Efforts intensify to ensure accessibility, sustainability of HSCT

Hematopoietic stem-cell transplant, initially developed as a rescue therapy for patients with cancer, has evolved over the past few decades into a standard treatment for many patients with benign and malignant hematologic conditions.

In 2012, the number of hematopoietic stem-cell transplants (HSCT) performed worldwide reached 1 million. They include allogeneic — or donor-derived — and autologous, or patient-derived, transplantation of marrow, peripheral blood stem cells or umbilical cord blood stem cells.

Two more milestones occurred this year: The Center for International Blood and Marrow Transplant Research (CIBMTR) celebrated its 10th anniversary, and the number of potential US donors listed on Be the Match Registry — maintained by the National Marrow Donor Program to help patients receive marrow or umbilical cord blood transplants — reached 10.5 million.

“There is no doubt that bone marrow transplantation is now a much more accessible tool for curative therapy in blood cancers than it was 40 years ago, when the field first began,” Mary Horowitz, MD, chief of the division of hematology and oncology at the Medical College of Wisconsin and chief scientific director of CIBMTR, told HemOnc Today. “It is now possible to find an acceptable, if not optimal, donor for almost everybody. Innovative regimens allow us to do transplants across compatibility barriers, with regimens that allow engraftment with much lesser degrees of toxicity.”

Despite these advances, considerable barriers to transplant remain.

Most relate to access, such as the lack of donors for patients of certain ethnicities, the limited number of transplant physicians and centers in the United States, and clinician biases against referring older patients for the procedure. Others are outcome driven: In some settings, such as chronic myeloid leukemia, newly developed targeted therapies have proven safer and more effective than transplant.

HemOnc Today spoke with several HSCT specialists about recent progress in the field, the intense effort to improve access to transplant, the ways in which the procedure’s safety and efficacy can be improved, and the role transplant will play in the evolving treatment paradigm for hematologic conditions.

The treatment landscape

E. Donnall Thomas, MD, pioneered the use of bone marrow transplantation in the 1970s by performing the procedure in pediatric patients with acute leukemia, a quarter of whom were cured.

This success — enabled by an increased understanding of tissue typing — was the watershed moment in the creation of the field, Sergio A. Giralt, MD, chief of the adult bone marrow transplant service at Memorial Sloan Kettering Cancer Center and a HemOnc Today Editorial Board member, said in an interview.

“After this finding, patients with marrow diseases like aplastic anemia, acute leukemia and myeloma who had a matched brother or sister could be cured,” Giralt said. “The big barrier to be able to get this curative treatment was not having a matched donor in the family.”

The likelihood of having a matched sibling in families of two to three children is about 30%, Giralt said. The National Marrow Donor Program provides a database of donors for patients without a matched sibling. Since the program’s launch in 1986, donor recruitment efforts have greatly improved the likelihood of finding unrelated matches.

A study by Gragert and colleagues — published in July in The New England Journal of Medicine — found patients with white European ancestry have a 97% probability of finding at least a 7/8 human leukocyte antigen (HLA)-matched donor in the US registry.

However, the likelihood of finding an optimal adult donor — meaning an 8/8 HLA match — ranges from 75% for patients of white European descent, to 16% for those of black South or Central American descent.

“Transplanting with a mismatched transplant is a better way to go given the diminishing likelihood that the miracle match will register in the next round of recruitment,” Martin Maiers, director of bioinformatics research at the National Marrow Donor Program, told HemOnc Today when the study was published. “This study supports taking a mismatch today vs. waiting for the possibility of an optimal match tomorrow.”

The ability to use cord blood for transplantation also has improved access, and the US registry contains 200,000 cord-blood units. Although cord blood contains a fraction of the stem cells found in marrow, cord blood mismatches are more suitable for transplant. The probability of finding at least a 4/6 HLA-matched cord blood unit is 95% or greater for all 21 ethnic groups analyzed in the Gragert study.

