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Issue 22

Fall 2011

Doctor to Doctor
In every issue of The Leading Edge we attempt to bring you important information that you, our valued referring physicians, will find useful in your practice as you care for patients who have cancer. We are excited to present findings from a clinical study about a new enzymatic therapy for pancreas cancer. PEGPH20 is bringing hope to patients with an unforgiving disease as it makes it possible for chemotherapies to do their job. Then, we have two interesting articles about bone marrow transplantation: one regarding the tricky balance of treating sickle cell disease and the other about making this life-saving treatment more accessible to older patients. We encourage you to read this information and see if it may be pertinent to the care of your patients in your clinic.

New Enzymatic Therapy for Advanced Pancreas Cancer
Seattle Cancer Care Alliance opened a new clinical trial in September to evaluate gemcitabine plus PEGPH20 compared to gemcitabine plus placebo in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. PEGPH20 specifically targets and degrades an abundant component of the extracellular matrix in pancreas cancer, hyaluronic acid (HA) or hyaluronan, and thereby increases delivery of cytotoxic agents to the tumor. 

Transplantation for Sickle Cell Disease
Bone marrow transplantation is currently the only curative therapy for sickle cell disease (SCD). Seminal studies done at Fred Hutchinson Cancer Research Center and elsewhere have documented disease-free survival of around 85 percent and overall survival around 95 percent in hundreds of SCD children with matched sibling donors. Unfortunately, fewer than one in five children with SCD have a matched sibling and unrelated donor transplantation in SCD has met with less success. “Without a good match, the outcomes have not been as good,” according to Michael A. Bender, MD, PhD, a clinician-researcher at Seattle Cancer Care Alliance (SCCA).

Removing the age limit for transplantation
Age alone should no longer be considered a defining factor when determining whether an older patient with blood cancer is a candidate for stem cell transplantation. That’s the conclusion of the first study summarizing long-term outcomes from a series of prospective clinical trials of patients age 60 and over who were treated with the minitransplant, a “kinder, gentler” form of transplantation developed at Fred Hutchinson Cancer Research Center. The findings were published on Nov 2, 2011 in the Journal of the American Medical Association (JAMA).

Upcoming CME Events
Symposium on Cancer Survivorship for Clinicians
February 10–11, 2012 | Fred Hutchinson Cancer Research Center To learn more about this course visit: www.fhcrc.org/cme2012.

Highlights of the 2012 GI Cancers Symposium
March 3, 2012 | Pelton Auditorium | Fred Hutchinson Cancer Research Center
For more information visit: www.seattlecca.org/cme.


 

Doctor to Doctor

In every issue of The Leading Edge we attempt to bring you important information that you, our valued referring physicians, will find useful in your practice as you care for patients who have cancer. We’re especially tuned into the needs of those who have finished their treatment and are considered cancer survivors. While they may be cancer free, there are still issues that they will likely live with for years to come. Please join us in February for an important CME to learn how you can help you patients who fit this profile.

In this issue we are excited to present findings from a clinical study about a new enzymatic therapy for pancreas cancer. PEGPH20 is bringing hope to patients with an unforgiving disease as it makes it possible for chemotherapies to do their job. Read the full details on page 3. Then, we have two interesting articles about bone marrow transplantation: one regarding the tricky balance of treating sickle cell disease and the other about making this life-saving treatment more accessible to older patients. We encourage you to read this information and see if it may be pertinent to the care of your patients in your clinic.

We’ll update you again in three months. In the meantime, past issues can be found on the www.seattlecca.org website. We also have a monthly
Clinical Trials News publication that will keep you apprised of the newest study openings at SCCA. Best regards to you, your family, and staff for a healthy holiday season,

F. Marc Stewart, MD
Medical Director, SCCA
 

New Enzymatic Therapy for Advanced Pancreas Cancer

Seattle Cancer Care Alliance opened a new clinical trial in September to evaluate gemcitabine plus PEGPH20 compared to gemcitabine plus placebo in patients with previously untreated metastatic pancreatic ductal adenocarcinoma. PEGPH20 specifically targets and degrades an abundant component of the extracellular matrix in pancreas cancer, hyaluronic acid (HA) or hyaluronan, and thereby increases delivery of cytotoxic agents to the tumor.

