Study ties bone marrow transplant to negative sexual side effects

Radiation, graft-versus-host disease cited as particularly damaging

New research ties preparative procedures and complications associated with blood or bone marrow transplantation (stem cell transplantation, SCT) with diminished sexual health in both men and women who have undergone the lifesaving procedure. Study data, published online today in Blood, the Journal of the American Society of Hematology (ASH), confirm chronic graft-versus-host disease (GVHD), a serious complication that occurs when donor cells attack the recipient’s cells, as a potential source of sexual dysfunction and are the first to demonstrate an association between total body irradiation and sexual dysfunction in men. This study is one of the longest and is the most inclusive to date evaluating sexual well-being in SCT survivors using rigorous, well-validated sexual function assessment tools.

SCT is an increasingly effective form of treatment for patients with blood cancer such as leukemia, lymphoma, and myeloma. The procedure, which involves the transplantation of cells taken either from a patient’s own blood or bone marrow (autologous transplantation) or from a matched donor (allogeneic transplantation), effectively “replaces” damaged cells with healthy cells. While SCT was once associated with high mortality, survival rates have steadily increased, prompting research seeking to study and maximize survivors’ quality of life.

“Thanks to improved transplant survival rates, we have now been able to focus our efforts on examining how the procedure affects key aspects of recipients’ overall quality of life, including sexual health,” said lead study author F. Lennie Wong, PhD, of City of Hope in Duarte, California. “Previous findings point to the unfortunate fact that, while recipients may physically recover, their sexual health might not rebound as much or as quickly. Data have been limited to this point, prompting us to take a closer look at this issue in a larger, more diverse group of autologous and allogeneic transplant survivors over an extended period.”

To further investigate long-term effects of SCT on the sexual health of survivors, a team of researchers led by senior author Smita Bhatia, MD, MPH, surveyed 277 adult patients (152 men and 125 women; median age 48) who underwent SCT at City of Hope for blood cancer between February 2001 and January 2005 about their sexual activity. Participants completed two questionnaires that together evaluated specific areas of sexual function (sexual cognition/fantasy, sexual arousal, sexual behavior/experience, orgasm, and drive/relationship) as well as sexual satisfaction at a median time of 17 days pre-transplant and at six, 12, 24, and 36 months post-transplant. A third questionnaire assessed overall health-related quality of life.

Investigators’ analysis of questionnaire results (led by Dr. Wong) confirmed previous studies in demonstrating a definitive impact of SCT on survivors’ post-transplant sexual activity. During the three-year post-transplant analysis period, the percentage of men who self-reported being “sexually active” (defined as having sex with a partner at least once in the preceding month) declined 7 percentage points, with 61 percent of men reporting sexual activity pre-transplant and 54 percent reporting activity post-transplant. The opposite – a 15 percentage point increase in sexually active individuals – was observed in women, with 37 percent reporting sexual activity pre-transplant and 52 percent reporting activity post-transplant.

In addition to further crystallizing transplantation’s impact on survivors’ sexual health, study data specifically associated diminished sexual function and satisfaction with transplant-related total body radiation in men and chronic GVHD with diminished sexual function in men and both sexual function and satisfaction in women.

Investigators observed a nearly 18 percent decline in sexual function in men surveyed who had received total body radiation. The same group also reported an approximate 32 percent decrease in sexual satisfaction, a 26 percent decrease in sexual behavior/experience, a 26 percent decrease in quality of orgasm, and 17 percent decrease in sex drive/relationship since their transplant. Despite these effects in men, radiation had no such reported effect in women, an effect that investigators hypothesize may be explained by inherent physiologic differences in the pathogenesis of sexual dysfunction among men and women.

In addition to documenting concrete effects of radiation on sexual function and satisfaction, investigators also observed negative sexual effects among those surveyed who had experienced chronic GVHD. Men surveyed who had developed the dangerous post-transplant complication reported a 21 percent decrease in sexual cognition/fantasy and a 24 percent decrease in the quality of orgasm since their transplant. Similarly, investigators observed a 27 percent decline in post-transplant sexual satisfaction among women surveyed who had experienced chronic GVHD, with survey respondents also indicating a 27 percent decline in sexual arousal.

When compared to men, the women surveyed suffered significantly worse effects overall, despite the fact that their sexual activity increased over the three-year survey period. Investigators concluded that this increase in activity may be explained by a corresponding improvement in female psychological quality of life post transplant.

