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Studies Investigate New Methodologies to Improve Recovery And Survival Strategies For Patients Undergoing Hematopoietic Cell Transplantation

December 12, 2011

Hematopoietic cell transplantation (HCT), the transplantation of blood-forming stem cells from the bone marrow, peripheral blood, or umbilical cord blood, is the primary option for treatment for many patients who suffer from various hematologic disorders, including blood cancers, sickle cell disease, bone marrow deficiencies, bleeding disorders, and autoimmune disorders. Research investigating breakthroughs in hematopoietic cell transplantation will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

“The studies that will be presented today demonstrate the major advances underway in the field of hematopoietic cell transplantation,” said Stephanie J. Lee, MD, MPH, moderator of the press conference and Professor of Medicine at the University of Washington School of Medicine in Seattle. “Although hematopoietic cell transplantation is considered a standard approach for treating blood disorders, there are still many complications involved, underscoring the continual need for novel research that can improve survival rates and quality of life for patients who undergo these procedures.”

This press conference will take place on Saturday, December 10, at 11:00 a.m. PST.

Increased Incidence of Chronic Graft-Versus-Host Disease (GVHD) and No Survival Advantage with Filgrastim-Mobilized Peripheral Blood Stem Cells (PBSC) Compared to Bone Marrow (BM) Transplants From Unrelated Donors: Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0201, a Phase III, Prospective, Randomized Trial [Abstract 1]

A new study reveals that peripheral blood stem cell (PBSC) transplants from unrelated donors are associated with higher rates of chronic graft-versus-host-disease (GVHD) and have no survival advantage when compared to transplants using stem cells taken from the bone marrow.

PBSCs are stem cells originally found in the bone marrow that have been moved, or mobilized, into the blood stream by a special drug regimen. Unlike bone marrow stem cells, which must be extracted from the bones in an operating room, PBSCs are more easily obtained through apheresis, a process similar to regular blood donation, which collects the PBSCs through a tube inserted in a vein. A critical step before the transplant is to find a donor that is tissue matched to the recipient.

About one-third of patients who need a PBSC or bone marrow transplant for treatment of a blood disease have a matched, related donor. According to the National Marrow Donor Program, of the 70 percent who cannot find a donor within their family, most will be able to find an unrelated donor. Since the majority of transplant patients ultimately receive cells from unrelated donors, there is a need to better understand the risks associated with transplants of unrelated donor cells.

Previous clinical trials on related donor transplants have demonstrated that PBSC transplants in patients with leukemia and other blood diseases result in better engraftment, lower relapse rates, and increased survival compared to transplants with bone marrow stem cells. However, those trials also found that PBSC transplants carry an increased risk of GVHD, a serious and often deadly post-transplant complication that occurs when the newly transplanted donor cells recognize the recipient´s own cells as foreign and attack them. Patients who survive early post-transplant may develop chronic GVHD, a disabling condition managed with long-term immunosuppressant therapy.

Many transplant centers are increasingly using PBSCs as a source for adult stem cells because of their superiority in clinical trials that have directly compared outcomes between PBSCs and bone marrow stem cells from related donors. However, to date, there has not been a comparative study of the two transplant sources that has prospectively analyzed patient outcomes in unrelated donor transplants.

To determine whether graft source — PBSCs or bone marrow — affects transplant outcomes in unrelated donor transplants for patients with leukemia or other hematologic malignancies, the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) conducted a clinical trial, BMT CTN Protocol 0201, to compare two-year survival probabilities for patients transplanted with PBSCs or bone marrow stem cells from unrelated donors. Fifty transplant centers in the United States and Canada participated in this large, Phase III, prospective, multicenter study which randomized patients to receive bone marrow (n=278) or PBSCs (n=273) as the graft source for transplant.

According to the trial analyses, there were no observed differences in overall survival, relapse, non-relapse mortality, or acute GHVD between the patients receiving PBSCs or bone marrow stem cells from unrelated donors. While engraftment was faster in patients receiving PBSCs, there was a higher incidence of overall chronic GVHD in these patients (53%) than in those transplanted with bone marrow stem cells (40%). Patients receiving transplants of PBSCs from unrelated donors also had a higher incidence of chronic extensive GVHD (46%) than patients who received bone marrow stem cells (31%).