Haploidentical transplant — or transplant from a half-matched family member, including a parent, child or sibling — also has demonstrated promise, Edward A. Copelan, MD, FACP, chairman of the department of hematologic oncology and blood disorders at Carolinas HealthCare System’s Levine Cancer Institute and a HemOnc Today Editorial Board member, said in an interview.

A study by Raiola and colleagues — published in June in Biology of Blood and Marrow Transplantation — showed 2-year transplant-related mortality was comparable among patients with haploidentical or matched sibling donors (18% to 24%) compared with those who had matched unrelated, mismatched unrelated or unrelated cord blood donors (33% to 35%; P=.1).

“Almost all minority patients without matched siblings will have haploidentical donors,” Copelan said. “I believe that this is the technique that will overcome our inability to find donors.”

Further, outcomes have significantly improved since the early days of transplantation.

Hahn and colleagues compared outcomes of 38,060 patients who underwent allogeneic HSCT between 1994 and 2005. Results — published in 2013 in Journal of Clinical Oncology — indicated 100-day survival rates significantly improved during the study period for patients who underwent HLA-matched sibling transplants with myeloablative conditioning. Researchers observed the survival improvements among patients with acute lymphoblastic leukemia in first remission (85% vs. 94%), CML in first chronic phase (84% vs. 98%), myelodysplastic syndrome (71% vs. 88%) and non-Hodgkin’s lymphoma (66% vs. 84%; P˂.001 for all). Results showed similar improvements for HLA-matched unrelated donor transplants. One-year survival rates also improved, but these improvements often were not statistically significant.

“The lack of a perfect donor shouldn’t deter people from considering transplant in situations where non-transplant therapy is not very effective,” Horowitz said. “I think most people agree that the best outcomes are with fully matched adult related or unrelated donors, but there are a variety of other alternatives with acceptable outcomes that offer very good therapeutic options for patients.”

Unanswered questions

Although the ability to find suitable donors and survival outcomes has improved, transplant physicians still face formidable challenges.

“There is substantial debate about transplant’s use in certain indications, in the upfront setting, and in high-risk situations that have been newly identified with immunoperoxidase staining and gene array testing,” Philip J. Bierman, MD, professor of internal medicine in the division of hematology and oncology at the University of Nebraska Medical Center and HemOnc Today’s associate editor for hematology, said in an interview. “Who should get an autologous transplant, and who should get an allogeneic transplant? What kind of conditioning is ideal with allogeneic transplants? How do alternative donors factor in?”

Each patient must be considered individually when deciding between standard therapy and transplantation, Richard E. Champlin, MD, chair of the department of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center, told HemOnc Today.

“With new molecular markers of the disease and understanding various chromosomal abnormalities, we can categorize patients into good-, intermediate- and bad-risk categories,” Champlin said. “These categories continue to be refined.”

Half of patients with favorable-risk cytogenetics can be cured with standard treatment, so physicians typically reserve transplantation for those with poor-risk markers or who have relapsed on standard therapy, Champlin said. However, the best treatment course is less clear for patients with intermediate-risk cytogenetics.

“It is hard to make the decision for patients in the middle,” Horowitz said. “We have tried to provide data on risk factors for transplant outcomes that are beneficial to that equation, but there are certainly some diseases in which an early vs. late transplant strategy would be worth exploring in a phase 3 setting, such as in an older population with high-risk myelodysplastic syndrome.”

The question about ideal timing of transplant has been the subject of extensive research.

Pai and colleagues assessed outcomes among infants with severe combined immunodeficiency. Results, published in July in The New England Journal of Medicine, showed 5-year OS was 94% (95% CI, 85-98) among patients who underwent HSCT while aged 3.5 months or younger, compared with 50% (95% CI, 39-61) among those who were aged older than 3.5 months.

“In almost every situation, we’re trying to identify the best time to do transplant, which we generally want to do before the disease worsens and becomes highly resistant to treatment,” Champlin said.

