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Adult Bone Marrow Transplant Update - Winter 2012

In this issue we cover the following pertinent topics:

SCCA Tests Allogeneic Transplantation as a Cure for Severe Crohn’s Disease

SCCA researchers have initiated a long-awaited clinical trial of allogeneic bone marrow transplantation (BMT) to cure severe treatment-refractory cases of Crohn’s disease (CD).

As with BMT for congenital immune deficiency disorders in children, the goal is to replace the patient’s faulty immune system with a healthy one.  Researchers hope that eliminating the underlying genetic immune-related causes of CD will eradicate the terrible symptoms of the disease and also allow patients to stop using immune-suppressive drugs or biological agents meant to halt immune dysregulation and inflammation.

Enrollment in this Crohn’s Allogeneic Transplant Study (CATS) is open to patients 18 to 60 years of age who have failed to respond to all other treatments—including systemic glucocorticoids and tumor necrosis factor alpha antagonists. Patients must also have a matched marrow donor and an insurance company willing to pay for the treatment.

Hundreds of patients have already applied for the 12 available slots in this Phase II study, an indication of the huge unmet need for effective therapy for this debilitating disease. However, SCCA investigators still encourage qualified patients to apply for the SCCA study—not only because the strict enrollment criteria will eliminate many patients from eligibility but also because larger follow-up studies for CD patients may soon expand the opportunities for transplantation.

Information about CATS for physicians and patients (including a questionnaire to determine eligibility) is available at and on the SCCA website at

For patients in a life of miseryphoto of Dr. McDonald

The word “miserable” rarely appears in the medical literature. But sit and talk with George McDonald, MD, for 20 minutes about his patients with severe CD, and the word pops up with unsettling regularity.

McDonald, a gastroenterologist and transplant researcher at SCCA, is principal investigator for CATS. He says that about 10 percent of patients with CD—approximately 100,000 people in the U.S.—have a particularly bad form of the disease.

“The new biologic therapies have been a godsend to many of these people with severe Crohn’s,” he says. “But there are still those who don’t respond or become resistant.”

These are the refractory patients, according to McDonald, who face unremitting life-long misery—pain, fever, diarrhea, and weight loss—due to the chronic abnormal immune responses that trigger intestinal inflammation, ulcers, bowel strictures, and fistulas. Many patients eventually require bowelshortening surgeries and total parenteral nutrition. Some endure serious and potentially deadly complications from the highly immunosuppressive biologic therapies. The disease impact on employability and social life can be extreme.

“In its worst formulation, it’s a bad disease,” says McDonald. “And because longevity is not affected, these patients will likely be miserable their entire lives. These are the patients we want to bring into the trial.”

Immune system transplantation for Crohn’s disease: an idea whose time has finally come

The idea that BMT can rid patients of their CD is not new. In 1998, McDonald and his colleagues at Fred Hutchinson Cancer Research Center published a retrospective analysis showing that of four of five patients with both CD and leukemia were completely cured of CD by allogeneic BMT. The other patient rejected his graft, developed mixed chimerism, and eventually had a relapse of CD. German researchers reported similar findings in 2003.

Autologous transplants have also been used in CD with some success. In many patients, the strong course of immune suppression that precedes an autologous transplant calms the disease for years.

“But the CD tends to recur,” explains McDonald, “mainly because patients get their own immune system back—the autologous transplant fails to eliminate the underlying genetic disorder.”

“Our concept is simple,” he says. “Give these patients a completely new normal immune system.”

As further proof of principle for allogeneic BMT, McDonald describes how young patients with a CD-like intestinal inflammation related to specific genetic disorders (e.g., immune dysregulation, polyendocrinopathy, enteropathy, X-linked, or IPEX, and interleukin-10 receptor mutation) have also benefited dramatically from allogeneic transplantation.

With all this evidence from case series, why has it taken so long to test allogeneic BMT in patients with CD?

“Twenty years ago, the risk of allogeneic transplantation was too high,” answers McDonald. “Mortality rates have fallen substantially since then. It’s still by no stretch of imagination a risk-free procedure but we have solved many of the major problems.”

Two years ago, McDonald and SCCA colleagues published a paper in The New England Journal of Medicine showing a significant decrease in allogeneic BMT mortality from the mid-1990s to the mid-2000s. He says such documentation of allogeneic BMT safety helped to rebalance the risk-benefit
equation for transplantation in CD and to persuade the FDA to approve the clinical trial.

Even with this new “ethical equipoise,” caution is the watchword in CATS.

“There is always a risk in doing a transplant,” says McDonald, citing the possibility of graft versus host disease and transplantrelated death. “That’s why in this protocol we want only the most ill people, those with the highest misery index, who have failed every Crohn’s treatment known to man.”