“Although PBSCs from related donors have demonstrated clinical benefits, our trial demonstrates that when these stem cells originate from unrelated donors they are not superior to bone marrow stem cells in terms of patient survival, and they increase the risk for chronic GVHD,” said lead author Claudio Anasetti, MD, Chair of the Department of Blood & Marrow Transplant at Moffitt Cancer Center in Tampa, Fla. “More effective strategies to prevent GVHD are needed to improve outcomes for all patients receiving unrelated donor transplants.”

This trial was supported by the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI) of the National Institutes of Health (NIH).

Dr. Anasetti will present this study during the Plenary Scientific Session on Sunday, December 11, at 2:05 p.m. PST at the San Diego Convention Center in Hall AB.

Burden of Morbidity in 10+ Year Survivors of Hematopoietic Cell Transplantation (HCT): A Report From the Bone Marrow Transplant Survivor Study (BMTSS) [Abstract 841]

New research concludes that long-term (10 or more years) survivors of hematopoietic cell transplant(HCT), when compared to their siblings,have a higher risk of psychological and chronic health conditions, including heart attack, stroke, diabetes, subsequent cancers, and long-term generalized pain or discomfort referred to as somatic distress.

While HCT is a life-saving treatment for patients with blood disorders, it is often accompanied by an increased risk of long-term physical complications such as infections, relapse, and GVHD. High-intensity conditioning regimens and powerful immunosuppressant medications given to recipients to prepare the body to receive donor cells and prevent rejection can have a variety of negative side effects. In addition to these complications, recent research has found that the psychological health of HCT survivors is also affected.

“Although previous research has shown that morbidity increases with length of survival after an HCT, this is the first study to specifically examine the burden of morbidity in those who have survived 10 or more years after a transplant,” said lead author Can-Lan Sun, PhD, Associate Research Professor at City of Hope in Duarte, Calif.

To study late medical effects and quality of life in HCT survivors, researchers analyzed patient data from 366 10-or-more-year HCT survivors and their 309 siblings from the Bone Marrow Transplant Survivor Study, the largest of its kind to date. Survivors and their siblings were evaluated for the presence of any chronic conditions, which were given a severity score from 1 (mild) to 5 (death due to condition), as well as any psychological conditions, including somatic distress, anxiety, and depression. The current status of health-care utilization by survivors, an estimated figure accounting for frequency of visits to doctors, hospitalizations, and other factors, was also evaluated.

Results from the analysis revealed that nearly three-fourths (74%) of HCT survivors reported at least one chronic health condition over the 15-year follow-up period, compared with 29 percent of siblings. Additionally, one-fourth of survivors reported severe or life-threatening conditions compared to only 8 percent of siblings. Commonly reported severe or life-threatening chronic health conditions included heart attack, stroke, blindness, diabetes, musculoskeletal problems, and subsequent cancers. The 15-year cumulative incidence of any chronic health conditions in survivors was 71 percent, while the incidence of particularly severe or life-threatening conditions or death was 40 percent. Investigators also found that HCT survivors were nearly six times more likely than their age- and sex-matched siblings to develop a severe or life-threatening condition.

While prevalence of anxiety and depression were comparable between the two groups, HCT survivors were nearly three times more likely than their siblings to report somatic distress. Approximately 90 percent of HCT survivors reported having health insurance; a high proportion needed ongoing specialized medical care. Nearly two-thirds (61%) of survivors reported a cancer- or HCT-related visit to a specialist at an average of 15 years after transplant.

“The long-term physical and psychological burden of HCT on survivors is substantial, resulting in high usage of specialized health care among this population,” said senior author Smita Bhatia, MD, MPH, Director of the Center for Cancer Survivorship and BMT Long-Term Follow-up Program and Ruth Ziegler Chair in Population Sciences at City of Hope in Duarte, Calif. “Patients, families, and health-care providers need to be made aware of this high burden so they can plan for post-HCT care, even many years after transplant.”

Dr. Sun will present this study in an oral presentation on Monday, December 12, at 4:30 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom FG. 

Over-Expression of TRAIL on Donor T-Cells Enhances GVT and Suppresses GVHD Via Elimination of Alloreactive T-Cells and Host APC [Abstract 817]

Scientists have discovered a method of using genetically engineered T-cells to help the body kill cancer cells more effectively without causing a deadly post-transplant complication.