Timing also may affect transplant recipients’ risk for second cancers.

“It is hard to define the precise extent to which transplant contributes to the risk for second malignancies, beyond just letting people live longer,” Copelan said. “It is clear that patients who are extensively pre-treated before transplant are at increased risk for second cancers, so it is important to do transplant earlier in the disease course. This risk is an important factor to consider, but of course the overwhelming factor for a patient is to cure their initial malignancy.”

Although researchers are continually improving transplant techniques, toxicities such as graft-versus-host disease (GVHD) also pose significant challenges. Studies have shown the more mismatched the donor, the greater the likelihood for GVHD and infections.

“The major problem that limits the wider use of hematopoietic transplants is GVHD,” Champlin said. “We are currently looking at both better immunosuppressive drugs that might modulate it, and regulatory T cells that suppress immune responses.”

Researchers also continue to strive to improve the efficacy of transplantation.

“An equally important problem as GVHD in allogeneic transplantation is the inability even with transplantation to control the primary disease,” Horowitz said. “The relapse rate after transplantation in AML in first remission is about 20%, and that has not really changed. Patients with refractory leukemias or lymphomas have much higher relapse rates. Unfortunately, we still are not very good at treating patients who relapse after transplantation.”

Stunted growth

Although researchers have made tremendous progress increasing donor recruitment, identifying alternative sources for transplantation and addressing toxicities, certain barriers threaten the sustainability of the field.

“Many of the landmark studies in stem cell transplantation were performed in the 1990s, and the landscape for many diseases has changed since then,” said John Sweetenham, MD, senior director for clinical affairs and executive medical director of Huntsman Cancer Institute at the University of Utah, and HemOnc Today’s Chief Medical Editor, Hematology. “In the case of lymphoma, diagnostic criteria have become much more refined, so the patient populations who were treated on transplant studies in the 1990s were poorly characterized compared with those treated on similar protocols today.”

There have been few randomized controlled trials to address remaining research questions, Sweetenham said.

“There are limitations to conducting randomized controlled trials, especially in the transplant arena, where no single institution is likely to have enough patients and transplants in any single disease state to do an adequate trial,” Copelan said. “The randomized trials that have been done are relatively small, and are almost preconditioned to be negative because they are too small to have the power to detect an important difference in outcome.”

However, the CIBMTR captures outcome data for almost every allogeneic transplant and 80% of autologous transplants in the United States, Horowitz said. These data allow for comparative studies across diseases, patient characteristics, types of transplant and transplant centers. They also can be compared with similar registries that capture data on non-transplant therapies.

“Since it was established in 2001, the Bone Marrow Transplant Clinical Trials Network has launched 30 trials, about half of which were randomized phase 3 trials, where we try to address some of the bigger issues in transplantation in a definitive way,” Horowitz said. “I think we do about as well as anybody in using large definitive trials to the extent that it is possible.”

The field’s growth also is threatened by a lack of transplant centers and specialists.

“There are entire areas of the country where there are no transplant centers nearby, and we know that the closer you are to a center, the higher the likelihood of getting the transplant,” Giralt said. “There aren’t enough centers because there aren’t enough transplanters. There is a huge workforce issue.”

This is particularly problematic for allogeneic transplants, after which patients might be away from their homes for 3 months, Bierman said.

Researchers have estimated that the country will require 1,000 more transplant physicians by 2025 to meet demand, Giralt said.

“The population is growing and aging, and as leukemia, lymphoma and myeloma are diseases of the elderly, we are going to need to do more transplants moving forward to treat the population in need,” Champlin said. “It is a struggle for us to keep up with the number of physicians and facilities needed for the procedure given the constrained health care spending in the current economic climate.”

Patients aged 65 years and older currently represent 25% to 30% of bone marrow transplant recipients, according to the CIBMTR. Refinements in reduced-intensity conditioning continue to improve outcomes in this population.