Looking to CATS and beyond

As McDonald and his team get closer to enrolling and transplanting their first patient, they emphasize the difficulty of finding appropriate CD patients who also have an insurance company willing to pay for the procedure.

While the trial’s planning and start-up infrastructure is supported by a one-year grant from the Broad Medical Research Program, insurance is still needed to pay for the actual transplant and related care.

“This is a real stumbling block,” McDonald says, pointing out that until the efficacy and safety of performing BMT in these patients is established, insurers will remain reluctant to reimburse for this Phase II trial.

By early next year the first CD patients should have received their reduced-intensity allogeneic transplants. Short-term results are expected within a year. The study’s main endpoint is freedom from any signs, symptoms, or inflammation of CD and survival at one year. Patients will be followed for at least five years.

“Some CD studies define success as the Crohn’s Disease Activity Index going down by 50 percent or more,” says McDonald. “We define success as absolutely no signs or symptoms related to the inflammation. The disease has to be completely gone. That’s a pretty high bar.”

“If we are successful, the follow-up protocol is likely to be broader in its entry criteria. This next step will be a multicenter trial with other transplant centers around the country using the methods we perfect. CATS is just the start.”

Information about CATS for physicians and patients (including a questionnaire to determine eligibility) is available at and on the SCCA website at

Now Enrolling: Alternative Donor Transplant Study for Patients Lacking HLA Match

Researchers have developed two main “alternative donor transplants” for patients who need a bone marrow transplant (BMT) but lack a human leukocyte antigen (HLA) match. One approach uses umbilical cord blood from an unrelated source and the other employs HLA-mismatched (haploidentical) marrow from parents, children, or siblings.

Small Phase II trials indicated that these two different approaches can produce survival outcomes that are very similar to each other and to standard approaches with HLA-matched donors.

But will those results hold up in a larger multicenter randomized trial? Is one approach to alternative donor transplants better than the other? This is the central question now being asked in a major NIH-sponsored study of cord blood transplantation and haploidentical related BMT in patients with hematologic malignancies.

Vital questions—especially for minorities

Transplant outcomes are strongly affected by the degree of HLA match. The HLA-identical sibling match is still the preferred route for any BMT. And today, many patients who need BMT but lack a matched sibling donor can find a matched unrelated donor in a marrow registry. Nationally, success rates with matched unrelated donors have improved steadily—from an average overall 1-year survival of 42 percent in 2003 to 58 percent in 2010 according to the National Marrow Donor Program. Outcomes at Seattle Cancer Care Alliance (SCCA) are even better than those nationally. But searching for a match typically takes about three months—time that a patient with leukemia or lymphoma often cannot spare. Many patients succumb to their disease during this waiting period. In others, outcomes may be jeopardized by the long wait. And for minorities such as African Americans and Asians, or especially for those of mixed ethnic heritage, the chance of ever finding a suitable HLA-matched donor is very low—on the order of about 20 percent.

Study details and eligibilityO'Donnell photo

SCCA joins about 40 centers around the country who are participating in this new Phase III randomized trial. Paul V. O’Donnell, MD, PhD is one of the three principal investigators for this trial.

Patients between ages 18 and 70 years of age with a diagnosis of hematologic malignancy (acute leukemia or lymphoma) will be eligible for enrollment. Only patients lacking an 8/8 HLAmatched donor (sibling or unrelated) will be considered. An exception to this matching criterion may be made in cases of clinical urgency for transplantation. Organ function must be adequate and Karnofsky performance score must be >_70. Each patient must also have available two partially HLA-matched cord blood units and a partially HLA-mismatched related donor.

After randomization to either double-dose cord blood transplant or haploidentical BMT, patients will receive the appropriate reduced-intensity conditioning regimen, undergo transplantation, and be followed for three years. The non-myeloablative conditioning, which was pioneered at Fred Hutchinson Cancer Research Center (FHCRC), improves engraftment, reduces the risk of graft versus host disease (GVHD), and helps older and less fit patients avoid complications.

The study’s primary endpoint is relapse-free or progression-free survival after two years. Other outcomes to be measured include engraftment, neutrophil and platelet recovery, acute and chronic GVHD, overall survival, infections, quality of life, and cost effectiveness.

The goal: no clinical barrier to BMT

If this study of over 400 patients can confirm the safety and efficacy of these two alternative approaches, it would prove that essentially all patients in need of a transplant would be able to get one. The HLA barrier to BMT would continue to fall.

“Use of alternative donors would expand the patient population benefiting from BMT by about 40 percent,” says O’Donnell. “Also, since we know that the time from diagnosis to transplant may impact survival, wider availability of alternative donor methods may also allow more timely transplantation—perhaps within one to two months of diagnosis—and therefore these alternatives may also spur the next phase of incremental improvement in survival for patients with high-risk hematologic malignancies.”

