Transplantation conditioning regimens and outcomes after allogeneic hematopoietic cell transplantation in children and adolescents with acute lymphoblastic leukemia.

Relapse is common after hematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukemia (ALL). Although 1200 cGy total body irradiation (TBI) and cyclophosphamide (Cy) is the standard conditioning regimen, attempts to reduce relapse have led to the addition of a second chemotherapeutic agent and/or higher dose of TBI. We examined HSCT outcomes in patients age <18 years with ALL, in second or subsequent remission or in relapse at transplantation. Most transplantations were performed with the patient in remission. Patients received grafts from an HLA-matched sibling or unrelated donor. Four treatment groups were created: (1) Cy + TBI ≤ 1200 cGy (n = 304), (2) Cy + etoposide + TBI ≤ 1200 cGy (n = 108), (3) Cy + TBI ≥ 1300 cGy (n = 327), and (4) Cy + etoposide + TBI ≥ 1300 cGy (n = 26). Neither TBI > 1200 cGy nor the addition of etoposide resulted in fewer relapses. The 5-year probability of relapse was 30% for group 1, 28% for group 2, 35% for group 3, and 31% for group 4. However, transplantation-related mortality was higher (35% versus 25%, P = .02) and overall survival lower (36% versus 48%, P = .03) in group 4 compared with group 3. Our findings indicate that compared with the standard regimen, neither TBI > 1200 cGy nor the addition of etoposide improves survival after HSCT for ALL.

Long-term survival and late deaths after allogeneic hematopoietic cell transplantation.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) is curative but is associated with life-threatening complications. Most deaths occur within the first 2 years after transplantation. In this report, we examine long-term survival in 2-year survivors in the largest cohort ever studied. PATIENTS AND METHODS: Records of 10,632 patients worldwide reported to the Center for International Blood and Marrow Transplant Research who were alive and disease free 2 years after receiving a myeloablative allogeneic HCT before 2004 for acute myelogenous or lymphoblastic leukemia, myelodysplastic syndrome, lymphoma, or severe aplastic anemia were reviewed. RESULTS: Median follow-up was 9 years, and 3,788 patients had been observed for 10 or more years. The probability of being alive 10 years after HCT was 85%. The chief risk factors for late death included older age and chronic graft-versus-host disease (GVHD). For patients who underwent transplantation for malignancy, relapse was the most common cause of death. The greatest risk factor for late relapse was advanced disease at transplantation. Principal risk factors for nonrelapse deaths were older age and GVHD. When compared with age, sex, and nationality-matched general population, late deaths remained higher than expected for each disease, with the possible exception of lymphoma, although the relative risk generally receded over time. CONCLUSION: The prospect for long-term survival is excellent for 2-year survivors of allogeneic HCT. However, life expectancy remains lower than expected. Performance of HCT earlier in the course of disease, control of GVHD, enhancement of immune reconstitution, less toxic regimens, and prevention and early treatment of late complications are needed.

Pregnancy after hematopoietic cell transplantation: a report from the late effects working committee of the Center for International Blood and Marrow Transplant Research (CIBMTR).

Preservation of fertility after hematopoietic cell transplantation (HCT) can have a significant influence on the quality of life of transplant survivors. We describe 178 pregnancies in HCT recipients that were reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 2002 and 2007. There were 83 pregnancies in female HCT recipients and 95 pregnancies in female partners of male HCT recipients. Indications for transplantation included hematologic and other malignancies (N = 99) and nonmalignant disorders (N = 79, of which 75 patients had severe aplastic anemia). The cohort included recipients of autologous HCT (20 women, 13 men), myeloablative (MA) allogeneic HCT (12 women, 50 men), and nonmyeloablative allogeneic HCT (2 women, 2 men). Age at HCT was <20 years for 50% of women and 19% of men. Conditioning regimens included total body irradiation (TBI) in 16% of women and 19% of men; doses were MA in 10% of women and in 16% of men. Live births were reported in 86% of pregnancies in partners of male transplant patients and 85% of pregnancies in female transplant patients, with most pregnancies occurring 5 to 10 years after HCT. We conclude that some HCT recipients can retain fertility, including patients who have received TBI and/or MA conditioning. Young patients undergoing HCT should be counseled both before and after HCT about potential loss of fertility, methods for preserving fertility, and planning for future pregnancy. Fertility and outcomes of pregnancy after HCT need prospective evaluation in large transplant cohorts.