A study by Brunner and colleagues, published in 2013 in Biology of Blood and Marrow Transplantation, indicated allogeneic transplant with reduced-intensity conditioning can be safe and effective in older patients. Among 46 patients with a median age of 71 years, 1-year PFS was 42% and OS was 55%.

However, a bias may exist against referring elderly patients for the procedure.

“Physicians whose perceptions of transplant come from a previous era — when we did not do transplant in older patients because toxicities were higher and outcomes were not as good — may still think of transplant as a last resort, or not an option at all,” Horowitz said. “The consequence is that patients do not get referred at all or they get referred at a point in their disease when the outcome is likely not to be as good as it would have been.”

Lack of insurance coverage becomes another obstacle to transplant in this population. The number of Medicare beneficiaries who underwent allogeneic transplants for myelodysplastic syndrome tripled after the procedure received coverage in 2010, Horowitz said.

Biases also may exist among younger patients and their referring physicians.

“More than half of the patients who are eligible for transplant who may have a matched unrelated donor in the registry never have searches done,” Copelan said. “We need to spread awareness of transplant for different diseases and close the knowledge gap.”

Continued evolution

Beyond the factors that threaten transplant’s accessibility and sustainability, the procedure’s role in the evolving treatment paradigm for hematologic malignancies is uncertain.

As the safety and efficacy of HSCT improved, so too have non-transplant therapies in certain settings that delay — or potentially eliminate — the need for transplant.

For example, imatinib (Gleevec, Novartis) confers long-term stable disease control in most patients with CML. Transplant is reserved for patients who fail to respond to imatinib or a similar tyrosine kinase inhibitor in this setting. Rituximab (Rituxan; Genentech, Biogen Idec) has had a similar impact on the treatment of lymphomas, Bierman said.

“There is no question that rituximab has improved the survival rates for diffuse large B-cell lymphoma and follicular lymphoma, the two most common types of lymphoma,” Bierman said. “As we are improving the survival rates, fewer patients relapse. Right off the bat, there is less indication for transplant.”

Some data suggest transplant can be combined with novel agents to improve outcomes.

Redondo and colleagues evaluated data from 375 patients with relapsed or refractory DLBCL or grade 3b follicular lymphoma. Of these patients, 248 received first-line rituximab and 127 did not. All patients underwent autologous transplantation.

Results — published in March in British Journal of Hematology — indicated a greater proportion of patients who received rituximab achieved 5-year PFS (63% vs. 48%) and OS (72% vs. 61%).

“There are some reports that say results of salvage therapy with transplantation may be worse in people who’ve had rituximab,” Bierman said. “But there are some reports that have shown the opposite result — that patients do better with prior rituximab. This is another question that is out there. We still don’t know the full impact of these new therapies.”

As more novel, targeted therapies are developed, transplant’s role in certain diseases may diminish.

“That would be the goal — to cure or manage patients with upfront therapy so that transplant is not required,” Bierman said.

However, skepticism about the sustainability of transplantation is nothing new, Copelan said.

“Twenty years ago, someone fairly prominent came into my office and told me that within 5 years we would not be doing transplants because all these targeted and better therapies were going to take over,” Copelan said. “In CML, that has come true. But in other places, I think we will learn better how to integrate transplantation into the total treatment of the disease.”

Researchers question whether the success seen with imatinib in CML is likely in other settings.

“CML is a disease with just one chromosomal abnormality. Obviously, if you target the driver you cure the disease,” Giralt said. “Lymphomas, myelomas and other leukemias are multiple pathway diseases, so they’re harder to target.”

The increased use of transplant suggests its position in the treatment paradigm remains secure, proponents contend.

“The bottom line is that every year we do more and more transplants,” Copelan said. “Despite the intuitive sense that these therapy improvements will minimize the use of transplants, instead what they have done is changed how we use transplants. But we still do them because we have made them applicable to nearly 100% of patients who need them. We understand better when to utilize them and have made them safer, which has increased their use.”

