Current Uses and Outcomes of Hematopoietic Stem Cell Transplantation INTRODUCTION: The Summary Slides are an annual report on data submitted to the CIBMTR by centers worldwide and describes information related to practices and general survival outcomes after hematopoietic cell transplantation. The current edition includes transplants performed prior to 2014. Slides 3 to 15 exhibit data on frequency of transplants according to age, donor and transplant type, graft source and disease, and causes of death. All frequencies represent first autologous and allogeneic transplants registered with the CIBMTR during the period. Slides 3, 4, 5 and 9 represent estimated frequencies of total number of transplants in the US. Slides 16 to 36 include overall survival outcomes according to disease, disease status, donor type, year of transplant and conditioning regimen intensity. Comparisons across survival curves are univariate and do not adjust for all potentially important factors; consequently, results should be interpreted cautiously. Acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and chronic myelogenous leukemia (CML) are classified as early disease (first complete remission [CR1] or first chronic phase [CP1]), intermediate (second or subsequent CR or CP or accelerated phase [AP]), or advanced (primary induction failure, active disease, or blastic phase) disease. Myelodysplastic syndrome (MDS) is divided into early (refractory anemia [RA] or refractory anemia with ringed sideroblasts [RARS]), or advanced (refractory anemia with excess of blasts [RAEB] or chronic myelomonocytic leukemia [CMML]) disease. Lymphoma is classified according to sensitivity to prior chemotherapy (chemosensitive or chemoresistant). The classification of conditioning regimen intensity is based on the agents, doses and schedules used. Several classification systems are available, and for this report we used a composite classification. Cases defined as reduced-intensity by the transplant center were classified as such. Cases without such information and with available data on chemotherapy agents, radiation and doses, were classified according to the CIBMTR operational definition of conditioning regimen intensity:  Myeloablative conditioning regimen: regimens with total body irradiation doses of ≥500 cGY, single fractionated doses of ≥800 cGY, busulfan doses of >9mg/kg, or melphalan doses of >150 mg/m2 given as single agents or in combination with other drugs. Reduced-intensity conditioning regimen: regimens with lower doses of total body irradiation, fractionated radiation therapy, busulfan, and melphalan than those used to define a myeloablative conditioning regimen (above). Pasquini MC, Zhu X. Current use and outcome of hematopoietic stem cell transplantation: CIBMTR summary slides, 2014. Available at: http://www.cibmtr.org

Location of Centers Participating in the CIBMTR 2014

Annual Number of Transplant Recipients in the US by Transplant Type Slide 3: Estimated annual numbers of transplant recipients in the U.S. were compiled according to the number first transplants registered with CIBMTR. Estimates of how closely the numbers reported are representative of actual transplant activity vary according to the type of transplant and number of centers reporting data per year. Prior to 2007, all except unrelated donor allogeneic transplant facilitated by the NMDP were reported voluntarily. It was estimated that the CIBMTR captured 90% of all unrelated donor transplants performed in the US, 60-90% of related donor allogeneic transplants and 65 to 75% of autologous transplants. These estimates were extrapolated from other databases that capture transplant center activity, accreditation or hospital discharges. After 2007, the Stem Cell Transplant Outcomes Database (SCTOD) was initiated which changed reporting requirements and data capture to an electronic format. The SCTOD requires that all allogeneic transplants performed in the US be registered with CIBMTR. Data reporting of autologous transplants remains voluntary and the numbers in the CIBMTR database are estimated to be 80%. US numbers of allogeneic transplants in the CIBMTR are representative of the actual transplant activity. The number of autologous transplants recipients in the U.S. continue to increase, most prominently since 2010 , mainly for treatment of plasma cell and lymphoproliferative disorders extending to older patients. The annual number of allogeneic transplants recipients is also increasing surpassing 8,000 a year in the US.

Transplant Recipients in the US, by Transplant and Donor Type Slide 4: By further stratifying the number of allogeneic transplants recipients in the US by donor type, recipients of unrelated donor transplants represent the largest group. The number of unrelated donor transplant has surpassed the number of allogeneic transplants from related donors after 2006 and the gap between these two types of approaches continues to widen annually. The numbers of transplants performed with other related donors increased steadily from 2011 to 2013, accounting for approximately 9% of all allogeneic transplants performed in the US. This trend is likely due to increase numbers of haploidentical transplantation.

