Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients ...of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.
PURPOSE Hematopoietic cell transplantation can cure hematologic malignancies and other diseases, but this treatment can also cause late complications. Previous studies have evaluated the cumulative ...effects of late complications on survival, but longer-term effects on life expectancy after hematopoietic cell transplantation have not been assessed. PATIENTS AND METHODS We used standard methods to evaluate mortality, projected life expectancy, and causes of death in a cohort of 2,574 patients who survived without recurrence of the original disease for at least 5 years after allogeneic or autologous hematopoietic cell transplantation from 1970 through 2002. Sex- and age-specific comparisons were made with US population data. Results Estimated survival of the cohort at 20 years after transplantation was 80.4% (95% CI, 78.1% to 82.6%). During 22,923 person-years of follow-up, 357 deaths occurred. Mortality rates remained four- to nine-fold higher than the expected population rate for at least 30 years after transplantation, yielding an estimated 30% lower life expectancy compared with that in the general population, regardless of current age. In rank order, the leading causes of excess deaths were second malignancies and recurrent disease, followed by infections, chronic graft-versus-host disease, respiratory diseases, and cardiovascular diseases. CONCLUSION Patients who have survived for at least 5 years after hematopoietic cell transplantation without recurrence of the original disease have a high probability of surviving for an additional 15 years, but life expectancy is not fully restored. Further effort is needed to reduce the burden of disease and treatment-related complications in this population.
Thyroid dysfunction is a known complication after hematopoietic cell transplantation (HCT) in children with reports involving relatively short follow-up and small patient numbers. This study involves ...791 patients less than 18 years of age at HCT at the Fred Hutchinson Cancer Research Center with follow-up from 1969 through 2007. Thyroid dysfunction continued for 28 years after transplantation. Hypothyroidism was the most common abnormality with other abnormalities of hyperthyroidism and thyroiditis. Multivariate analysis showed that thyroid dysfunction was more likely if patients were less than 10 years of age (P < .001), but there was no difference between receiving a total body irradiation or busulfan based regimens (P = .48) compared with cyclophosphamide conditioning alone (P = .008). Thyroid tumors occurred at a median of 9.9 (4.5-22.3) years after HCT and included 13 with papillary carcinoma and 5 with benign adenomas. Children who receive a HCT should be monitored for thyroid abnormalities throughout life.
Relapse occurs frequently after allogeneic hematopoietic cell transplantation (HCT) for treatment of high-risk Philadelphia chromosome–positive (Ph+) leukemia. Administration of imatinib early after ...HCT might provide an effective approach for preventing recurrent Ph+ leukemia, but the feasibility of this approach has not been systematically tested. Twenty-two patients, 15 with Ph+ acute lymphoblastic leukemia and 7 with high-risk chronic myelogenous leukemia, were enrolled in a prospective study and given imatinib from the time of engraftment until 365 days after HCT. Before day 90, adults (n = 19) tolerated a median average daily imatinib dose of 400 mg/d (range, 200-500 mg/d), and children (n = 3) tolerated 265 mg/m2/d (range, 200-290 mg/m2/d). The most common adverse events related to imatinib administration were grade 1-3 nausea, emesis, and serum transaminase elevations. We conclude that imatinib can be safely administered early after myeloablative allogeneic HCT at a dose intensity comparable to that used in primary therapy.
The overall survival (OS) of patients with relapsed Ewing's sarcoma family of tumors (ESFT) is poor, and the relative benefit of high-dose therapy (HDT) is controversial.
We retrospectively ...identified 55 consecutive ESFT patients with adequate medical records for review, who were treated at Children's Hospital and Regional Medical Center and who developed disease recurrence between January 1, 1985 and December 31, 2002.
The median relapse-free interval (RFI) from diagnosis to first recurrence was 17 months (range, 5 to 90 months). Most recurrences were metastatic only (39 patients) or local and metastatic (10 patients). Twenty-seven patients (49%) achieved a partial or complete response to second-line treatment, with a median duration of response of 27 months (range, 5 to 119+ months). The 5-year OS rate for all relapsed patients was 23% (95% CI, 11% to 35%). By univariate analysis, improved OS was associated with response to second-line treatment versus no response (46% v 0%, respectively; P < .0001), RFI > or = 24 months versus less than 24 months (48% v 12%, respectively; P = .0001), and no metastases at initial diagnosis versus presence of metastases (31% v 12%, respectively; P = .05). Because all 13 patients who received HDT also had responsive relapse, we performed a multivariate analysis. Reduced risk of death was associated with response to second-line therapy (relative risk, 0.14; 95% CI, 0.05 to 0.40), RFI > or = 24 months (relative risk, 0.29; 95% CI, 0.13 to 0.66), and receiving HDT (relative risk, 0.26; 95% CI, 0.08 to 0.85).
HDT as consolidation therapy for relapsed ESFT seems to be associated with improved OS, even after adjusting for RFI and response to second-line treatment.
Aplastic anemia (AA), a potentially fatal disease, may be cured with marrow transplantation. Survival in pediatric patients has been excellent early after transplantation, but only limited data are ...available regarding late effects. This study evaluates late effects among 152 patients followed 1-38 years (median, 21.8 years). Transplantation-preparative regimes were mostly cyclophosphamide with or without antithymocyte globulin. Survival at 30 years for the acquired AA patients is 82%, and for the Fanconi anemia patients it is 58% (P = .01). Multivariate analysis demonstrated that chronic GVHD (P = .02) and Fanconi anemia (P = .03) negatively impacted survival. Two Fanconi patients and 18 acquired AA patients developed a malignancy that was fatal for 4. There was an increased incidence of thyroid function test abnormalities among those who received total body irradiation. Cyclophosphamide recipients demonstrated normal growth, basically normal development, and pregnancies with mostly normal offspring. Quality-of-life studies in adult survivors of this pediatric transplantation cohort indicated that patients were comparable with control patients except for difficulty with health and life insurance. These data indicate that the majority of long-term survivors after transplantation for AA during childhood can have a normal productive life.