“This trial represents the latest advance in our new strategy of combining therapies targeting the tumor microenvironment, or stroma, in combination with drugs against the tumor cell itself and we believe it holds great promise for improving the treatment of patients with pancreas cancer,” says Sunil R. Hingorani, MD, PhD, SCCA medical oncologist, and director of the Pancreas Cancer Specialty Clinic, as well as a pancreas cancer biologist and principal investigator for this global trial. “In terms of systemic admin-istration of an enzymatic agent, it represents a first-in-its-class trial.”

PEGPH20 is a long-lasting PEGylated version of human recombinant PH20 hyaluronidase. In preclinical studies, the agent has been shown to degrade HA from the extracellular matrix surrounding tumor cells. This is thought to break down a barrier to drug delivery. As a single agent, PEGPH20 has reduced tumor-associated HA and led to favorable changes in DCEMRI readouts. In tumors that are rich in HA, such as nearly 90 percent of pancreatic ductal adenocarcinomas, treatment with PEGPH20 may make the tumors especially vulnerable to the cytotoxic effects of gemcitabine.

In animal model studies performed by the Hingorani laboratory at Fred Hutchinson Cancer Research Center, the PEGPH20 plus gemcitabine combination has shown a very high objective response rate and significant survival benefit. Modifying the extracellular environment to increase the penetration and efficacy of anti-cancer agents represents a novel approach to treating pancreas cancer and may provide important therapeutic outcomes in a setting that traditionally has limited efficacy.

For details and to enroll patients in this trial, go to www.seattlecca.org/clinical-trials/phase1-NCT01453153.cfm.

(A Phase 1B/2 Multicenter, International, Randomized, Double Blind, Placebo-Controlled, Study of Gemcitabine Combined with PEGPH20 [PEGylated Recombinant Human Hyaluronidase] Compared to Gemcitabine Combined with Placebo in Patients with Stage IV Previously Untreated Pancreatic Cancer).

Transplantation for Sickle Cell Disease

By Paul Courter, Medical Writer

Bone marrow transplantation is currently the only curative therapy for sickle cell disease (SCD). Seminal studies done at Fred Hutchinson Cancer Research Center and elsewhere have documented disease-free survival of around 85 percent and overall survival around 95 percent in hundreds of SCD children with matched sibling donors. Unfortunately, fewer than one in five children with SCD have a matched sibling and unrelated donor transplantation in SCD has met with less success. “Without a good match, the outcomes have not been as good,” according to Michael A. Bender, MD, PhD, a clinician-researcher at Seattle Cancer Care Alliance (SCCA).

Outcomes in adults with SCD have also been less successful due to both disease- and transplant-related mortality. “When you consider the lack of good matches plus the risk of the complicated procedure, including risks such as sterility,” Bender says, “and when you also consider that many people can now learn to manage their SCD and live a long life with the disease, you can see why many families are hesitant about transplant.” This also explains why only a few hundred of the 70,000 people in the U.S. now living with SCD have had a bone marrow transplant.

A tricky balance

Despite the risks for some with SCD, transplantation eventually becomes the best option for maintaining quality of life and adding years of life. “Patients with severe disease complications are mainly the ones having transplantation today,” Bender says. “In general, transplant candidates have multiple severe vaso-occlusive pain episodes in a year, multiple episodes of acute chest syndrome, or stroke. It’s a tricky balance. You don’t want patients who are too healthy, because transplant is still risky, but you also don’t want patients who are too sick with severe organ disease because then the transplant becomes even riskier.”

Dr. Bender goes on to describe how this balance between disease risk and transplant risk has shifted over the years: “Because of our better comprehensive care for SCD, most newborns with SCD today don’t develop major organ damage and morbidity until late adolescence. They don’t really get sick until they’re in their twenties. That’s why it’s important to educate the families early on, to teach them how to minimize organ damage, and to make sure they are open for more aggressive treatment options if things get bad.”