Factors associated with self-reported physical and mental health after hematopoietic cell transplantation.

Hematopoietic cell transplantation (HCT) is an intensive treatment for hematologic malignancies that has the potential to cure disease or prolong life, but also to impair quality of life for survivors. Earlier studies have suggested that various factors are associated with physical and mental health after HCT. In this study, we evaluated demographic and clinical factors before and after HCT and selected psychosocial factors after HCT, exploring their association with self-reported physical and mental health. We studied a cohort of 662 survivors at a median of 6.6 years after HCT. Pre-HCT demographic and clinical factors accounted for only a small amount of the variance in physical and mental health post-HCT (3% and 1%, respectively). Adding post-HCT clinical variables to the pre-HCT factors accounted for 32% and 7% of physical and mental outcomes, respectively. When both clinical and psychosocial factors were considered, better physical health post-HCT was associated with younger age, race other than white, higher current family income, currently working or being a student, less severe transplantation experience (ie, not experiencing graft-versus-host disease), fewer current comorbidities, higher Karnofsky status, less social constraint, less social support, and less trait anxiety. This multivariate model accounted for 36% of the variance in physical health, with the psychosocial variables contributing very little. When both clinical and psychosocial factors were considered, better mental health after HCT was associated with more severe transplantation experience, less social constraint, greater spiritual well being, and less trait anxiety. This multivariate model accounted for 56% of the variance in mental health, with the psychosocial factors accounting for most of the variance. These data suggest that clinical factors are explanatory for much of the post-HCT physical health reported by HCT survivors, but very little of self-perceived mental health. These observations provide insight into the identification of factors that can allow recognition of at-risk patients, as well as factors amenable to intervention.

Relapse and late mortality in 5-year survivors of myeloablative allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in first chronic phase.

PURPOSE Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT. PATIENTS AND METHODS Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen-matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients. RESULTS Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9). CONCLUSION Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population.

The preventive health behaviors of long-term survivors of cancer and hematopoietic stem cell transplantation compared with matched controls.

Little is known about the health promotion, prevention, and disease screening behaviors of cancer survivors treated with hematopoietic cell transplantation (HCT), who undergo arduous treatment and may be at particular risk for late effects and secondary malignancies. The purposes of this study were to examine the current health and secondary prevention behaviors of long-term HCT survivors compared with matched controls without cancer, and to identify sociodemographic and clinical factors associated with appropriate preventive practices. HCT survivors (n = 662) were drawn from 40 North American transplantation centers. Peer-nominated acquaintances of survivors matched on sex, age, education, and marital status served as controls (n = 158). Data were collected a mean of 6.7 years post-HCT (range, 1.8-22.6 years). Despite a greater frequency of physical exams, the HCT survivors had similar health and screening behaviors as the matched controls. Sociodemographic factors were associated with health prevention behaviors in expected ways. Some differences between disease group and type of transplant were found, with survivors of acute leukemia less likely to report regular exercise, autologous transplant survivors more likely than allogeneic transplant survivors to report screenings for breast and cervical cancer, and allogeneic transplant survivors more likely than autologous transplant survivors to report undergoing a skin exam in the previous year. Despite higher levels of engagement with health care providers, HCT survivors had similar health behaviors as matched controls and comparable to those reported by cancer survivors who did not undergo HCT. There remains considerable room for improvement. These findings support the need for further education of both HCT survivors and health practitioners.

Outcome of transplantation for myelofibrosis.

Myelofibrosis is a myeloproliferative disorder incurable with conventional strategies. Several small series have reported long-term disease-free survival (DSF) after allogeneic hematopoietic cell transplantation (HCT). In this study, we analyze the outcomes of 289 patients receiving allogeneic transplantation for primary myelofibrosis between 1989 and 2002, from the database of the Center for International Bone Marrow Transplant Research (CIBMTR). The median age was 47 years (range: 18-73 years). Donors were HLA identical siblings in 162 patients, unrelated individuals in 101 patients, and HLA nonidentical family members in 26 patients. Patients were treated with a variety of conditioning regimens and graft-versus-host disease (GVHD) prophylaxis regimens. Splenectomy was performed in 65 patients prior to transplantation. The 100-day treatment-related mortality was 18% for HLA identical sibling transplants, 35% for unrelated transplants, and 19% for transplants from alternative related donors. Corresponding 5-year overall survival (OS) rates were 37%, 30%, and 40%, respectively. DFS rates were 33%, 27%, and 22%, respectively. DFS for patients receiving reduced-intensity transplants was comparable: 39% for HLA identical sibling donors and 17% for unrelated donors at 3 years. In this large retrospective series, allogeneic transplantation for myelofibrosis resulted in long-term relapse-free survival (RFS) in about one-third of patients.