One of the reasons cancer cells are able to grow, multiply, and spread so quickly is that the body recognizes them as normal, rather than diseased. Patients with blood cancers often receive a transplant of healthy hematopoietic, or blood-forming, stem cells to help attack cancer cells, called hematopoietic cell transplantation(HCT). When these immune system cells found in the bone marrow are transplanted from a healthy donor to a cancer patient, donor cells may recognize the cancer cells in the recipient´s body and attack them, a desirable phenomenon known as the graft-versus-tumor (GVT) effect. However, one of the challenges of HCT is the risk for graft-versus-host disease (GVHD), a serious and often deadly post-transplant complication which occurs when the donor cells attack the recipient´s healthy cells instead.

To combat GVHD, doctors administer powerful medications to suppress the immune system. While these medications reduce the probability of GVHD, they can also reduce the GVT effect. Recognizing this challenge, researchers sought to create a new method to suppress GVHD without compromising the GVT effect by using genetically engineered donor T-cells that over-express a protein known to induce cell death in an effort to specifically attack cancer cells.

The protein, Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand, or TRAIL, is naturally expressed on some immune cells in the body. TRAIL targets tumor cells and keeps them from multiplying and spreading by interacting with death receptor molecules, which are highly expressed on the surface of tumor cells, making them more susceptible to therapeutic targeting using TRAIL.

To evaluate the effect of genetically engineered donor T-cells over-expressing TRAIL (TRAIL+) on GVHD and GVT, investigators from Memorial Sloan-Kettering Cancer Center performed HCT using TRAIL+ donor T-cells versus control donor T-cells in experimental mouse models with cancerous tumors. Mice that received TRAIL+ donor T-cells displayed significantly higher survival rates, indicating greater antitumor activity than in those treated with control donor T-cells. The researchers also used donor TRAIL+ progenitor T-cell with autologous (stem cells from the patient) HCT in tumor-bearing mice and found a significantly higher anti-tumor effect compared with controls. In addition to enhanced GVT effect, the transplant recipients treated with TRAIL+ T-cells experienced significantly less severe GVHD. Researchers further found that the immune cells, which trigger GVHD, also express TRAIL-sensitive death receptors, and TRAIL+ T-cells can suppress GVHD by targeting these cells.

“Our data show that donor T-cells over-expressing TRAIL can suppress GVHD while simultaneously enhancing the GVT effects. We hope this approach will provide fresh insights into separating cancer cell killing from indiscriminate killing of normal tissues,” said Arnab Ghosh, MD, PhD, lead author and a Research Scholar in the laboratory of Dr. Marcel van den Brink at Memorial Sloan-Kettering Cancer Center in New York. “Furthermore, the ability to combine genetic engineering with T-cell progenitor cells highlights the possibilities of developing these approaches into an effective, ℠off the shelf´ cell therapy.”

Dr. Ghosh will present this study in an oral presentation on Monday, December 12, at 4:30 p.m. PST at the Manchester Grand Hyatt in Douglas Pavilion A.

Haploidentical Transplantation Using T-Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies who Lack Conventional Donors is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of a Prospective Phase II Trial [Abstract 889]

Researchers have found that a new preparatory regimen prior to haploidentical hematopoietic stem cell transplantation (HCT) may improve outcomes in patients with high-risk blood cancers who lack a matched donor.

Patients with blood cancers are often treated with HCT, the transplantation of blood-forming bone marrow stem cells, including peripheral blood stem cells (PBSCs), stem cells originally found in the bone marrow that have been moved, or mobilized, into the blood stream. According to experts, the gold standard for HCT is to have a transplant from a matched donor, but for some patients a matched donor is not available. A haploidentical (partial match) HCT is the next best treatment option, but it comes with higher risk of relapse and non-relapse mortality.

For those patients without a matched donor, past approaches including ex vivo T-cell depletion and myeloablative preparative regimens (intense chemotherapy and/or radiation to help prevent the immune system from attacking transplanted cells) have been associated with high rates of graft rejection, infection, and severe GVHD. Some progress has been demonstrated recently by using a less aggressive, non-myeloablative preparative regimen, followed by an infusion of unmanipulated bone marrow and the post-transplant use of a common chemotherapy drug, cyclophosphamide (Cy), but relapse is relatively common, especially in those with high-risk myeloid malignancies. This study sought to determine whether it is possible to decrease the probability of relapse in these high-risk patients by using a myeloablative preparative regimen with PBSCs, instead of bone marrow, as the graft source.