Cumulative Plot of Transplant Recipients in the US by Transplant Type Slide 5: Cumulative number of transplant recipients in the US reached 320,000 in 2013.

Stem Cell Sources for Allogeneic Transplants by Year Slide 6: Mobilized peripheral blood stem cells is the primary graft source for transplantation and it is use is increasing and representing 65% of graft source being utilized for allogeneic transplants. The number of transplants using umbilical cord grafts during the period of 2008 to 2012 also increased compared to previous period. Conversely, use of bone marrow grafts decreased in the most recent period, accounting for 24% of all grafts being utilized for allogeneic transplants.

Trends in Autologous Transplants by Recipient Age* Slides 7 & 8: The number of autologous and allogeneic transplants for treatment of malignant diseases in older patients continue to increase. Thirty-nine percent of autologous transplant recipients and 17% of allogeneic transplant recipients in 2006-2012 were older than 60.

Trends in Allogeneic Transplants by Recipient Age* Slides 7 & 8: The number of autologous and allogeneic transplants for treatment of malignant diseases in older patients continue to increase. Thirty-nine percent of autologous transplant recipients and 17% of allogeneic transplant recipients in 2006-2012 were older than 60.

Indications for Hematopoietic Stem Cell Transplants in the US, 2012 Slide 9: The most common indications for HCT in the US in 2012 were multiple myeloma and lymphoma, accounting for 57% of all HCTs. AML and myelodysplasia are the most common indications for allogeneic transplants accounting for 51% of allogeneic HCTs.

Allogeneic Transplants in Patients ≤ 20 Years, Registered with the CIBMTR Slide 10: Annual numbers for transplants in pediatric population demonstrates increase in alternative donor transplants compared to sibling donors. The number of umbilical cord transplant steadily increased in the last decade and peaked in 2009. In the recent years there was increase in the number of unrelated donor transplants surpassing the number of sibling donor transplants performed in children. The number of other related donor transplants has fluctuated little in the last decade.

Allogeneic Transplants for Age > 20 years, Registered with the CIBMTR Slide 11: Among patients older than 20, there has also been an increase in the number of unrelated donor transplants which surpassed the number of related donor transplants. The utilization of umbilical cord blood in adults remains in the minority of transplants at the same proportion as transplants using other related donors.

Causes of Death after Autologous Transplants done in 2011-2012 Slides 12-14: After an autologous transplant, primary disease is the most commonly reported cause of death. Among allogeneic transplant recipients, unrelated donor transplants have fewer deaths related to the primary disease, however organ failure and infections are higher after unrelated donor transplants.

Causes of Death after HLA Match Sibling Transplants done in 2011-2012 Slides 12-14: After an autologous transplant, primary disease is the most commonly reported cause of death. Among allogeneic transplant recipients, unrelated donor transplants have fewer deaths related to the primary disease, however organ failure and infections are higher after unrelated donor transplants.

Causes of Death after Unrelated Donor Transplants done in 2011-2012 Slides 12-14: After an autologous transplant, primary disease is the most commonly reported cause of death. Among allogeneic transplant recipients, unrelated donor transplants have fewer deaths related to the primary disease, however organ failure and infections are higher after unrelated donor transplants.

Allogeneic Transplants Registered with the CIBMTR Slide 15: The overall number of transplants utilizing reduced intensity conditioning regimens is increasing, accounting for 42% of allogeneic transplants performed in 2012. This trend is in parallel with a greater number of transplants performed in older adults.

Survival after HLA Match Sibling Donor Transplants for AML, 2002-2012 Slides 16 & 17: The CIBMTR has data for 27,941 patients receiving an HLA-matched sibling (n=12,309) or unrelated donor (n=15,632) transplant for AML between 2002 and 2012. Their disease status at the time of transplant and the donor type are the major predictors of post-transplant survival. The 3-year probabilities of survival after HLA-matched sibling transplant in this cohort was 58% ± 1%, 50% ± 1%, and 24% ± 1% for patients with early, intermediate, and advanced disease, respectively. The probabilities of survival after an unrelated donor transplant were 49% ± 1%, 47%± 1%, and 22% ± 1% for patients with early, intermediate, and advanced disease, respectively.