O’Donnell also points out that expanded access to transplant would have profound consequences for thousands of cancer patients and their families every year, as well as the government and private health insurers who pay for this expensive treatment. That’s why the economic consequences of expanding Ramsey phototransplantation access with alternative methods are also now being evaluated in a parallel study by O’Donnell and his FHCRC partners Scott D. Ramsey, MD, PhD and Mark E. Bensink, PhD. (See: Measuring the Price of Success: Cost-Effectiveness Study of Alternative Donor Transplants)

More information

This study of alternative donor transplant methods is now enrolling patients at SCCA. More information is online at

To see the full protocol and FAQs on the BMT-CTN website, go to:

To ask questions or enroll a patient, contact Paul V. O’Donnell, MD, PhD at or call SCCA at (800) 804-8824.

Measuring the Price of Success: Cost-Effectiveness Study of Alternative Donor Transplants

Many patients needing a bone marrow transplant (BMT) never find HLA-matched donor cells. Others fall gravely ill during the long search for a suitable match. All told, about a third of patients requiring BMT—thousands of patients every year in the U.S.—fall into this “marrow match gap.”

In recent years, two “alternative donor transplant” methods have been developed for these patients. One uses umbilical cord blood and the other uses HLA-mismatched marrow from family. Both methods are now being evaluated in a multicenter randomized trial, a description of which can be found elsewhere in this issue. (See: Alternative Donor Transplant Study for Patients Lacking HLA Match)

Although the alternative donor trial only started in September, researchers at Seattle Cancer Care Alliance (SCCA) are already looking down the road and asking, if this works, and if more patients suddenly can receive a transplant, how much will it cost? The answer will have implications for patients and families, for insurers, and for society as a whole.

A piggyback study of costs

Scott D. Ramsey, MD, PhD, is principal investigator of the cost effectiveness trial. Paul V. O’Donnell, MD, PhD, and Mark E. Bensink, PhD, are his SCCA co-investigators on the new NIH-funded trial.

Ramsey says the alternative donor study provides a unique opportunity to capture all economic impacts of the new methods—from start to finish and from multiple perspectives. That’s exactly why his study was designed as an economic evaluation to parallel the parent multicenter study.

“Bone marrow transplants are one of the most expensive interventions in healthcare,” he says, citing a cost of around $800,000 in direct medical costs per allogeneic transplant on average. (This estimate is based on proprietary claims data from Milliman, the large healthcare and insurance consulting firm, in one of the few recent studies to look at the cost of transplant in the U.S.)

According to Ramsey, the alternative methods may be even more expensive. “For example, the costs of umbilical cord blood procedures,” he says, “may increase costs by up to 40 percent because of the extra costs for acquiring and storing the cord blood.”

Ramsey, who heads up the Research and Economic Assessment in Cancer and Healthcare (REACH) group at Fred Hutchinson Cancer Research Center, says these high costs alone make it critical to project the full budget impacts of expanded transplantation access.

But he also points to the need for determining the exact cost differences between the two alternative methods, as well as any differences in outcomes such as engraftment, infection risk, progression-free survival, overall survival, and quality-of-life.

“Only by measuring all these unknowns in prospective fashion,” he says, “can we construct a solid cost-effectiveness analysis that is capable of guiding insurance coverage decisions that reflect the interests of both patients and payers.”

Patient perspectives on cost

Many patients or families who have been through a transplant can tell you that the money aspects—even if the procedure is a complete success and if insurance covers the bulk of it—can add major stress to the whole ordeal. The financial planning and bill-paying can be nightmarish. Out-of-pocket costs, copays, and post-transplant prescriptions are often significant. Time away from work also takes a toll on family income, with bankruptcy rates known to be higher in younger patients with leukemia and lymphoma.

To get a better handle on the complete financial impact of BMT, Ramsey and his colleagues will also use their study to gather information on costs from the patient and family perspective.

To increase participation in this part of the study, the SCCA group has created a novel web-based survey tool. This e-survey can be completed at home or on a mobile device. Expenses related to copays, uncovered medical bills, travel, accommodations, child care, and family caregiver time will all be probed in the survey.

“This patient and family perspective has never been systematically studied in BMT," says Ramsey.

Rituximab shift lymphoma landscape. But what about patients still out of the picture?

Introduced over a decade ago, rituximab has dramatically improved survival in patients with lymphomas. When combined with CHOP therapy (cyclophosphamide, hydroxydoxorubicin, oncovin, and prednisone) in first-line treatment, this anti-CD20 monoclonal antibody has boosted cure rates to 60 or 70 percent in those presenting with advanced disease.

But the good news has a residual downside effect: the group of relapsed or refractory patients, although smaller in size, is now known to be more likely to fail the standard next step of salvage therapy: autologous stem cell transplantation.