Between January 2009 and March 2011, the investigators initiated a clinical trial enrolling 20 patients with high-risk blood cancers, including leukemia and both Hodgkin and non-Hodgkin lymphoma, undergoing haploidentical HCT. Participants were eligible for the trial if they were perceived to be at a high risk of relapse using a less aggressive preparative regimen following transplantation. Eleven patients (55%) had relapsed or refractory disease, while the remaining nine patients (45%) had standard-risk disease, the majority being leukemia patients in remission but associated with poor-risk features. After the administration of the myeloablative preparative regimen, patients underwent transplantation with PBSCs, followed by an immunosuppressive regimen of Cy (50mg/kg/day) on days three and four post transplant along with other supportive therapies.

After an average follow-up of 14 months, investigators reported an estimated one-year overall survival rate of 74 percent and a disease-free survival (DFS) rate of 51 percent for all patients; for standard risk patients, one year overall survival was 100 percent and DFS was 76 percent. Non-relapse mortality at 100 days and 12 months was 10 percent for all patients and zero for standard risk patients. The cumulative incidence of chronic GVHD at one year was 42 percent.

Non-infectious fever developed in 90 percent of patients within a median of 2.5 days of transplant and was resolved by day six following post-transplant administration of Cy. Viral cystitis (viral infection of the bladder) occurred in 75 percent of patients and was severe in 35 percent of patients. Other severe infections were not seen at increased frequency compared to conventional donor myeloablative transplants conducted at the transplant center.

“The results of our study demonstrate that haploidentical HCT using this unique pre- and post-transplant conditioning regimen is associated with improved rates of engraftment, GVHD, non-relapse mortality, and disease-free survival, making it a potentially important option to help improve outcomes in patients with high-risk malignancies who may not have a matched donor,” said senior author Scott R. Solomon, MD, Medical Director of the Stem Cell Processing Laboratory and the Matched Unrelated Donor Program at Northside Hospital in Atlanta. “With the exception of viral cystitis, post-transplant toxicity was manageable and similar to what might be expected with any myeloablative transplant regimen in high-risk patients. Future studies aim to reduce the incidence of viral cystitis, which, although not life-threatening, can be a significant problem for patients.”

Dr. Connie A. Sizemore will present this study in an oral presentation on Monday, December 12, at 6:15 p.m. PST at the San Diego Convention Center in Room 31.

American Society of Hematology 53rd Annual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new treatment techniques for patients with bleeding and clotting disorders, targeted therapies for acute and chronic leukemia, emerging treatments for lymphoma and myeloma, and assessing therapeutic strategies for sickle cell disease. For the complete annual meeting program and abstracts, visit www.hematology.org/2011abstracts. Get up-to-date information about the annual meeting by following ASH on Twitter @ASH_hematology.

The American Society of Hematology is the world´s largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood, the most cited peer-reviewed publication in the field, which is available weekly in print and online.

[1] Increased Incidence of Chronic Graft-Versus-Host Disease (GVHD) and No Survival Advantage with Filgrastim-Mobilized Peripheral Blood Stem Cells (PBSC) Compared to Bone Marrow (BM) Transplants From Unrelated Donors: Results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Protocol 0201, a Phase III, Prospective, Randomized Trial

Claudio Anasetti, MD1, Brent R. Logan, PhD2*, Stephanie J. Lee, MD, MPH3, Edmund K Waller, MD PhD4, Daniel J. Weisdorf, MD5, John R. Wingard, MD6, Corey S. Cutler, MD, MPH, FRCPC7, Peter Westervelt, MD, PhD8*, Ann Woolfrey, MD9, Stephen Couban, MD, FRCPC10, Laura Johnston, MD11, Richard T. Maziarz, MD12, Michael Pulsipher, MD13, Paolo Anderlini, MD14, William I Bensinger, MD15*, Susan F. Leitman, MD16, Scott D Rowley, MD17, Shelly L Carter, ScD18*, Mary M. Horowitz, MD, MS19 and Dennis L Confer, MD20

1H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
2Medical College of Wisconsin, Milwaukee, WI
3Fred Hutchinson Cancer Research Center, Seattle, WA
4Department of Heamtology/Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA
5Blood and Marrow Transplant Program, University Of Minnesota Medical Center, Minneapolis, MN
6Shands Cancer Center, University of Florida, Gainesville, FL
7Dana-Farber Cancer Institute, Boston, MA
8Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO
9Pediatric Hematologic Cell Transplant, Fred Hutchinson Cancer Research Center, Seattle, WA
10Hematology, Dalhousie University, Halifax, NS, Canada
11Stanford Univ. Med. Ctr. , Stanford, CA
12Oregon Health and Science University, Portland, OR
13University of Utah Medical Center, Salt Lake City, UT
14Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX
15Clinical Division, Fred Hutchinson Cancer Research Center, Seattle, WA
16Department of Transfusion Medicine, National Institutes of Health, Bethesda, MD
17The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
18The EMMES Corporation, Rockville, MD
19Medical College of Wisconsin, Center for International Blood and Marrow Transplant Research, Milwaukee, WI
20National Marrow Donor Program, Minneapolis, MN