Chronic graft-versus-host disease (GVHD) requires long-term immunosuppressive therapy after hematopoietic cell transplantation. We retrospectively analyzed a cohort of 751 patients with chronic GVHD ...to identify characteristics associated with the duration of immunosuppressive treatment. Among the 274 patients who discontinued immunosuppressive therapy after resolution of chronic GVHD before recurrent malignancy or death, the median duration of treatment was 23 months. Results of a multivariable model showed that treatment was prolonged in patients who received peripheral blood cells, in male patients with female donors, in those with graft-versus-host HLA mismatching, and in those with hyperbilirubinemia or multiple sites affected by chronic GHVD at the onset of the disease. Nonrelapse mortality was increased among patients with HLA mismatching or hyperbilirubinemia but not among those with other risk factors associated with prolonged treatment for chronic GVHD. Nonrelapse mortality was also increased in older patients and those with older donors, in patients with platelet counts less than 100 000/μL or progressive onset of chronic GVHD from acute GVHD, and in those receiving higher doses of prednisone immediately before the diagnosis of chronic GVHD. After the dose of prednisone was taken into account, progressive onset was not associated with an increased risk of nonrelapse mortality.
Fifty-six patients, 10 to 66 years of age, with idiopathic myelofibrosis (IMF) or end-stage polycythemia vera or essential thrombocythemia received allogeneic hematopoietic cell transplants from ...related (n = 36) or unrelated (n = 20) donors. Forty-four patients were prepared with busulfan plus cyclophosphamide and 12 with total body irradiation plus chemotherapy. The source of stem cells was marrow in 33 and peripheral blood in 23 patients. All but 3 patients achieved engraftment. While 50 patients showed complete donor chimerism, 3 patients were found to be mixed chimeras at 26, 48, and 86 months after transplantation, respectively. Two patients died from relapse/progressive disease, and 18 died from other causes. There are 36 patients surviving at 0.5 to 11.6 (median, 2.8) years, for a 3-year Kaplan-Meier estimate of 58% (CI, 43%-73%). Dupriez score, cytogenetic abnormalities, and degree of marrow fibrosis were the most significant risk factors for posttransplantation mortality. Patients conditioned with a regimen of busulfan targeted to plasma levels of 800 to 900 ng/mL plus cyclophosphamide had a higher probability of survival (76% CI, 62%-91%) than other patients. Results with unrelated donors were comparable with those with HLA-identical sibling transplants. Thus, allogeneic hematopoietic cell transplantation offers long-term relapse-free survival for patients with myelofibrosis.
Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with current therapy, the event-free survival (EFS) of infants with ALL, particularly those with mixed lineage ...leukemia (MLL) gene rearrangements, is only 30% to 40%. Relapse has been the major source of treatment failure for these patients. The parallel Children's Cancer Group (CCG) 1953 and Pediatric Oncology Group (POG) 9407 studies were designed to test the hypothesis that more intensive therapy, including dose intensification of chemotherapy, and hematopoietic stem-cell transplantation (HSCT) would improve the outcome for this group of patients.
One hundred eighty-nine infants (CCG 1953, n = 115; POG 9407, n = 74) were enrolled between October 1996 and August 2000. For infants with the MLL gene rearrangement and an appropriate donor, HSCT was the preferred treatment on CCG 1953 and investigator option on POG 9407 after completion of the second phase of therapy. Fifty-three infants underwent HSCT.
The 5-year EFS rate was 48.8% (95% CI, 33.9% to 63.7%) in patients who received HSCT and 48.7% (95% CI, 33.8% to 63.6%) in patients treated with chemotherapy alone (P = .60). Transplantation outcomes were not affected by the preparatory regimen or donor source.
Our data suggest that routine use of HSCT for infants with MLL-rearranged ALL is not indicated. However, limited by small numbers, this study should not be considered the definitive answer to this question.
Hematopoietic cell transplantation (HCT) is an effective and widely used treatment for hematologic malignancies. The rate and predictors of physical and emotional recovery after HCT have not been ...adequately defined in prospective long-term studies.
To examine the course of recovery and return to work after HCT.
Prospective, longitudinal cohort study at a US academic center specializing in HCT. Function was assessed from pretransplantation to 5-year follow-up for 319 adults who had myeloablative HCT for treatment of leukemia or lymphoma and spoke English. Of the 99 long-term survivors who had no recurrent malignancy, 94 completed 5-year follow-up.
Physical limitations, return to work, depression, and distress related to treatment or disease were evaluated before transplantation, at 90 days, and at 1, 3, and 5 years after HCT.
Physical recovery occurred earlier than psychological or work recovery. Only 21 patients (19%) recovered on all outcomes at 1 year. The proportion without major limitations increased to 63% (n = 57) by 5 years. Among survivors without recurrent malignancy, 84% (n = 74) returned to full-time work by 5 years. Patients with slower physical recovery had higher medical risk and were more depressed before HCT (P< or =.001). Patients with chronic graft-vs-host disease (P =.01), with less social support before HCT (P =.001), and women (P<.001) were more depressed after transplantation. Transplant-related distress was slower to recover for allogeneic transplant recipients and those with less social support before HCT (P< or =.01). Patients who had more experience with cancer treatment before beginning HCT had more rapid recovery from depression (P =.04) and treatment-related distress (P =.009).
Full recovery after HCT is a 3- to 5-year process. Recovery might be accelerated by more effective interventions to increase work-related capabilities, improve social support, and manage depression.
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