“Essentially, by having better treatment up front,” says Ryan D. Cassaday, MD, senior fellow in medical oncology at Seattle Cancer Care Alliance (SCCA), “we are only seeing those relapsed patients with lymphomas that are by their nature more aggressive or harder to cure. We’ve shrunk the relapsed population, but we’ve also selectively enriched it with difficult-to-treat lymphomas.”

Cassaday, who specializes in management of aggressive lymphomas, says that physicians need to stay aware of these shifting patterns of survival and risk at the first- and second-line stages of therapy. In particular, he says, early referral of patients who fail R-CHOP may give them a better chance.

“Here at SCCA,” he says, “we identify relapsed high-risk patients who will likely not do as well with standard autologous transplantation. We are working to understand the biology of these aggressive B-cell lymphomas and find better targets and better treatments. Early referral of these high-risk patients allows them to access the new options that might improve their chances.”

New transplant options for high-risk aggressive lymphoma patients

Over two dozen investigational therapies for relapsed or refractory lymphoma patients are now being tested in SCCA clinical trials. They include novel combination regimens at all stages as well as targeted chemotherapeutics, biological agents, radioimmunotherapies, and transplantation.

Cassaday and Ajay K. Gopal, MD, director of Clinical Research for Hematology
Malignancies at SCCA, are currently conducting two trials using radioimmunotherapy—basically a radioactive isotope attached to a monoclonal antibody that zeros in on a lymphoma surface protein—as part of the conditioning regimen for stem cell transplantation. Radiolabeled anti-cancer agents have been available for decades (and in fact were pioneered here in Seattle) but they have not yet found an established role in transplant conditioning.

  • In a Phase I trial, iodine-131 attached to anti-CD45 monoclonal antibody BC8 is used as part of the conditioning before an autologous transplant. This trial includes lymphoma patients with documented CD45+ cells (tumor or adjacent) who have failed prior systemic therapy. (More information online at
  • In a Phase II trial, high-dose yttrium-90 attached to ibritumomab tiuxetan (anti-CD20) is given together with a reduced-intensity conditioning regimen for allogeneic transplantation (chemotherapy and low-dose systemic radiation). This trial is open to patients with diffuse large B-cell lymphoma, Burkitt lymphoma, or other aggressive CD20+ B-cell lymphomas who have either suffered relapse following, or are ineligible for, high-dose therapy and autologous transplantation. (More information online at

Recognizing the extreme difficulty in establishing cure in certain patients who have already failed standard chemotherapy, David Maloney, MD, PhD, medical oncologist and researcher at SCCA, is providing an even more proactive transplant option: a sequential autologous-then-allogeneic transplant. The goal here is to identify patients at highest risk of failure with conventional autologous transplant alone and, instead, use the tandem protocol as a one-two punch that knocks the lymphoma into remission and then immediately delivers a powerful graft-versus-lymphoma effect.

Who is highest risk?

While relapse after rituximab-containing therapies certainly raises a red flag for high risk in lymphoma, researchers are now searching for better—earlier and more biologically based—indicators to predict treatment outcome. In general, the type of lymphoma has long been considered a key risk factor, with diffuse B-cell lymphomas and transformed indolent lymphomas tending to be among the most aggressive. The International Prognostic Index (which includes age, stage, lactate dehydrogenase [LDH]) is another way to predict likelihood of relapse, but this index does not reflect the underlying biology nor does it account for evolving treatment patterns, such as younger patients who may be able to tolerate transplants.

To refine risk prediction and help determine who would benefit most from clinical trials such as those described above, new risk stratification strategies are being developed. For example, the gene expression profile and the cell of origin (i.e., maturation stage of the lymphocyte) may impact aggressiveness. Specific chromosomal rearrangements are also known to correlate with lower cure rates. In fact, new tests for such rearrangements based on immunohistochemistry (IHC) rather than gene detection may soon allow improved risk stratification. In particular, recent research indicates that patients with “double-hit” lymphomas (IHC-positive for both MYC and bcl-2) have a particularly low rate of five-year survival. (For a quick audio overview of these recent results, listen to Dr. Gopal at

While none of these risk markers is specific enough to predict the outcome in a given newly diagnosed patient, they are increasingly being considered after rituximab failure to identify patients who might benefit from alternative transplantation protocols or from one of the many other lymphoma trials now being tested at SCCA (e.g., for combination chemotherapies or for post-transplant maintenance therapy). (More information online at

“Early referral of patients with these high-risk features or at the first sign of relapse can ensure they get access to the most appealing investigational therapy,” says Cassaday.

Related Documents:

11-27-2012 SCCA_AdBMT_Nov12_F.pdf (1191kb)
A printable, PDF version of the Adult Bone Marrow Transplant Update Nov. 2012 issue.

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.