From this research, investigators conclude that nearly half of SCT survivors are sexually inactive at three years post transplant and suggest that patients may benefit from speaking with their doctors about sex.

“It is not often that the transplant team and patient will have a conversation about how this procedure could impact their sex life, even after recovery; however, we hope these findings will help encourage patients and their doctors to openly discuss concerns related to sexual dysfunction and address them with specialists who can help,” said Dr. Wong.

Wong et al., (2013). Longitudinal trajectory of sexual functioning after hematopoietic cell transplantation: impact of chronic graft vs. host disease and total body irradiation. Blood, EPub Ahead of Print [Abstract

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Immune system marker may improve bone marrow transplant outcomes

St. Jude Children’s Research Hospital investigators prove that an immune marker predicts transplant success and improves selection of bone marrow donors.

The risk of death following bone marrow transplantation can be reduced about 60 percent using a new technique to identify bone marrow donors who make the most potent cancer-fighting immune cells, according to research from St. Jude Children’s Research Hospital. The findings appear in the September 16 online issue of the Journal of Clinical Oncology.

The research builds on an earlier St. Jude discovery that specialized immune cells called natural killer (NK) cells dispatched cancer cells more efficiently when the NK cells carried a particular version of a KIR protein on their surface. KIR is short for killer-cell immunoglobulin-like receptor. KIR proteins regulate NK cells.

For this study, researchers reviewed the outcomes of the 313 bone marrow transplants performed at St. Jude during the decade ending in January 2010. Investigators found that patients were far more likely to have survived the transplant and far less likely to have their disease progress if their new bone marrow came from donors whose NK cells included the same version of the protein, rather than the alternative form.

A test developed at St. Jude Children’s Research Hospital is linked to a 60 percent reduced risk of death following bone marrow transplantation and a 62 percent reduced risk of disease progression.
Credit: Joshua Stokes, St. Jude Children’s Research Hospital

“This approach should dramatically improve the outcome for patients undergoing bone marrow transplantation, regardless of their age or underlying condition,” said Wing Leung, M.D., Ph.D., the paper’s corresponding author and chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy. “NK cells also play an important role in autoimmune disorders, chronic infections and other conditions, so these results will likely have an impact beyond cancer.”

Transplant patients benefited regardless of their disease, previous treatment, completeness of the genetic match or other donor characteristics, including whether the donor was a relative, Leung said. Screening for the NK cell variation uses blood collected for the current donor screening process and will not slow donor selection.

NK cells account for less than 15 percent of white blood cells, but play a major role in defending against cancer and viral infections. This research focused on a protein named KIR2DL1, which belongs to the KIR family of proteins. The KIR2DL1 protein is found on NK cells of nearly all healthy individuals.

Proteins are made up of long chains of amino acids. Due to natural genetic variation, there are 25 versions of KIR2DL1, each with a slightly different amino acid sequence.

In an earlier study, Leung and his colleagues discovered that NK cells with one of the KIR2DL1 variations killed cancer cells growing in the laboratory more efficiently than NK cells with a different version of the protein. The potent NK cells featured the amino acid arginine at position 245 of KIR2DL1 rather than the amino acid cysteine in that spot. That discovery led to this study, which offers the first proof that the amino acid difference impacts patient outcomes.

The new screening approach developed by St. Jude involves identifying donors who make the most potent version of specialized immune cells called natural killer (NK) cells. Illustrated is an NK cell destroying a cancer cell.
Credit: Joshua Stokes, St. Jude Children’s Research Hospital

Researchers checked the outcomes of all bone marrow transplants performed at St. Jude during the 10-year period. They found that donor bone marrow with two copies of the gene for the arginine 245 version of KIR2DL1 was associated with a 60 percent decreased risk of death following transplantation and a 62 percent reduced risk of disease progression compared to transplants with donor bone marrow that carried instructions for making just the cysteine version. The transplants involved patients battling both acute lymphoblastic and acute myeloid leukemia as well as other conditions.

St. Jude has patented and licensed a test to identify potential donors with the preferred amino acid. The goal is to make the screening test widely available to other transplant centers as soon as possible, officials said.

