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Adult Bone Marrow Transplant Update - Spring 2014

In this Issue

Seeking New Leverage Against Multiple Myeloma

In most cases, multiple myeloma (MM) is treatable but not curable. This malignant neoplasm of plasma cells is often sensitive to cytotoxic drugs, but the effect is transient, partly due to evolving tumor biology. Most patients go on to develop resistance and eventually relapse and die from the disease.

Despite the lack of definitive therapy, great progress has been made in the fight against MM. In fact, five-year survival rates have doubled in recent decades because of more effective treatments—perhaps none more important than melphalan-based high-dose therapy followed by autologous bone marrow transplantation (BMT), which remains a standard therapy for many younger patients. Newer agents such as thalidomide, lenolidomide, and bortezomib have further improved MM outcomes. Seeking even greater leverage in the fight against MM, Seattle Cancer Care Alliance (SCCA) has initiated several clinical studies involving BMT methods as well as new immunotherapies, radiotherapies, and targeted drug treatments. Here, we summarize the current role of BMT in MM treatment and briefly review MM studies underway or in planning at SCCA.

Key Points about Myeloma Therapy and Transplantation

  • Newer, more effective combination therapies can now help nearly all patients with newly diagnosed MM achieve a clinical response.
  • Autologous transplantation after high-dose chemotherapy is still standard for many younger MM patients to provide a more durable remission.
  • Harvesting stem cells before any extended drug therapy may be prudent to keep the transplantation option open.
  • Many clinical trials are ongoing to determine roles of newer targeted therapies and autologous and allogeneic transplantation.
  • Referral to a MM specialist is recommended.

Autologous Transplantation in MM: Deeper Remission, Longer Survival

According to William I. Bensinger, MD, University of Washington School of Medicine professor, transplanting the patient’s own stem cells following high-dose chemotherapy allows for a deeper level of disease remission and extended survival compared to standard therapy.

“For a patient who would otherwise have resistant disease after standard chemotherapy, the autologous transplant after high-dose therapy can help get their disease under control,” he said. “And for a patient who would have a fairly good response to standard chemotherapy, the transplant option can convert them into a complete responder.”

Bensinger explains that this extra boost provided by transplant has now been documented not only using conventional measures of response (e.g., proteins in the blood or urine and plasma cell morphology) but also using more sensitive, or “stringent” techniques (e.g., serum-free light-chain assay and flow cytometry). Even in patients taking combinations of the newest drugs, a transplant is now known to increase the proportion of patients achieving this stringent complete response.

This matters because achieving a stringent response can also lengthen the disease-free interval and improve survival—a fact supported most recently in data presented at the December 2013 American Society of Hematology meeting.

Many Older Patients Not Eligible for Autologous BMT

Of the 22,000 new cases of MM each year in the United States, only about half are eligible for autologous transplantation. The main reason for this is MM has a median onset age of 70 years, and the evidence does not support transplant efficacy in elderly patients. Advanced age also brings more comorbid conditions—such as severe lung or heart disease or advanced diabetes—that increase transplant risk. Thus, although transplantation can be safe in some patients over 70, these MM patients are generally ineligible for transplant.

Of the younger MM patients who are eligible for autologous BMT, Bensinger said only about half actually get one. “Obviously, there are many patients who could benefit who are not having it done,” he said.

Some of the hesitation may exist because it remains difficult to predict which young patients will benefit most from BMT. Transplant timing—for example, whether it should occur early or late in the disease process—is also debated. Until ongoing studies answer these questions, Bensinger said transplantation should continue to be the clear recommendation for the majority of younger qualified patients.

Allogeneic Transplantation, an Investigational Option

Allogeneic transplantation, an even riskier procedure than autologous transplantation, is considered investigational in MM patients for similar age-related reasons.

“Older patients have more immune deficiencies, which makes them more susceptible to infection,” Bensinger said. “As a group, MM patients are more fragile than most leukemia patients. They have more severe side effects and greater mortality after donor transplantation.”