Background: Randomized trials demonstrated that filgrastim-mobilized PBSC compared to BM from HLA-identical siblings improved engraftment kinetics, increased risks of acute and chronic GVHD, but also decreased relapse and improved survival in patients with high risk leukemia. Retrospective analyses of unrelated donor transplants did not appreciate the same PBSC protective effect.

Patients and Methods: The BMT CTN, sponsored by the NHLBI and NCI, conducted a Phase III, randomized, multicenter, trial of unrelated donor PBSC versus BM. The primary objective was to compare two-year survival probabilities in the two study arms using an intent-to-treat analysis. Both patients and donors provided informed consent. Fifty centers in the U.S. and Canada enrolled patients between January, 2004 and September 2009. Median follow up is 36 months (interquartile range 25 — 37 months). Randomization was performed in a 1:1 ratio to either PBSC or BM and stratified by transplant center and disease risk. Of the 278 subjects randomized to BM, 5% had no transplant, and 4.3% crossed over to PBSC; of the 273 randomized to PBSC, 4% had no transplant, and 0.4% crossed over to BM, so subjects on both arms had greater than 90% compliance with the assigned therapy. Patient primary disease (AML, ALL, CML, MDS, CMML, and MF), disease risk, gender, age, race, ethnicity, CMV serology, performance status, comorbidity, organ function, conditioning regimen, GVHD prophylaxis, use of growth factors, and donor characteristics were all well balanced between the two groups. Overall, 90% were adults over age 20, 47% had AML, 28% had high risk disease, 48% were conditioned with cyclophosphamide plus total body irradiation, and 71% received tacrolimus plus methotrexate for GVHD prophylaxis.

Results:There were no observed differences in outcomes between the two groups except for a higher incidence of overall chronic GVHD (see Table) and more common chronic extensive GVHD with PBSC (46% vs. 31%). There were no survival differences according to graft sources in planned subset analyses of low and high risk malignancy or in those received HLA-matched or mismatched grafts. Primary causes of death were relapse in 54% vs. 49%, graft failure in 7% vs. 0%, acute or chronic GVHD in 22% vs. 34%, others in 16% vs. 16% of the BM and PBSC arms, respectively.

Conclusion: This large randomized trial shows that PBSC from unrelated donors is associated with higher rates of chronic GVHD compared to BM, although rates of acute GVHD, relapse, non-relapse mortality and overall survival are similar.

Disclosures: Off Label Use: Cyclophosphamide, busulfan, melphalan, fludarabine, anti-thymocyte globulin, irradiation were used to eradicate malignancy. Tacrolimus, cyclosporine, methotrexate were used for GVHD prophylaxis. Weisdorf:Genzyme: Consultancy, Research Funding. Westervelt:Novartis: Speakers Bureau.

[841] Burden of Morbidity in 10+ Year Survivors of Hematopoietic Cell Transplantation (HCT): A Report From the Bone Marrow Transplant Survivor Study (BMTSS) 

Can-Lan Sun, Ph.D1, John H. Kersey, MD2, Liton Francisco, B.S.1*, K. Scott Baker, MD, MS3, Saro H. Armenian, DO, MPH1, Daniel J. Weisdorf, MD4, Forman Stephen, M.D.1* and Smita Bhatia, MD, MPH1

1City of Hope, Duarte, CA
2Cancer Center, Univ. of Minnesota, Minneapolis, MN
3Fred Hutchinson Cancer Research Center, Seattle, WA
4Hematology, Oncology and Transplantation, University of Minnesota , Minneapolis, MN

Background: High-intensity therapeutic exposures and prolonged immunosuppression increase the risk of long-term complications after HCT, with an attendant increase in the healthcare needs of these long-term survivors. We have previously demonstrated that morbidity increases with increasing time after HCT (Sun CL, Blood, 2010;116:3129-39). However, the burden of morbidity in patients who survive extended lengths of time after HCT and the consequent healthcare needs of these survivors are unknown.

