostics and disease manage-

ment. The 7th Annual Medical Innovation Summit

offers an exciting lineup of speakers, panel discus-

sions, live surgeries and clinical presentations to

learn about the latest trends in medical innovation

and what they mean to you.

The Summit provides an unrivaled perspective on

the newest medical technologies and the financial

drivers behind those innovations. It is dedicated to

providing singular insights, networking opportuni-

ties and actionable take away for all participants.

Once again, the summit also will include the

unveiling of the “Top 10” Medical Innovations for

2010, with moderator Michael Roizen, MD, Chair-

man of Cleveland Clinic’s Wellness Institute.

For more information or to register, please visitclevelandclinic.org/2009Summit

REFERRALS24/7 Hospital Transfers/Physician Consults800.553.5056

Taussig Cancer InstituteAppointments/Referrals216.444.7923 ortoll-free 866.223.8100

Bone Marrow Transplantation Appointments/Referrals216.445.5660 or800.223.2273, ext. 55600

Bone Marrow Failure Clinic Appointments/ReferralsThis subspecialty clinic offers expertise in aplastic anemia, myelodysplasia, single-lineage cytopenias, paroxysmal nocturnal hemoglobinuria, large granular lymphocytic leukemia and other immune mediated hematologic diseases.

216.445.5962 or800.223.2273, ext. 55962

Radiation OncologyAppointments/Referrals216.444.5571 or800.223.2273, ext. 45571

ONLINE ACCESSto Your Patient’s Treatment ProgressWhether you are referring from near or far, Cleveland Clinic’s DrConnect stream-lines communication from Cleveland Clinic physicians to your office. This online tool offers you secure access to your patient’s treatment progress at Cleveland Clinic. With one-click convenience, you can track your patient’s care using the secure DrConnect Web site.

To establish a DrConnect account, please visit clevelandclinic.org or email drconnect@ ccf.org.

INSTITUTE LOCATIONSCleveland ClinicTaussig Cancer Institute9500 Euclid Ave./R35Cleveland, OH 44195216.444.7923

BeachwoodFamily Health and Surgery Center26900 Cedar RoadBeachwood, OH 44122216.839.3000 or 800.801.2233

Fairview Hospital18101 Lorain AvenueCleveland, OH 44111216.476.7000

Hillcrest Hospital6780 Mayfield RoadMayfield Heights, OH 44124440.312.4500

IndependenceCancer Center6100 Westcreek Road, Ste. 15 & 16Independence, OH 44131216.524.7979, Medical Oncology216.447.9747, Radiation Oncology

LorainFamily Health and Surgery Center5700 Cooper Foster Park RoadLorain, OH 44053440.204.7400 or 800.272.2676

ParmaCommunity Hospital6525 Powers Blvd.Parma, OH 44129440.743.4747

StrongsvilleFamily Health and Surgery Center16761 SouthPark CenterStrongsville, OH 44136440.878.2500 or 800.239.1098

Willoughby HillsFamily Health Center2570 SOM Center RoadWilloughby Hills, OH 44094440.943.2500 or 800.807.2888

Wooster Family Health Center1740 Cleveland RoadWooster, OH 44691

330.287.4500 or 800.451.9870

Cancer Consult - Cleveland Clinic · 2015. 8. 13. · CAnCer ConSult ASH 2008 edition Dear Colleagues and Friends: This issue of Cancer Consult is devoted to the Taussig Cancer Institute’s

Documents