Bari et al., (2013). Effect of donor KIR2DL1 allelic polymorphism on the outcome of pediatric allogeneic hematopoietic stem-cell transplantation. J. Clin. Oncology., EPub Ahead of Print, doi: 10.1200/JCO.2012.47.4007 [Abstract]

Guidelines for stem cell transplants in older patients with myelodysplastic syndromes

A new study by an international team led by Dana-Farber Cancer Institute scientists provides the first statistically-based guidelines for determining whether a stem cell transplant is appropriate for older patients with myelodysplastic syndromes (MDS) – the most common blood disorders in people over 60 years of age, and frequently a precursor for leukemia.

Using mathematical models to analyze hundreds of MDS cases from around the world, the researchers found reduced intensity transplants of donor stem cells are advisable for patients aged 60-70 who have higher-risk forms of MDS that are likely to turn into leukemia in the near future. For patients with lower-risk MDS, non-transplant treatments are preferable, the model indicates. The research was reported online today in the Journal of Clinical Oncology.

“Our study helps inform older MDS patients and their doctors whether a stem cell transplant is preferred or whether it makes more sense to pursue other options,” says John Koreth, MBBS, DPhil, medical oncologist in the Division of Hematologic Malignancies at Dana-Farber, who is the study’s lead author and co-principal investigator (with Joseph Pidala, MD, MS, of the H. Lee Moffitt Cancer & Research Institute, and senior author Corey Cutler, MD, MPH, of the Division of Hematologic Malignancies at Dana-Farber). “Until now, there haven’t been statistically-quantified guidelines for making these decisions for older patients, who are most impacted by the disease.”

MDS arises in the blood-forming cells of the bone marrow, causing a drop in the number of healthy white and red blood cells and of platelets needed for blood clotting. Depending on which type of cells are in short supply, the result can be fatigue, shortness of breath, easy bruising and bleeding, or infection and fever. An estimated 12,000 people in the United States are diagnosed with MDS each year, and more than 80 percent of whom are over age 60. (Some researchers believe MDS to be widely under-diagnosed, so the number of people affected may be much larger.)

In some cases, MDS produces only mild symptoms that don’t worsen for years. In others, the symptoms can be severe, leading to the development of a fast-growing form of leukemia. The most common tool for predicting the course of MDS is the International Prognostic Scoring System (IPSS), which is based on a patient’s blood counts, percentage of immature “blast” cells in the blood or bone marrow, and occurrence of chromosomal abnormalities in these cells. Based on IPSS scores, the disease is classified as low risk, intermediate-1 or -2 risk, or high risk.

Patients in the first two categories, with lower-risk disease, usually receive treatments such as antibiotics, transfusions, blood cell growth-promoting agents, or other supportive therapies to alleviate their specific symptoms. Patients in the latter two categories, with higher-risk disease, often receive chemotherapy.

While these treatments are often helpful, they cannot cure the disease. The only potentially curative treatment is a donor stem cell transplant, which can, in principle, be used for patients with any stage of MDS. But because even reduced-intensity transplants are fatal in a significant minority of cases, there has been some uncertainty over the use of transplantation for older patients with MDS.

“It hasn’t been clear for which older patient groups the benefits of transplant outweigh the risks,” Koreth says. To find out, researchers collected data on 514 patients, age 60-70, who were newly diagnosed with MDS. For both lower- and higher-risk groups, they built separate mathematical models to compare treatment outcomes in patients who received reduced-intensity donor stem cell transplants with outcomes in patients who received non-transplant therapies. They analyzed not only length of survival but also the quality of life of patients in those groups.

Patients in the lower-risk groups who underwent transplant lived an average of 38 months after treatment, less than the 77 months for those who were treated without transplant. For patients in the higher-risk groups, by contrast, average life expectancy was 36 months for those receiving transplants, better than the 28 months for those receiving non-transplant therapies. Adjusting for patients’ quality of life did not change the conclusions regarding the relative merits of the treatments.

“The clear result is that, on balance, reduced-intensity stem cell transplantation offers a survival benefit for patients with higher-risk MDS, but not for those with lower-risk disease,” Koreth says. “The findings should offer useful guidance for older patients with MDS on deciding the best course of treatment.”

Koreth et al., (2013). Role of reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation in older patients with de novo myelodysplastic syndromes: An international collaborative decision analysis. J. Clin. Oncol., EPub Ahead of Print [Abstract]