Despite the clear risks and controversy, certain situations still call for allogeneic transplantation in treating MM, either alone or after an autologous transplant. These approaches sometimes involve a nonmyeloablative preparative therapy. As reported recently by Bensinger and his SCCA colleagues [Bone Marrow Transplant 2012;47:1312-1317], MM patients receiving reduced-intensity transplants at SCCA had significantly less acute graft-versus-host disease (GVHD), lower transplant mortality, and better overall survival compared to those having myeloablative transplants. New regimens of both autologous and allogeneic anti-MM transplant are now being tested in SCCA clinical studies.

Studies for MM Patients

At SCCA at any given time, there are typically a dozen or more clinical study opportunities for patients with MM. For example, two Phase III studies involving BMT, one testing different doses of melphalan and the other testing lenalidomide maintenance, recently completed enrollment. The following actively recruiting or soon-to-open clinical studies show the range of BMT-focused MM research now underway at SCCA.

  • Targeted radiation before allogeneic transplantation (2450) The newest SCCA trial to get underway, this Phase I study is testing a radioisotope (yttrium 90) attached to an anti-CD45 monoclonal antibody (BC8) that targets cancer cells in the bone marrow, spleen, and lymph tissues. The patient then receives nonmyeloablative chemotherapy (fludarabine) and low-dose total-body irradiation before receiving healthy stem cells from a suitably matched donor. The goal is to study tissue localization and side effects and determine the best dosing. Patients with MM who are 18 to 65 years of age are eligible.
  • Tandem transplantation and then bortezomib maintenance (2070) This Phase II study will measure the safety and efficacy of tandem autologous-then-nonmyeloablative allogeneic BMT. Patients will receive nine months of maintenance follow-up therapy with bortezomib, a MM-specific proteasome inhibitor. The nonrandomized study seeks to enroll adult patients with newly diagnosed high-risk MM.
  • Carfilzomib plus melphalan in autologous transplantation (Open spring 2014) This new study will measure the potential benefit of combining high-dose melphalan with an agent called carfilzomib, an injectable proteasome inhibitor approved for use as a single-agent therapy for MM. The study will determine if the combination can boost eradication of diseased plasma cells before stem cell recovery with autologous transplantation.

Several other SCCA studies are evaluating novel agents in MM populations that often include transplanted patients. Agents now or soon to be tested include:

  • oral proteasome inhibitor
  • apoptosis-promoting agent
  • selective histone deacetylase inhibitor
  • monoclonal antibody that targets CD-30
  • monoclonal antibody that targets CD-38
  • monoclonal antibody that targets CXCR4
  • Bruton’s tyrosine kinase inhibitor
  • anti-CD38 monoclonal antibody linked to aurostatin

These and other even newer agents that target MM cellular pathways will continue to be tested in coming years. In some cases, they will be used in transplant-ineligible patients or as salvage therapy for relapsed or refractory disease. In other situations, they will be tested as pre-transplant induction therapy or post-transplant maintenance therapy. Often, they will be combined with other agents to heighten the overall therapeutic effects. And in an increasing number of MM settings, these emerging therapies will be used in conjunction with BMT in an attempt to prolong remissions and increase survival.

It will be several years before researchers determine the best combination strategies for MM therapy. Because of the complexity and evolving nature of this treatment, referral to a myeloma specialist is recommended. See the complete listing of SCCA MM clinical trials.

How to Help Your BMT Patient in the Years After Transplant

Stephanie J. Lee, MD, MPH, first became interested in bone marrow transplantation (BMT) in 1994 during her fellowship in hematology/oncology at Brigham Women’s Hospital in Boston.

“When I started, how to monitor survivors was not an issue,” she said. “The papers on transplant survivorship were just starting to come out.”

But with all the transplantation advances of the past 20 years, success rates have increased steadily.

“Now survivorship is a much more pertinent issue,” she said. “Getting through the transplant and curing the disease is obviously critical, but we want to do it with a good quality of life.” For Lee, who grew up in Redmond, Wash., got her undergraduate degree at the University of Washington, and still has family in the area, returning to Seattle in 2006 was a natural move that allowed her to continue her research in transplant survivorship.