Survival after Unrelated Donor Transplants for AML, 2002-2012 Slides 16 & 17: The CIBMTR has data for 27,941 patients receiving an HLA-matched sibling (n=12,309) or unrelated donor (n=15,632) transplant for AML between 2002 and 2012. Their disease status at the time of transplant and the donor type are the major predictors of post-transplant survival. The 3-year probabilities of survival after HLA-matched sibling transplant in this cohort was 58% ± 1%, 50% ± 1%, and 24% ± 1% for patients with early, intermediate, and advanced disease, respectively. The probabilities of survival after an unrelated donor transplant were 49% ± 1%, 47%± 1%, and 22% ± 1% for patients with early, intermediate, and advanced disease, respectively.

Survival after HLA Match Sibling Donor Transplants for AML, Age < 20 Years, 2002-2012 Slide 18: Among 1,702 patients younger than 20 with AML between 2002 and 2012, the 3-year probabilities of survival following transplant for early, intermediate, and advanced disease were 66% ± 1%, 57% ± 4%, and 30% ± 3%, respectively.

Survival after Allogeneic Transplants for MDS, 2002-2012 Slides 19 & 20: Allogeneic transplant is a potentially curative treatment for myelodysplastic syndrome (MDS). Outcomes differ according to disease status at the time of transplant. The CIBMTR has data on 5,820 patients receiving an allotransplants for early (n=2,137) and advanced (n=3,683) MDS. The 3-year probabilities of survival were 53% ± 2% and 49% ± 2% for recipients of sibling and unrelated donor transplants for early MDS, respectively. Among patients with advanced MDS, corresponding probabilities were 45% ± 1% and 39% ± 1%.

Survival after Allogeneic Transplants for MDS, 2002-2012 Slides 19 & 20: Allogeneic transplant is a potentially curative treatment for myelodysplastic syndrome (MDS). Outcomes differ according to disease status at the time of transplant. The CIBMTR has data on 5,820 patients receiving an allotransplants for early (n=2,137) and advanced (n=3,683) MDS. The 3-year probabilities of survival were 53% ± 2% and 49% ± 2% for recipients of sibling and unrelated donor transplants for early MDS, respectively. Among patients with advanced MDS, corresponding probabilities were 45% ± 1% and 39% ± 1%.

Survival after HLA Match Sibling Donor Transplants for ALL, Age < 20 Years, 2002-2012 Slides 21 & 22: Among young patients with ALL, for whom chemotherapy has a high success rate, allogeneic transplantation is generally reserved for patients with high-risk disease (i.e. high leukocyte count at diagnosis and the presence of poor-risk cytogenetic markers), who fail to achieve remission or who relapse after chemotherapy. Among the 2,096 patients younger than 20 receiving an HLA-matched sibling transplant for ALL between 2002 to 2012, the 3-year probabilities of survival were 67% ± 2%, 56% ± 2 %, and 26% ± 4% for patients with early, intermediate, and advanced disease, respectively. The corresponding probabilities of survival among the 3,291 recipients of an unrelated donor transplant were 66% ± 2%, 49% ± 1%, and 31% ± 3%.

Survival after Unrelated Donor Transplants for ALL, Age < 20 years, 2002-2012 Slides 21 & 22: Among young patients with ALL, for whom chemotherapy has a high success rate, allogeneic transplantation is generally reserved for patients with high-risk disease (i.e. high leukocyte count at diagnosis and the presence of poor-risk cytogenetic markers), who fail to achieve remission or who relapse after chemotherapy. Among the 2,096 patients younger than 20 receiving an HLA-matched sibling transplant for ALL between 2002 to 2012, the 3-year probabilities of survival were 67% ± 2%, 56% ± 2 %, and 26% ± 4% for patients with early, intermediate, and advanced disease, respectively. The corresponding probabilities of survival among the 3,291 recipients of an unrelated donor transplant were 66% ± 2%, 49% ± 1%, and 31% ± 3%.