Methods: Utilizing resources offered by the BMTSS, we evaluated the risk of chronic health conditions and psychological health of 366 10+ year HCT survivors and their siblings (n=309). A severity score (grade 1 [mild]; grade 2 [moderate], grade 3[severe], grade 4 [life-threatening], and grade 5 [death due to chronic health condition]) was assigned to each health condition using the CTCAE, v3.0. Cumulative incidence of chronic health conditions was evaluated, using competing risks method. Brief Symptom Inventory (BSI) was used to describe adverse psychological health. Multivariate regression analysis allowed identification of vulnerable subgroups. The current status of healthcare utilization by the HCT survivors was also evaluated.

Results: The mean age at HCT was 22 years (range: 0.4-59.8) and at study participation was 37 years (range: 11-72); mean length of follow-up was 15 years (range: 10-28). Primary diagnoses included AML (28%), ALL (17%), CML (17%), NHL (11%), aplastic anemia (11%), HL (7%), and other diagnoses (9%). Stem cell graft was autologous (27%); allogeneic related (65%) and unrelated donor (8%); 72% of the patients received TBI-based conditioning. At least one chronic health condition was reported by 74% of the HCT survivors, compared with 29% of siblings (p<0.001); 25% of the survivors reported severe/life-threatening conditions compared to only 8% of the siblings (p<0.001). Commonly reported severe/life-threatening chronic health conditions included myocardial infarction, stroke, blindness, diabetes, musculoskeletal problems, and subsequent malignancies. As shown in Figure 1A, the 15-year cumulative incidence of any chronic health condition (grades 1-5) was 71% (95% CI, 67-75%), and of severe-life-threatening conditions or death was 40% (95% CI, 33-47%). HCT survivors were 5.6 times as likely to develop a severe/life-threatening condition (95% CI, 3.7-8.6), compared with age- and sex-matched siblings. The cumulative incidence of severe/ life-threatening conditions did not differ by type of HCT (p=0.79, Figure 1B). Using BSI, we evaluated somatic distress, anxiety, and depression among HCT survivors and their siblings. While the prevalence of anxiety and depression were comparable between survivors and siblings, HCT survivors were 2.7 times more likely to report somatic distress (p<0.001). Among survivors, female gender (OR=3.6, 95% CI, 1.4-9.0), low household income (<$20,000 OR=4.4, 95% CI, 1.1-17.2), and poor self-rated health status (OR=10.6, 95% CI, 4.0-27.9) were associated with increased risk for somatic distress. Fortunately, 90% of HCT survivors carried health insurance coverage, because a high proportion needed ongoing specialized medical care; 69% of the HCT survivors reported cancer/HCT-related visits at an average of 15 years after HCT.

Conclusions: The burden of long-term physical and emotional morbidity borne by 10+ year HCT survivors is substantial, resulting in a high utilization of specialized healthcare. Patients, families and healthcare providers need to be made aware of the high burden, such that they can plan for post-HCT care, even many years after HCT.

Disclosures: Weisdorf:Genzyme: Consultancy, Research Funding.

[817] Over-Expression of TRAIL on Donor T Cells Enhances GVT and Suppresses Gvhd Via Elimination of Alloreactive T Cells and Host APC

Arnab Ghosh, MD, PhD1, Yildirim Dogan, PhD2*, Amanda M. Holland, BS1*, Odette M Smith, BA1*, Lauren F. Young, BS1*, Mallory L West, BS1*, Natalie V Singer, BS1*, Robert R Jenq, MD1*, Il-Kang Na, MD/PhD3*, Olaf Penack, MD/PhD4*, Alan M Hanash, MD, PhD1, Martin G. Sauer, MD5, Michel Sadelain, MD, PhD6 and Marcel R.M. van den Brink, MD, PhD1

1Department of Medicine and Immunology, Memorial Sloan-Kettering Cancer Center, New York, NY
2Department of Cell Biology, Memorial Sloan-Kettering Cancer Center, New York, NY
3Department of Hematology and Oncology, Charité CBF, Berlin, Germany
4Charité CBF – Universitätsmedizin Berlin, Berlin, Germany
5Ped. Hematology and Oncology, Hannover Medical School, Hannover, Germany
6Center of Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY

Strategies to suppress GVHD are often associated with broader suppression of the immune system leading to a compromised GVT effect. Using experimental models, we have demonstrated a novel strategy to enhance GVT effects and explicitly suppress GVHD using genetically engineered T lineage cells over-expressing TNF-Related Apoptosis Inducing Ligand (TRAIL). TRAIL can induce apoptotic signals through death receptor (DR) 4 and 5 molecules (only DR5 in mice) expressed on target cells. Expression of DR5 is higher on certain tumors and can be enhanced on others using small molecules rendering them susceptible to TRAIL mediated killing. TRAIL is therefore an attractive candidate for genetic engineering of donor T cells to enhance their GVT potential. We evaluated the effect of TRAIL over-expression (TRAIL+) in donor T cells (mature and precursor) on GVHD and GVT. Mature T cells derived from donor B6 splenocytes were transduced with a lentiviral TRAIL expression vector. The transduced TRAIL+ T cells were adoptively transferred on day 0 into lethally irradiated CBF1 recipients of T cell depleted allografts and LB27.4 tumor (B6 ˆCBF1+LB27.4) to assess their GVHD and GVT activity. TRAIL+ T cells displayed significantly enhanced antitumor immunity compared to T cells transduced with a control vector against LB27.4 tumor cell lines in vitro and upon transfer into tumor bearing allo-BMT recipients (p<0.01, 100% survival in TRAIL+ T cell group) (Fig 1A, also shown at the annual meeting last year). Precursor (pre)T cells have the benefit of regenerating the T cell compartment without causing GVHD and being available for “off the shelf” use. We generated TRAIL+ preT cells from transduced B6 hematopoietic stem cells and expanded them using the OP9-DL1 co-culture system. Adoptive transfer of B6 TRAIL+ preT cells into syngeneic-transplanted BALB/c mice could reconstitute the T cell compartment with TRAIL-expressing T cells and caused enhanced antitumor activity (p<0.05) compared to mock (GFP)-transduced controls.

Interestingly, in addition to enhanced GVT, the recipients treated with TRAIL+ T cells had significantly less GVHD lethality and morbidity (Fig1B). This was observed across multiple GVHD models (B6 ˆ CBF1, B6ˆ BALB/c and B10.BRˆB6). To explore the factors contributing to TRAIL-mediated suppression of GVHD, we used animals deficient in DR5 (DR5ko) in our models of GVHD. We found that GVHD suppressive effects of TRAIL were lost when hosts were DR5ko or when DR5ko TRAIL+ T cells were adoptively transferred indicating that TRAIL+ T cells suppress GVHD by targeting both host and donor compartments. We observed a higher DR5 expression in host MHC-IIhi antigen presenting cells (APC) following total body irradiation, suggesting that TRAIL+ donor T cells could potently eliminate host APC, resulting in less GVHD. Further, on transferring wild type T cells into irradiated hosts, we found that alloreactive CD25+ T cells had a significantly higher DR5 expression compared to CD25- T cells. This indicates that TRAIL+ T cells can specifically target the alloreactive CD25+ T cells in order to suppress GVHD.

Collectively, our data demonstrate that donor T cells genetically engineered to express TRAIL can enhance GVT effects and suppress the development of lethal GVHD in recipients of allo-HSCT. Our data suggests that his suppression of GVHD is mediated by the elimination the alloreactive donor T cells and the elimination of GVHD-promoting residual APC. Furthermore, we demonstrated that allogeneic ex vivo generated preT cells expressing TRAIL could mediate a strong protection against tumor challenge in syngeneic HSCT recipients. TRAIL over-expression thus represents a potential off the shelf approach to enhancing GVT in both allogeneic and autologous transplantation. Despite elimination of alloreactive donor T cells, TRAIL+ T cells demonstrated enhanced GVT by directly targeting DR5+ tumors in the absence of alloreactivity.

Disclosures: No relevant conflicts of interest to declare.

[889] Haploidentical Transplantation Using T-Cell Replete Peripheral Blood Stem Cells and Myeloablative Conditioning in Patients with High-Risk Hematologic Malignancies Who Lack Conventional Donors Is Well Tolerated and Produces Excellent Relapse-Free Survival: Results of A Prospective Phase II Trial

Connie A. Sizemore, PharmD1*, Asad Bashey, MD, PhD1, Melissa Sanacore, PharmD1*, Karen Manion, RN1*, H. Kent Holland, MD1, Lawrence E. Morris, MD1, Stacey Brown, B.A.1*, Xu Zhang, PhD2* and Scott R. Solomon, MD1*

1The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA
2Mathematics and Statistics, Georgia State University, Atlanta, GA