LTFU Resources for Physicians

As the new director for the Long-Term Follow-Up Program (LTFU) at Seattle Cancer Care Alliance (SCCA)/Fred Hutchinson Cancer Research Center, Lee is in a perfect position to track patients who have had a blood or marrow transplant and identify the main problems seen in the years and decades following the procedure.

Communicating research results to the patient’s primary physicians is one of her goals.

“We don’t expect the oncologists and internists taking care of these patients after transplant to have the latest information at their fingertips,” Lee said. “These are patients with unique complications, risks, and treatments. That’s why the LTFU is always happy to guide physicians.”

One main LTFU resource for physicians is the detailed and up-to-date Patient & Caregiver Resource Manual. Lee has also co-authored national guidelines and generalist reviews on managing these patients [Biol Blood Marrow Transplant 2012;18:348-371; J Clin Oncol 2012;30:71-77; Blood 2011;117:3002-3009].

“Even more important than the general resources, our clinical group also gives physicians a patient-specific discharge summary with guidance on their patient’s expected course and screening schedule,” Lee said. “We hope this gives physicians a pathway for what to expect, and for when the patient needs to come back to our clinic for testing.”

The LTFU staff is also available by phone at (855) 557-0555 to answer any questions about identifying symptoms of graft-versus-host disease (GVHD), managing complications, starting or stopping treatments, or dealing with work reintegration, travel, and insurance.

Cardiovascular Risks Can Be Modified

In her research, Lee is trying to characterize longer-term complications and experiences of patients. One of her chief research tools is the survey sent to thousands of SCCA transplant survivors every year. In addition to soliciting routine data on health status, employment, and other core outcomes, the survey asks questions on one specific issue each year. In recent years, these themes have included cardiovascular disease, depression and fatigue, and resilience.

Results from the cardiovascular project, which were just published [J Clin Oncol 2014;32:191-198], demonstrated significantly higher rates of cardiomyopathy, stroke, and diabetes—but, importantly, all these conditions were attenuated in survivors with healthier lifestyle characteristics.

“This is very relevant for referring physicians because it shows how traditional risk factors are still at work in our population,” Lee said. “These patients have so many other special issues related to the transplant, sometimes people question whether they should bother to treat conventional cardiovascular risks like obesity, lipids, smoking, or hypertension. This study showed, yes, it’s actually extra important to recognize and treat cardiovascular risk in these high-risk patients.”

Depression, Fatigue, Resilience

In her new study of depression and fatigue, done in collaboration with investigators at Moffitt Cancer Center in Florida, Lee is exploring possible genetic or biologic traits that might predispose a patient to these problems.

“If we know who is at risk before transplant,” she said, “maybe we can do something differently or at least be prepared for these complications.” Similarly, in the LTFU study of resilience after transplant, Lee and Abby Rosenberg, MD, of UW Pediatrics are hoping to find specific behaviors that help patients as they go through the trauma of transplant.

“Some people come through a transplant and are happy to be alive,” Lee said. “Even if they don’t feel 100 percent, they turn it into a positive experience. Others never really recover, even if they feel well. You might think resilience can’t be modified, that it’s part of your personality. But resilience is more complicated. You can actually train people to be more adaptive and more positive in the face of a severe challenge like transplant. We are just at the beginning of understanding this.”

Other SCCA Studies

In addition to her LTFU studies, Lee leads a consortium of institutions trying to improve understanding of GVHD. Funded by National Institutes of Health and the U.S. Office of Rare Disease Research, these studies are evaluating risk factors as well as treatments.

She points out that GVHD research and, indeed, practically all SCCA research today is aimed at improving long-term outcomes—whether in terms of relapse prevention, control of complications, or improvement of quality of life.

“We researchers are taking different approaches,” Lee said, “including some who start interventions at the time of transplant. The new treatments with personalized T cell infusions and other cell and drug therapies are very exciting. It’s all evolving quickly and that offers hope that we’ll continue to see success rates improve.”

Can Statins Prevent GVHD?