Improved conditioning might shift the balance

One consequence of this later onset of SCD disease complications is that adult patients are increasingly interested in transplantation—and these older patients tend to have more problems with harsh transplant conditioning regimens. In fact, because transplant conditioning regimens are so tough for many adults, age guidelines for transplantation in SCD were once set at age 16. “But now this age cutoff is part of the dilemma,” Bender says.

This explains why it’s so important to find new, less intensive conditioning and immunosuppressive regimens that will work with both pediatric and adult patients. Lauri Burroughs, MD, pediatric blood and marrow transplantation specialist at SCCA, is testing several promising non-myeloablative regimens in patients with all kinds of non-malignant conditions. SCCA is working to open transplant protocols for sickle cell patients up to age 25.

Needed: more research, more education

“Transplantation for SCD is different than for other diseases,” Bender says. “We need to learn what is needed for SCD and then keep making improvements. Better ways of predicting who will develop severe SCD complications would be helpful, as well as finding early markers of when someone is about to develop a complication. While there are advances on these fronts, more is needed. In addition, more generally, we need to educate the community about SCD. Many people still don’t know they are at risk for having a child with sickle cell or that there is true cure for it.”

Overall, Bender is optimistic about the prospects for stem cell transplantation to treat SCD. “Today many of these kids do fantastic after transplantation,” he says. “And after transplant, they are cured. They no longer need the sickle cell treatments. The pain is gone. The lung disease and the neurological disease do not get worse.” “If we can make transplantation safer and identify appropriate patients sooner, many more patients will benefit,” Bender says.

Removing the age limit for transplantation

By Dean Forbes (from Center News Weekly; November 7, 2011)

Age alone should no longer be considered a defining factor when determining whether an older patient with blood cancer is a candidate for stem cell transplantation. That’s the conclusion of the first study summarizing long-term outcomes from a series of prospective clinical trials of patients age 60 and over who were treated with the minitransplant, a “kinder, gentler” form of transplantation developed at Fred Hutchinson Cancer Research Center. The findings were published on Nov 2, 2011 in the Journal of the American Medical Association (JAMA).

The five-year rates of overall and disease-progression-free survival among mini-transplant patients were 35 percent and 32 percent, respectively. Patients in three age groups: 60 to 64, 65 to 69, and 70 to 75 had comparable survival rates, which suggested that age played a limited role in how patients tolerate the mini-transplant.

Increased medical problems unrelated to cancer (comorbidities) and a higher degree of cancer aggressiveness were the two factors that affected survival among these older patients. For example, patients who had less-aggressive cancer and fewer comorbidities had a five-year survival rate of 69 percent, while patients with more aggressive cancer and a significant number of comorbidities had a survival rate of 23 percent, regardless of age.

Although a long-term survival rate of one-third of patients may seem low, these patients all would have died of their diseases within a matter of months without a transplant. “The majority of patients were referred for a transplant after they had exhausted all forms of conventional therapy,” says corresponding author Mohamed Sorror, MD, PhD of the Clinical Research Division at the Hutchinson Center. Sorror works in the research group led by Rainer Storb, MD, PhD who developed the mini-transplant.

Conventional vs. mini-transplants

“While there is much room for improvement, particularly with regard to relapse, these results are encouraging given the poor outcomes with nontransplantation treatments, especially for patients with high-risk AML (acute myeloid leukemia), fludarabine-refractory CLL (chronic lymphocytic leukemia), or progressive lymphoma,” the authors write.

The mini-transplant, also known as non-myeloablative transplantation, was developed by researchers at the Hutchinson Center for older and sicker patients who otherwise could not tolerate the standard, more toxic, high-dose regimens used to prepare patients for transplantation.

Conventional transplants, which are generally not performed for people over age 60 or others who are medically unfit, use high doses of totalbody irradiation and potent chemotherapy to eliminate leukemic cells. The intense treatment destroys the blood and immune system and is fatal unless the patient is rescued by infusion of donor bone marrow or stem cells isolated from peripheral blood.