The effect of smoking on allogeneic transplant outcomes.

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) data, we compared the transplant outcomes of patients with chronic myelogenous leukemia (CML) who were nonsmokers (NS) and past or current smokers (PCS). There were 2193 NS and 625 PCS who received matched sibling and unrelated donor allografts for CML in first chronic phase. We looked for dose effects and identified low and high dose smoking groups (>10 pack years, >1 pack per day). Outcomes were adjusted for known prognostic variables including the European Group for Blood and Marrow Transplant (EBMT) risk score. In multivariate analyses of sibling allograft recipients, relapse risk (RR) was higher (RR=1.67, P=.003) in smokers than NS, but the dose effects were not consistent. High-dose smokers experienced a 50% treatment-related mortality (TRM) versus 28% in the NS group at 5 years on univariate analysis, and the RR was 1.57 (P=.005) on multivariate analysis. Overall survival (OS) at 5 years was 68% in NS versus 62% in the low-dose smoking group versus 50% in the high-dose smoking group (P < .001). Smoking did not significantly affect outcomes in unrelated donor recipients, but numbers were smaller. High-dose smoking is associated with a reduction in OS in patients having sibling allografts for CML. A prospective study with detailed demographic, pulmonary function, and quality-of-life data would improve our understanding of this issue.

Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation.

We evaluated 26 901 patients who underwent allogeneic hematopoietic cell transplantation (HCT) at 271 centers worldwide to define patterns of posttransplantation lymphoproliferative disorders (PTLDs). PTLDs developed in 127 recipients, with 105 (83%) cases occurring within 1 year after transplantation. In multivariate analyses, we confirmed that PTLD risks were strongly associated (P < .001) with T-cell depletion of the donor marrow, antithymocyte globulin (ATG) use, and unrelated or HLA-mismatched grafts (URD/HLA mismatch). Significant associations were also confirmed for acute and chronic graft-versus-host disease. The increased risk associated with URD/HLA-mismatched donors (RR = 3.8) was limited to patients with T-cell depletion or ATG use (P = .004). New findings were elevated risks for age 50 years or older at transplantation (RR = 5.1; P < .001) and second transplantation (RR = 3.5; P < .001). Lower risks were found for T-cell depletion methods that remove both T and B cells (alemtuzumab and elutriation, RR = 3.1; P = .025) compared with other methods (RR = 9.4; P = .005 for difference). The cumulative incidence of PTLDs was low (0.2%) among 21 686 patients with no major risk factors, but increased to 1.1%, 3.6%, and 8.1% with 1, 2, and more than 3 major risk factors, respectively. Our findings identify subgroups of patients who underwent allogeneic HCT at elevated risk of PTLDs for whom prospective monitoring of Epstein-Barr virus activation and early treatment intervention may be particularly beneficial.

Solid cancers after allogeneic hematopoietic cell transplantation.

Transplant recipients have been reported to have an increased risk of solid cancers but most studies are small and have limited ability to evaluate the interaction of host, disease, and treatment-related factors. In the largest study to date to evaluate risk factors for solid cancers, we studied a multi-institutional cohort of 28 874 allogeneic transplant recipients with 189 solid malignancies. Overall, patients developed new solid cancers at twice the rate expected based on general population rates (observed-to-expected ratio 2.1; 95% confidence interval 1.8-2.5), with the risk increasing over time (P trend < .001); the risk reached 3-fold among patients followed for 15 years or more after transplantation. New findings showed that the risk of developing a non-squamous cell carcinoma (non-SCC) following conditioning radiation was highly dependent on age at exposure. Among patients irradiated at ages under 30 years, the relative risk of non-SCC was 9 times that of nonirradiated patients, while the comparable risk for older patients was 1.1 (P interaction < .01). Chronic graft-versus-host disease and male sex were the main determinants for risk of SCC. These data indicate that allogeneic transplant survivors, particularly those irradiated at young ages, face increased risks of solid cancers, supporting strategies to promote lifelong surveillance among these patients.