Testing an Old Drug in a New Setting

Graft-versus-host disease (GVHD) remains a major barrier to successful allogeneic bone marrow transplantation (BMT). Acting on evidence from retrospective studies and animal tests, researchers at Seattle Cancer Care Alliance (SCCA) are now evaluating one of the world’s most widely used drugs—atorvastatin—for its potential in preventing severe acute GVHD after BMT.

Meanwhile in the laboratory, SCCA researchers are inching closer to understanding exactly how statins may act—separate from their well-known cholesterol-lowering effects—to alter donor T cells and elicit this clinical effect. (See following article, How Statins Prevent GVHD.)

A Life-Threatening Complication

Despite ever-improving prophylaxis with immunosuppressants, about three of every four patients still develop some degree of GVHD after allogeneic BMT. The good news is that most GVHD can be controlled—for example, with drugs such as prednisone or cyclosporine—and usually fades away with time as the donor T cell population gradually becomes more tolerant of its new surroundings.

About one in every 10 patients, however, is struck with difficult-to-treat acute, severe GVHD. This life-threatening GVHD can provoke major inflammatory damage in the gastrointestinal tract with severe diarrhea and cramping. Skin rash and liver problems are other potential consequences, but the rampant GI inflammation remains the main cause of morbidity and mortality.

Hints of a Statin Role in GVHD

Statins may be the Swiss Army knife of the drug world, with one blade slicing into a liver enzyme, another cutting away at inflammatory functions, and a corkscrew popping open an array of immune actions. These drugs have multiple actions or, as scientists say, “pleiotropic effects.” For decades, doctors and scientists have understood that statins do more than just block cholesterol synthesis. In fact, the same pharmacologic pathway where statins act to inhibit cholesterol biosynthesis has a major branch that works to attach short fatty acids to proteins—called prenylation. Several prenylated proteins act as molecular switches that help control basic functions in all types of cells—including immune cells.

“If prenylation is disrupted, certain transduction proteins involved in activated T cells could be affected,” explained Marco Mielcarek, MD, an oncologist and the medical director of the Fred Hutchinson Bone Marrow Transplant Program at SCCA. “This is one possible way we think statins impact immunity.” Mielcarek was first motivated to explore how statin immune actions might translate into anti-GVHD effects after seeing animal data documenting that statins given to donor and recipient mice in a stem cell transplantation model significantly reduced GVHD.

Building on this evidence and on a small clinical case series hinting at the same effect, Mielcarek and his colleagues looked back over SCCA’s entire historical database to determine the impact of statin therapy in transplants involving sibling donors. This retrospective SCCA study [Rotta et al. Blood 2010;115:1288-1295] involving 567 transplantation procedures found that if the donor was on a statin when he or she donated stem cells, the likelihood of Grade 3 or 4 acute GVHD was dramatically reduced.

Two other findings stood out in this retrospective analysis. First, the statin effect was far greater in recipients taking cyclosporine rather than tacrolimus after the transplant. Second, if the recipient was on the statin, but not the donor, there was no net positive effect, a result subsequently confirmed in a follow-up SCCA retrospective study that included unrelated donors. [Rotta et al. Bio Blood and Marrow Trans 2010;16:1463-1466]

Although these data were compelling, and although SCCA is now collaborating with the National Marrow Donor Database to confirm these results in an even larger population of unrelated donor transplants, only a prospective study will define the true role of statins in preventing GVHD.

SCCA Prospective Studies of Statins

The two prospective clinical studies now underway at SCCA are asking whether statin treatment of sibling stem cell donors before a transplant can prevent severe acute GVHD after transplant. The sibling donors will be given two weeks of oral atorvastatin before their stem cell donation. Other study features:

  • The studies are open label and single group (i.e., no blinding or placebo group)
  • One study focuses on myeloablative procedures, the other on nonmyeloablative
  • Adult patients with all types of blood cancers are eligible
  • Donors currently using statins are excluded
  • The primary endpoint is the incidence of Grade 3 or 4 acute GVHD
  • Secondary endpoints include chronic GVHD incidence, recurrent or progressive malignancy, nonrelapse mortality, survival, and statin discontinuation due to side effects)

“The milder forms of GVHD are relatively easy to treat,” said Mielcarek, who is the principal investigator on both studies. “But Grades 3 and 4 are resilient and cause significant mortality in patients. If we can get rid of these severe forms, that would make a real impact.”