Survival after HLA Match Sibling Donor Transplants for ALL, Age ≥ 20 Years, 2002-2012 Slides 23 & 24: Older age at disease onset is a high-risk feature in ALL. Consequently, a larger proportion of ALL patients 20 years of age or older undergo allogeneic HCT for early disease. Among 3,773 patients ≥20 years of age receiving HLA-matched sibling HCT for ALL between 2002-2012, the 3-year survival probabilities were 55% ± 1%, 34% ± 2%, and 26% ± 2% for patients with early, intermediate, and advanced disease, respectively. Corresponding probabilities among the 4,323 recipients of unrelated donor HCT were 53% ± 1%, 35% ± 2%, and 20% ± 2%.

Survival after Unrelated Donor Transplants for ALL, ≥ 20 Years, 2002-2012 Slides 23 & 24: Older age at disease onset is a high-risk feature in ALL. Consequently, a larger proportion of ALL patients 20 years of age or older undergo allogeneic HCT for early disease. Among 3,773 patients ≥20 years of age receiving HLA-matched sibling HCT for ALL between 2002-2012, the 3-year survival probabilities were 55% ± 1%, 34% ± 2%, and 26% ± 2% for patients with early, intermediate, and advanced disease, respectively. Corresponding probabilities among the 4,323 recipients of unrelated donor HCT were 53% ± 1%, 35% ± 2%, and 20% ± 2%.

Survival after HLA Match Sibling Transplants for CML, 2002-2012 Slide 25: Allogeneic transplants for CML are currently reserved for patients who failed or poorly tolerate tyrosine kinase inhibitors. The CIBMTR has data for 2,833HLA-matched sibling donor allotransplants for CML from 2002 to 2012 . Three-year probabilities of survival were 69% ± 1%, 53% ± 3% and 26% ± 4% for patients in chronic phase (CP), in accelerated phase (AP) and blastic phase; respectively.

Survival after Allogeneic Transplants for CLL, 2002-2012 Slide 26: Allogeneic transplants are the main transplant modality for treatment of chronic lymphocytic leukemia (CLL) patients who fail standard chemotherapy or have high-risk features (e.g. cytogenetic abnormalities, short remission intervals, purine analog resistant disease). Among the 2,932 patients who underwent transplantation for CLL, the 3-year probabilities of survival were 57% ± 1% and 47% ± 1% after transplants with HLA Match sibling and unrelated donors, respectively.

Survival after Allogeneic Transplants for Severe Aplastic Anemia, < 20 Years, 2002-2012 Slides 27 & 28: Allogeneic HCT is the treatment of choice for young patients with severe aplastic anemia and available HLA-matched sibling donor. Among the 2,734 patients receiving HLA-matched sibling donor HCT for severe aplastic anemia between 2002 and 2012, the 3-year probabilities of survival were 88% ±1% for those younger than 20 years and 75% ± 1% for those 20 years of age or older. Among the 1515 recipients of unrelated donor HCT during the same period, the corresponding probabilities of survival were 73% ± 2% and 64% ± 2%.

Survival after Allogeneic Transplants for Severe Aplastic Anemia, ≥ 20 Years, 2002-2012 Slides 27 & 28: Allogeneic HCT is the treatment of choice for young patients with severe aplastic anemia and available HLA-matched sibling donor. Among the 2,734 patients receiving HLA-matched sibling donor HCT for severe aplastic anemia between 2002 and 2012, the 3-year probabilities of survival were 88% ±1% for those younger than 20 years and 75% ± 1% for those 20 years of age or older. Among the 1515 recipients of unrelated donor HCT during the same period, the corresponding probabilities of survival were 73% ± 2% and 64% ± 2%.

Survival after Autologous Transplants for Hodgkin Lymphoma, 2002-2012 Slide 29: Transplantation for Hodgkin Lymphoma (HL) is indicated in patients who have failed initial chemotherapy or radiation therapy. Survival after HCT for HL depends on disease response to previous salvage therapy. Among the 6,479 patients receiving autotransplants for HL between 2002 and 2012, the 3-year probabilities of survival were 81% ± 1% and 59% ± 2% for patients with chemosensitive and with chemoresistant disease, respectively.

Survival after Allogeneic Transplants for Hodgkin Lymphoma, 2002-2012 Slide 30: Allogeneic HCT for HL is generally performed in patients who experience disease relapse after receiving multiple lines of therapy including autotransplant or who have refractory disease and an available HLA-matched donor. Among 2,063 patients receiving allotransplants for HL between 2002 and 2012, the 3-year probabilities of survival were 52% ± 2% and 45% ± 2% after sibling and unrelated donor transplants, respectively.