Impact of imatinib therapy on the use of allogeneic haematopoietic progenitor cell transplantation for the treatment of chronic myeloid leukaemia.

The discovery and approval of imatinib drastically changed the therapeutic algorithm for chronic myeloid leukaemia (CML). Imatinib is now considered the therapy of choice for patients with newly diagnosed CML, including those previously considered candidates for allogeneic haematopoietic cell transplantation (HCT). We compared numbers and types of allogeneic HCTs performed for CML in North America before and after the introduction of imatinib, and publication of the International Randomized Trial of Interferon and STI571 (IRIS) using transplants reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). The number of HCTs for CML registered with the CIBMTR in 1998 was 617; 62% were performed in first chronic phase (CP1). Only 1% of patients had received imatinib prior to transplantation. In 2003, the number of HCTs reported was 223; 44% were performed in CP1 and 77% of patients received imatinib prior to transplantation. The introduction of imatinib therapy has had a profound impact on the use of allogeneic transplantation for CML, with a marked decrease in the number of transplants for CML and an accompanying decrease in the proportion done in CP1. Most patients now receive a trial of imatinib before proceeding to HCT.

Late effects of cancer and hematopoietic stem-cell transplantation on spouses or partners compared with survivors and survivor-matched controls.

PURPOSE: Little is known about the long-term effects of cancer and hematopoietic stem-cell transplantation (HCT) on spouses or partners. The purpose of this study was to examine the health-related quality of life and post-traumatic growth (PTG) of spouses/partners compared with survivors and controls and to identify factors associated with those outcomes. PATIENTS AND METHODS: HCT survivor/partner pairs (n = 177), coupled continuously since HCT, were drawn from 40 North American transplantation centers. Married peer-nominated acquaintances (of survivors) served as controls (n = 133). Outcomes were measured a mean of 6.7 years after HCT (range, 1.9 to 19.4 years). RESULTS: As expected, self-reported partner physical health was similar to controls and better than survivors (P < .001). However, partners reported more fatigue and cognitive dysfunction than controls (P < .001 for both), although less than survivors. Partners and survivors reported more depressive symptoms and sleep and sexual problems than controls (P < .001, P < .01, and P < .01, respectively). Odds of partner depression were nearly 3.5 times that of controls (P < .002). Depressed partners were less likely than depressed survivors to receive mental health treatment (P < .04). Partners reported less social support (P < .001), dyadic satisfaction (P < .05), and spiritual well-being (P < .05) and more loneliness (P < .05) than both survivors and controls. In contrast to survivors, partners reported little PTG (P < .001). Factors associated with partner outcomes included partner health problems, coping, female sex, social constraint, survivor depression, optimism, multiple life changes, and social support. CONCLUSION: Spouses/partners experience similar emotional and greater social long-term costs of cancer and HCT than survivors without the potential compensatory benefits of PTG. Some of the factors associated with partner outcomes are amenable to intervention.

Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study.

Previous studies of recipients of hematopoietic stem-cell transplants suggest that graft-versus-host disease (GVHD) and its therapy may increase the risk for solid cancers, particularly squamous-cell carcinomas (SCCs) of the buccal cavity and skin. However, the importance and magnitude of these associations are not well characterized. We conducted a case-control study of 183 patients with posttransplantation solid cancers (58 SCCs, 125 non-SCCs) and 501 matched control patients within a cohort of 24,011 patients who underwent hematopoietic stem-cell transplantation (HSCT) at 215 centers worldwide. Our results showed that chronic GVHD and its therapy were strongly related to the risk for SCC, whereas no increase in risk was found for non-SCCs. Major risk factors for the development of SCC were long duration of chronic GVHD therapy (P < .001); use of azathioprine, particularly when combined with cyclosporine and steroids (P < .001); and severe chronic GVHD (P = .004). Given that most patients who received prolonged immunosuppressive therapy and those with severe chronic GVHD were also treated with azathioprine, the independent effects of these factors could not be evaluated. Additional analyses determined that prolonged immunosuppressive therapy and azathioprine use were also significant risk factors for SCC of the skin and of the oral mucosa. These data provide further encouragement for strategies to prevent chronic GVHD and for the development of more effective and less carcinogenic treatment regimens for patients with moderate or severe chronic GVHD. Our results also suggest that clinical screening for SCC is appropriate among patients exposed to persistent chronic GVHD, prolonged immunosuppressive therapy, or both.