Introduction: Haploidentical hematopoietic stem cell transplantation (HSCT) provides an opportunity for nearly all patients to benefit from HSCT when a human leukocyte antigen (HLA) genotypically matched donor is not available. Initial approaches to mismatched allografting using ex-vivo T-cell depletion and intense preparative regimens were associated with high rates of graft rejection, severe graft-versus-host disease (GVHD) and infectious complications, resulting in an unacceptable treatment-related morbidity and mortality. More promising outcomes have been recently demonstrated by a new approach to haploidentical transplantation, utilizing a nonmyeloablative preparative regimen, followed by a T cell-replete bone marrow infusion and post-transplantation immunosuppression with high dose Cyclophosphamide (Cy), tacrolimus, and mycophenolate mofetil (MMF). However, relapse represents the major cause of treatment failure in these patients, particularly with high-risk myeloid malignancies.

Methods: In order to decrease relapse risk in patients with high-risk malignancies, we initiated a trial between January 2009 and March 2011, of haploidentical allografting using a myeloablative preparative regimen and peripheral blood stem cells (PBSC) instead of bone marrow as the graft source. Eligibility was limited to patients perceived to be at prohibitively high risk of relapse following nonmyeloablative haploidentical BMT. Initial conditioning (n=5) consisted of Fludarabine 30 mg/m2 on days -7 to -2 , IV Busulfan 130 mg/m2 on days -7 to -4, and Cy 14.5 mg/kg on days -3 and -2 followed by an unmanipulated PBSC infusion in all patients. In response to increased rates of mucositis, fludarabine and busulfan doses were decreased by 30% and 15%, respectively, in subsequent patients. Post-grafting immunosuppression consisted of Cy 50mg/kg/day on days 3 and 4, MMF, and tacrolimus.

Results: A total of twenty patients were enrolled in the study: median age 44 years (25-56); diagnoses AML=12, ALL= 2, HD=1, CML=3, CLL=1, NHL=1; allograft from 5/10 locus matched (n=14), 6/10 locus matched (n=2), 7/10 locus matched (n=3), or 8/10 locus matched (n=1). CIBMTR disease risk-high risk =7 (35%), intermediate risk = 4 (20%) or low risk = 9 (45%). Of the 9 low risk patients, seven were cytogenetically poor-risk AML and/or required 2 induction cycles to induce complete response. Donor engraftment occurred in all 20 patients, with a median time to neutrophil and platelet recovery of 16 and 27 days, respectively. All evaluable patients achieved complete donor T cell and myeloid chimerism by Day +30. The cumulative incidence of grades II-IV and grades III-IV aGVHD was 30% and 20%, respectively. The cumulative incidence of cGVHD at one year was 42%. Non-relapse mortality (NRM) at 100 days and 1 yr was 10% for all patients and 0% for low-risk patients. Non-infectious fever (median tmax 103.9; 101.2-106.8), possibly related to cytokine release from proliferating alloreactive cells, developed in 90% of patients within a median of 2.5 days (1-5) of transplant and resolved by day 6 (5-7) following post-transplant Cy. BK virus-associated cystitis occurred in 75% of patients, and was severe (requiring hospital admission for bladder irrigation and/or pain management) in 35%. Other severe infections were not seen at increased frequency compared to conventional donor myeloablative transplants at our center. With a median follow-up of 14 months, the estimated 1 year overall and disease-free survival was 74% and 51%, respectively for all patients; 100% and 76%, respectively for low-risk patients.

Conclusion: HLA haploidentical HSCT using this myeloablative regimen with T-cell replete PBSC and post-transplant Cy is associated with excellent rates of engraftment, GVHD, NRM and DFS, it is therefore a valid option in patients with high-risk malignancies who lack timely access to a conventional donor.

Disclosures: Sizemore: Otsuka America Pharmaceuticals, Inc. : Research Funding. Bashey: Otsuka America Pharmaceuticals, Inc.: Research Funding. Sanacore: Otsuka America Pharmaceuticals, Inc.: Research Funding. Manion: Otsuka America Pharmaceuticals, Inc.: Research Funding. Holland: Otsuka America Pharmaceuticals, Inc.: Research Funding. Morris: Otsuka America Pharmaceuticals, Inc.: Research Funding. Brown: Otsuka America Pharmaceuticals, Inc.: Research Funding. Solomon: Otsuka America Pharmaceuticals, Inc.: Research Funding.

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