Some experts suggested these improvements must continue for transplantation to remain a valid therapeutic option. Autologous transplants may require the greatest improvements, Giralt said.

“There is a lot of question about whether this type of strategy — where you are giving high doses of chemotherapy and radiation and using stem cells to rescue the patient from these high doses — will survive 10 to 15 years down the road,” Giralt said. “Research has to make autologous transplant easier.”

Researchers are conducting outpatient autologous transplants and have considered home-bound transplants, Giralt said. The goal is to induce more rapid immune recovery so patients can resume their normal routines more quickly.

Yet, researchers should anticipate changes in all aspects of the field.

“If we are still doing transplant the same way 10 or 20 years from now, we should be slapped silly,” Giralt said. “We are going to be able to do it more safely, without such high doses of chemotherapy and radiation, and we may find better ways to rid of the cancer cells. But the principle of transplant — that we are going to replace the patient’s marrow with the marrow from somebody else — is probably here to stay.” — by Alexandra Todak

References:

Brunner AM. Biol Blood Marrow Transplant. 2013;19:1374-1380.

Gragert L. N Engl J Med. 2014;371:339-348.

Hahn T. J Clin Oncol. 2013;31:2437-2449.

Pai S. N Engl J Med. 2014;371:434-446.

Raiola AM. Biol Blood Marrow Transplant. 2014;20:1573-1579.

Redondo AM. Br J Haematol. 2014;164:668-674.

For more information:

Philip J. Bierman, MD, can be reached at The Nebraska Medical Center Cancer Center, 111 North 175th St., Omaha, NE 68118; email: pjbierma@unmc.edu.

Richard E. Champlin, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; email: rchampli@mdanderson.org.

Edward A. Copelan, MD, FACP, can be reached at Levine Cancer Institute, 1021 Morehead Medical Drive, Charlotte, NC 28204; email: edward.copelan@carolinashealthcare.org.

Sergio A. Giralt, MD, can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: giralts@mskcc.org.

Mary Horowitz, MD, can be reached at Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226; email: Marymh@mcw.edu.

John W. Sweetenham, MD, can be reached at Huntsman Cancer Hospital, Clinic 2C/BMT, Hematology-Malignant, 1950 Circle of Hope, Salt Lake City, UT 84112; email: john.sweetenham@hci.utah.edu.

Disclosure: Bierman, Champlin, Copelan, Giralt, Horowitz and Sweetenham report no relevant financial disclosures.

 

 

Should patients with intermediate-risk myelodysplastic syndrome undergo transplantation?

Transplantation is most often recommended for patients with intermediate-2–risk or high-risk myelodysplastic syndrome based on the International Prognostic Scoring System (IPSS).

A prospective study by the French Transplantation Group demonstrated that individuals with intermediate-2–risk or high-risk myelodysplastic syndrome benefitted from having a donor for transplantation (Robin M. Abstract #3334. Presented at: ASH Annual Meeting and Exhibition; Dec. 7-10, 2013; New Orleans). Similar studies are being conducted by the German Transplantation Group, and the Blood and Marrow Transplantation Clinical Trials Network.

The timing of transplantation has similarly been addressed by decision analyses, the first of which suggested a benefit for patients with intermediate-2–risk and high-risk disease (Cutler C. Blood. 2004;104:579-585). A more recent analysis in reduced-intensity transplantation confirmed these findings (Koreth J. J Clin Oncol. 2013;31:2662-2670). However, an analysis by the European Group for Blood and Marrow Transplantation (EBMT) suggested that the optimal timing for transplantation might be earlier in patients with intermediate-1–risk disease, or in patients with intermediate-risk disease according to the WHO Prognostic Scoring System (Alessandrino EP. Am J Hematol. 2013;88:581-588).