Survival after Autologous Transplants for Follicular Lymphoma, 2002-2012 Slide 31: Transplantation for follicular lymphoma (FL) is generally reserved for patients with recurrent or aggressive disease. Autotransplantation is most commonly done in patients with chemosensitive disease. Among the 2,239 patients receiving an autotransplant for FL between 2002 and 2012. The 3-year probabilities of survival were 77% ± 1% and 61% ± 4% for patients with chemosensitive and chemoresistant disease, respectively.

Survival after Allogeneic Transplants for Follicular Lymphoma, 2002-2012 Slide 32: Allogeneic transplants for FL are performed in patients who experience disease relapse after multiple lines of therapy or who have refractory disease and an available HLA match donor. Among 921patients receiving HLA-matched sibling donor transplants for FL between 2002 and 2012, the 3-year probabilities of survival were 73% ± 2% and 59% ± 4% for patients with chemosensitive and chemoresistant disease, respectively. Corresponding probabilities among 689 patients receiving unrelated donor transplants in the same period were 62% ± 2% and 44% ± 4%.

Survival after Autologous Transplants for DLBCL, 2002-2012 Slides 33 & 34: Autotransplants are an accepted treatment indication for diffuse large B-cell lymphoma (DLBCL) and, similar to FL, most autotransplants are performed in patients with chemosensitive disease. Among the 8,373 patients who received an autotransplant for DLBCL between 2002 and 2012, the 3-year probabilities of survival were 65% ± 1% and 41% ± 2% for patients with chemosensitive and chemoresistant disease, respectively. Allogeneic HCT for treatment of DLBCL is performed less frequently than for FL and is generally used only in patients with aggressive disease that has been resistant to previous therapies, including autotransplants. Among the 836 patients who underwent an HLA-matched sibling HCT for DLBCL from 2002 to 2012, the 3-year probabilities of survival were 50% ± 2% and 23% ± 3% for patients with chemosensitive and chemoresistant disease, respectively.

Survival after HLA Match Sibling Transplants for Diffuse Large Cell Lymphoma, 2002-2012 Slides 33 & 34: Autotransplants are an accepted treatment indication for diffuse large B-cell lymphoma (DLBCL) and, similar to FL, most autotransplants are performed in patients with chemosensitive disease. Among the 8,373 patients who received an autotransplant for DLBCL between 2002 and 2012, the 3-year probabilities of survival were 65% ± 1% and 41% ± 2% for patients with chemosensitive and chemoresistant disease, respectively. Allogeneic HCT for treatment of DLBCL is performed less frequently than for FL and is generally used only in patients with aggressive disease that has been resistant to previous therapies, including autotransplants. Among the 836 patients who underwent an HLA-matched sibling HCT for DLBCL from 2002 to 2012, the 3-year probabilities of survival were 50% ± 2% and 23% ± 3% for patients with chemosensitive and chemoresistant disease, respectively.

Survival after Transplants for Mantle Cell Lymphoma, 2002-2012 Slide 35: The optimal timing and type of HCT for mantle cell lymphoma (MCL) is not well defined. As with other mature B-cell lymphoproliferative disorders, autotransplantation is the most common transplant approach. Among the 3,965 patients who received an autotransplant for MCL between 2002 and 2012, the 3-year probability of survival was 76% ± 1%. Among 1,417 patients (HLA-match sibling donor, N=684 ; unrelated donor, N=733), who underwent an allogeneic transplantation for MCL during the same period, the 3-year probabilities of survival was 53% ± 1% .

Survival after Transplants for Multiple Myeloma, 2002-2012 Slide 36: Multiple myeloma (MM) is the most common indication for autologous HCT. Among 33,800 patients who received an autotransplant for MM between 2002 and 2012, the 3-year probability of survival was 74% ± 1%. Allogeneic transplantation for MM is reserved for patients with high risk disease and the majority performed after an autologous HCT with reduced intensity or nonmyeloablative conditioning regimens. Among the 1,104 patients (HLA-match sibling donor, N=386 ; unrelated donor, N=130) who received an allogeneic HCT from 2002 to 2012, the 3-year probabilities of survival was 50% ± 2%.