The mini-transplant, in contrast, relies on the ability of donor immune cells to target and destroy the cancer without the need for high-dose chemotherapy and radiation. Instead, low-dose radiation and chemotherapy is used to suppress the immune system rather than destroy it. This helps the body accept the donor stem cells, which then go to work to attack cancer cells—called the graft-vs.-leukemia effect—and rebuild the immune system. The study involved 372 patients ages 60 to 75 who were enrolled in pro-spective clinical trials between 1998 and 2008 at 18 collaborating U.S. and European cancer centers known as the “Seattle Consortium.” All patients at these centers were treated with the same regimen, which was developed at the Hutchinson Center. The patients in the study were treated for acute and chronic leukemia, lymphoma, multiple myeloma, myelodysplastic syndromes (which can progress to acute myeloid leukemia if not treated), and myeloproliferative diseases such as chronic myelogenous leukemia.

Relapse rates

In addition to survival and the impact of comorbid conditions, the study examined rates of relapse, hospitalization, acute and chronic graft-vs.- host disease (GVHD), and the toxicity of the treatment to internal organs. In one key finding, disease relapse risks, but not increasing age, were associated with worse outcomes. Other results showed that two-thirds of the surviving older patients who were affected by chronic GVHD had complete resolution of their symptoms and were able to discontinue immunosuppressive medications after a median time of two-and-a-half years from diagnosis. This was comparable to the duration of response reported by previous studies on younger patients who were treated with high-dose radiation and chemotherapy. Half of the older patients never required hospitalization after transplant.

“These findings, together with the normal to near-normal performance status of surviving patients, should help allay reluctance in entering older patients with hematologic cancers on non-myeloablative transplantation protocols,” Sorror says. “The lack of a matched sibling donor also should no longer be a limitation given that transplants with matched unrelated donor grafts had comparable outcomes.”

The Seattle Consortium investigators continue to explore novel variations on the mini-transplant theme to reduce the relapse rate, particularly among patients with more aggressive blood cancers. More information about bone marrow transplants at SCCA can be found at www.seattlecca.org/diseases/bone-marrow-transplant-overview.cfm.

Upcoming CME Events


Symposium on Cancer Survivorship for Clinicians

February 10–11, 2012 | Fred Hutchinson Cancer Research Center
Survivorship is now recognized as a distinct phase of care in the cancer continuum, with the focus on long-term surveillance and management of late effects resulting from treatment, as well as health and disease prevention strategies promotion. Featuring leaders in cancer survivorship, this conference will help fill in the relevant gap in medical education clinicians receive regarding cancer survivors. CME, CNE, and CE credit will be available.

To learn more about this course visit: www.fhcrc.org/cme2012.

Highlights of the 2012 GI Cancer Symposium

March 3, 2012 | Pelton Auditorium | Fred Hutchinson Cancer Research Center
Three days of information are packed into a one-day Gastrointestinal Cancer Symposium covering the highlights from the major national GI cancer meeting of 2012—the ASCO/AGA/ASTRO/SSO GI Cancers Symposium (held January 19–21 in San Francisco). Three presentations of state-of-the-art research focused on the diagnosis and multi-modality evidenced-based treatment of esophageal, pancreas/hepatobiliary, and colorectal cancers. Keynote speaker: Al Benson, MD, worldrenowned GI cancer medical oncologist from Feinberg School of Medicine and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, join our leading-edge team of GI cancer specialists. Please join us for this premier educational event.

For more information visit: www.seattlecca.org/cme.


Adult Bone Marrow Transplant News

The SCCA Adult Bone Marrow Transplant News is a publication presenting the latest information on bone marrow transplant research at SCCA, providing up-to-date information for all health care professionals caring for transplant patients.

Pediatric Bone Marrow Transplant News

Read about important outcomes research at the Fred Hutch that may benefit your patients.

Clinical Trials Monthly

Each issue of Clinical Trials Monthly highlights several of the more than 200 clinical trials that are currently recruiting patients at SCCA.

The Leading Edge Newsletter

Each quarterly Leading Edge newsletter will highlight a new topic to give you the latest news on leading-edge therapies that SCCA physicians are offering.