The above analyses use the IPSS but not the revised IPSS (IPSS-R) scores. Therefore, we cannot confidently recommend or not recommend transplantation based on these analyses. When comparing the two IPSS scoring systems, it is apparent that the majority of subjects with intermediate-risk disease by IPSS-R would be classified as having intermediate-1–risk disease or higher according to IPSS (Greenberg PL. Blood. 2012;120:2454-2465), a group in whom transplantation would be recommended according to the EBMT decision model. With this in mind, we can consider early transplantation referral for patients with intermediate-risk disease according to the IPSS-R.

There are other factors that need to be considered when recommending transplantation. The use of comorbidity indices and newer molecular prognostic information can be very important tools when recommending transplantation over non-transplant therapies. Individuals with very high comorbidity or those with very adverse molecular prognostic features might have very poor prognosis with transplantation and should be considered for non-transplant therapy, even when the decision models suggest otherwise.

Corey S. Cutler, MD, MPH, FRCPC, is an assistant professor of medicine at Harvard Medical School and a physician of medical oncology at Dana-Farber Cancer Institute. He can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, Mailstop: Dana 1B30; email: corey_cutler@dfci.harvard.edu. Disclosure: Cutler reports no relevant financial disclosures. 

Transplant offers long-term outcomes to only a small percentage of these patients.

One of the most difficult aspects in caring for patients with myelodysplastic syndrome is the selection of candidates for transplant and the timing of the procedure. In my opinion, this requires the integrated effort of the transplant and non-transplant physicians involved in the care of the individual patient. This decision is based on risk of the disease, age, comorbidities, donor availability and, more recently — at least in my practice — cytogenetic and molecular information.

Age is a complicated issue in the United States, as it is now financially possible to transplant patients aged older than 65 years. In some centers, the procedure is offered to patients up to age 75 years. Donor search and assessment of comorbidities are the main focus of the transplanter.

The next question is risk. Currently, the standard of care is not to offer transplant to patients with lower-risk disease and to consider it in patients with higher-risk disease. This is based on IPSS assessment of the disease and data published by Cutler and colleagues (Cutler CS. Blood. 2004;104:579-585; Koreth J. J Clin Oncol. 2013;31:2662-2670). In the IPSS, there is no intermediate-risk category. This is included in the more recent IPSS-R classification (Greenberg PL. Blood. 2012;120:2454-2465). I struggle with this subset of patients in my clinic. Clinically, they are defined as having more than 3 and up to 4.5 points. Patients with intermediate-risk cytogenetic alterations — including, for instance, deletion in the long arm of chromosome 7 and more than 2% marrow blasts or some degree of cytopenia — will be in that category, as will those with poor-risk cytogenetics. An Italian group recently developed a model to assess outcomes with transplant (Della Porta MG. Blood. 2014;123:2333-2342). Characteristics associated with poor outcome were age older than 50 years, intermediate- or poor-risk cytogenetics, presence of comorbidities and refractoriness to induction therapy. To further complicate this issue, a recent report suggests that presence of p53 mutations is associated with very poor prognosis with transplant in myelodysplastic syndrome (Bejar R. J Clin Oncol. 2014;32:2691-2698).

All these data suggest that only certain patients (younger, fit, good-risk disease characteristics) will benefit from transplantation, and my experience is that transplant offers long-term outcomes to only a small percentage of patients. The main challenge now for transplant physicians is to develop strategies to overcome the poor prognosis of cytogenetic and molecular alterations. For non-transplant physicians, the challenge is to develop newer, more effective approaches to increase the number of candidates for transplant. Working together, perhaps we could develop a “total” therapy approach to this deadly disease.

Guillermo Garcia-Manero, MD, is a professor of medicine and chief of the section of myelodysplastic syndrome in the department of leukemia at The University of Texas MD Anderson Cancer Center. He can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Disclosure: Garcia-Manero reports no relevant financial disclosures.