Mielcarek is assuming a baseline Grades 3-4 acute GVHD risk of 12 percent in the myeloablative study (target enrollment = 60) and eight percent in the nonmyeloablative study (target enrollment = 100 patients). Thus, he projects that seeing fewer than six patients develop severe acute GVHD in each study would validate a statin effect. Recently, he reached out to other cancer treatment centers to increase the speed of enrollment in this high-priority trial.

By reducing or eliminating one of the most significant transplant complications, the knowledge gained in these SCCA studies will make transplantation a safer and more successful treatment for many more patients with serious blood cancers.

Read more about these studies at Atorvastatin for Preventing GVHD After Myeloablative Transplant (FHCRC-2545) and Atorvastatin for Preventing GVHD After Nonmyeloablative Transplant (FHCRC-2546).

How Do Statins Prevent GVHD?

As SCCA clinical studies test whether statins can reduce GVHD after stem cell transplantation, researchers are probing the possible mechanisms for this action. At Fred Hutchinson Cancer Research Center, this line of laboratory investigation is led by Marco Mielcarek, MD.

Why Does it Matter?

Mielcarek admits that finding the drug mechanism is not necessary for the clinical study to move ahead—or, if the trials are positive, for the drug to be used clinically in transplantation. Indeed, statins are already on the market, they are cheap, and they are considered relatively safe.

“You could argue that you don’t need to know the mechanism as long as we have a drug that does the job,” he said. Which calls to mind the Chinese proverb: “It doesn’t matter if it is a white cat or a black cat; as long as it can catch mice, it is a good cat.”

But knowing the mechanism of action—the color of the cat, the sharpness of its claws—does matter, according to Mielcarek. “If we understand the mechanism,” he said, “it might spur development of even more effective treatments with even fewer side effects and, more fundamentally, help develop a better understanding of how T cells are driven to cause GVHD.”

One Hypothesis: Mitochondria and Apoptosis

To gain insights into statin actions, Mielcarek and his associates are testing a variety of ways T cells might be affected by these drugs in the laboratory. Recently, they have focused on statin-induced changes in T cell mitochondrial function. Their working hypothesis is that both cyclosporine and statins impact the mitochondria.

This would help explain why, in the SCCA retrospective study, statin-primed grafts did not cause severe GVHD in patients who were taking cyclosporine—but did cause significant GVHD in those taking tacrolimus. Both these GVHD-preventing drugs are calcineurin-inhibitors, but they interfere with T cell function in slightly different fashions.

An expert on mitochondrial function, David Hockenberry, MD, in the Clinical Research Division of the Hutch, has collaborated on the experiments related to possible statin-cyclosporine synergism within the T cell mitochondria. One key action they are watching closely in the T cells is the induction or prevention of apoptosis—programmed cell death—under various culture conditions.

Changes in the Donor Graft Composition

Another way to zero in on potential statin immune mechanisms is to compare the composition of statin-primed donor blood cell grafts with those of the “typical” non-statin grafts. If one particular type or subclass of T cells predominates in the statin graft, this will provide a powerful clue about the anti-GVHD mechanism.

For this effort on evaluating donor grafts, Mielcarek is partnering with Shelly Heimfeld, PhD, of the Clinical Research Center at the Hutch. “We want to know how statins impact the graft composition,” Mielcarek said. “Dr. Heimfeld has a large SCCA database showing normal graft composition, so we will be in a good position to detect any statin-related variations in immune cell populations.”

The statin-treated grafts for this investigation are coming from the two SCCA prospective clinical studies of statin-mediated GVHD prevention. As statin actions in T cells are revealed, clinicians will be more confident in employing this new weapon against the worst forms of GVHD, and researchers will have a better understanding of the basis for post-transplant GVHD as well as a head start in developing even better anti-GVHD agents.

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