Long-term health-related quality of life, growth, and spiritual well-being after hematopoietic stem-cell transplantation.

PURPOSE: To examine health-related quality of life (HRQOL) and growth, and spiritual well-being in adult survivors of hematopoietic stem-cell transplantation (HSCT) for a malignant disease. METHODS: HSCT survivors (n = 662) were recruited through the International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry and were drawn from 40 transplantation centers. HSCT survivors completed a telephone interview and a set of questionnaires a mean of 7.0 years post-HSCT (range, 1.8 to 22.6 years). Study measures included a variety of standardized measures of HRQOL and growth and spiritual well-being. An age- and sex-matched healthy comparison (HC) group (n = 158) was recruited using a peer nomination method. The HC group completed a parallel telephone interview and set of questionnaires. RESULTS: Multivariate analysis of variance analyses found the HSCT survivor group reported poorer status relative to the HC group for all HRQOL outcome clusters including physical health, physical functioning, social functioning, psychological adjustment, and dyadic adjustment. In contrast, the HSCT survivor group reported more psychological and interpersonal growth. Mean effect size for the 24 outcome indices examined was 0.36 standard deviations, an effect size often considered clinically meaningful or important. The largest group differences were found for measures of general health, physical function and well-being, depression, cognitive function, and fatigue. CONCLUSION: The experience of HSCT for a malignant disease has a wide-ranging, longstanding, and profound impact on adult recipients. Relative to healthy controls, HSCT survivors reported poorer physical, psychological, and social functioning but, conversely, more psychological and interpersonal growth, differences that appeared to persist many years after HSCT.

Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants.

The European Group for Blood and Marrow Transplantation (EBMT) devised a scoring system to predict survival after allogeneic haematopoietic stem cell transplantation (HSCT) for chronic myeloid leukaemia (CML). The present International Bone Marrow Transplant Registry study of 3211 patients tested the EBMT Risk Score in a independent population, investigated the value of adding other variables, evaluated a new risk score specifically for chronic phase and compared the allograft risk scores with risk scores established by Sokal in 1984 and Hasford in 1998 for survival with non-transplant treatments. The primary outcome was 5-year survival after HSCT; survival curves, regression models and measurements of explained variation were used to compare scores. Using the EBMT scoring system, survival in the independent dataset was almost identical to those in the original EBMT publication, thus validating the EBMT Risk Score. Adding one extra variable, performance status, or designing a score specifically for early chronic phase by using the original five variables with different breakpoints gave results only slightly better than the original EBMT Score. Sokal and Hasford Scores did not predict survival after HSCT. We concluded that the EBMT Risk Score does not currently require modification.

Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study.

Although numerous reports indicate that patients receiving autotransplants for lymphoma are at increased risk for myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), the separate contributions of pretransplantation- and transplantation-related therapy are not well characterized. We conducted a case-control study of 56 patients with MDS/AML and 168 matched controls within a cohort of 2 739 patients receiving autotransplants for Hodgkin disease or non-Hodgkin lymphoma at 12 institutions (1989-1995). Detailed abstraction of medical records was undertaken to determine all pre- and posttransplantation therapy, and transplantation-related procedures. In multivariate analyses, risks of MDS/AML significantly increased with the intensity of pretransplantation chemotherapy with mechlorethamine (relative risks [RRs] = 2.0 and 4.3 for cumulative doses < 50 mg/m2 and > or = 50 mg/m,2 respectively; trend over dose categories, P =.04) or chlorambucil (RRs = 3.8 and 8.4 for duration < 10 months or > or = 10 months, respectively; trend, P =.009), compared with cyclophosphamide-based therapy. Transplantation-conditioning regimens including total-body irradiation (TBI) at doses 12 Gy or less did not appear to elevate leukemia risk (RR = 1.3; P =.48) compared with non-TBI regimens; however, a statistically significant increased risk was found for TBI doses of 13.2 Gy (RR = 4.6; P =.03). Peripheral blood stem cells were associated with a nonsignificant increased risk of MDS/AML (RR = 1.8; P =.12) compared with bone marrow grafts. Our data show that type and intensity of pretransplantation chemotherapy with alkylating agents are important risk factors of MDS/AML following autotransplantation. Transplantation-related factors may also modulate this risk; however, the apparent contribution of high-dose TBI requires confirmation.