New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors.

PURPOSE: To determine the incidence and risk factors for the development of new malignancies occurring after stem-cell transplantation (SCT). PATIENTS: Between January 1, 1974, and March 31, 2001, 3,372 patients underwent SCT at the University of Minnesota. From these transplants, 147 posttransplant malignancies (PTMs) were identified in 137 patients. RESULTS: Excluding nonmelanoma skin cancers (n = 19) and carcinoma-in-situ (n = 5), the remaining 123 cases represented an 8.1-fold (95% confidence interval [CI], 6.7 to 9.6) increased risk of a PTM, an excess risk of 102.7 cases/10,000 persons/yr (age and sex adjusted). This includes a significantly elevated risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; standardized incidence ratio [SIR] = 300; 95% CI, 210 to 406), non-Hodgkin's lymphoma including posttransplant lymphoproliferative disorder (PTLD; SIR = 54.3; 95% CI, 39.5 to 41.1), Hodgkin's disease (SIR = 14.8; 95% CI, 3.9 to 32.9), or solid tumors overall (SIR = 2.8; CI, 2.0 to 3.7) and in specific for melanoma, brain, and oral cavity tumors. The cumulative incidence for the development of any PTM was 6.9% (95% CI, 5.2 to 8.6) at 20 years post-SCT. For PTLD (n = 43), the cumulative incidence plateaued at 1.4% (95% CI, 1.0 to 1.8) by 10 years post-SCT. For MDS or AML, the cumulative incidence plateaued at 1.4% (95% CI, 0.9 to 1.9) by 10 years post-SCT. The cumulative incidence of developing a solid tumor did not plateau and was 3.8% (95% CI, 2.2 to 5.4) at 20 years post-SCT. CONCLUSION: These data reveal that the risk of PTMs, especially solid tumors, continues to increase even 20 years after transplant, necessitating long-term close follow-up for these patients.

Pulmonary nodular lesions in bone marrow transplant recipients: impact of histologic diagnosis on patient management and prognosis.

Bone marrow transplantation is associated with numerous pulmonary complications, which may manifest as nodules. We studied 33 bone marrow transplant (BMT) recipients in whom pulmonary nodular lesions (PNLs) developed during a 5-year period and who underwent open lung biopsy (OLB) for diagnosis. Of 33 patients with PNL, 15 (45%) had pulmonary cytolytic thrombi (PCT), a recently described condition characterized histologically by occlusive vascular lesions and hemorrhagic infarcts and clinically by a favorable outcome. Clinical symptoms and radiologic abnormalities disappeared during a period of a few weeks. None of the patients died of PCT; 10 were alive at last contact. The second most common cause of PNL (8/33 [24%]) was Aspergillus infection, which was the cause of death in 6. OLB is an effective way of obtaining diagnostic tissue in BMT recipients with PNLs. Histologic examination is accurate in determining the cause of PNLs and identifying lesions that have a favorable outcome and those that require a change in treatment.

Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study.

We assessed late mortality in 1479 individuals who had survived 2 or more years after allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 25.9 years and median length of follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% (SE = 1.9%) for those who were disease-free at entry into the cohort, and the relative mortality was 9.9 (95% confidence interval, 8.7-11.2). Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio = 2.2). Relapse of primary disease (29%) and chronic graft-versus-host disease (cGVHD: 22%) were the leading causes of premature death. Nonrelapse-related mortality was increased among patients older than 18 years at HCT (18-45 years: relative risk [RR] = 1.7; 46+ years: RR = 3.7) and among those with cGVHD (RR = 2.7), and was lower among patients who received methotrexate for GVHD prophylaxis (RR = 0.5). HCT survivors were more likely to report difficulty in holding jobs (odds ratio [OR] = 13.9), and in obtaining health (OR = 7.1) or life (OR = 9.9) insurance compared with siblings. This study demonstrates that mortality rates remain twice as high as that of the general population among 15-year survivors of HCT, and that the survivors face challenges affecting their health and well-being.

Long-term results of autologous stem cell transplantation for primary refractory or relapsed Hodgkin's lymphoma.

Autologous hematopoietic stem cell transplantation (ASCT) has become standard therapy for primary refractory (PR REF) or relapsed (REL) Hodgkin's lymphoma (HL); however, more than half of these patients eventually relapse and die of their disease. We studied long-term outcomes and evaluated factors influencing progression-free survival (PFS) in 141 patients with PR REF or REL HL who underwent ASCT between 1985 and 2003. Median age at ASCT was 30 years (range, 7-60 years); 21 patients had PR REF, and 120 had REL HL. With a median follow-up of 6.3 years (range, 1-20 years), the probability of PFS at 5 and 10 years was 48% (95% confidence interval [CI], 39%-57%) and 45% (95% CI, 36%-54%) and that of overall survival (OS) was 53% (95% CI, 44%-62%) and 47% (95% CI, 37%-57%), respectively. Transplant-related mortality at 100 days was 1.4%. Among 45 5- to 20-year survivors, no late relapses of HL were observed. In multivariate analysis, 3 factors were independently predictive of poor PFS: chemoresistant disease (relative risk [RR], 2.9; 95% CI, 1.7-5.0), B-symptoms at pretransplantation relapse (RR, 2.1; 95% CI, 1.3-3.4), and presence of residual disease at the time of transplantation (RR, 2.3; 95% CI, 1.1-4.8). Patients with 0 or 1 of these 3 adverse factors (low-risk disease) had a 5-year PFS of 67% (95% CI, 55%-79%) compared with 37% (95% CI, 22%-52%) in those with 2 factors (intermediate-risk group) and 9% (95% CI, 0-20%) in those with all 3 factors (high-risk group) (P < .001). The rates of OS at 5 years were 71% (95% CI, 60%-82%), 49% (95% CI, 33%-65%) and 13% (95% CI, 0-27%) in the 3 groups, respectively (P < .001). ASCT is associated with durable PFS in appropriately selected patients with PR REF or REL HL. Using a simple prognostic model, we can identify patients with high-risk disease who have predictably unfavorable outcome after ASCT and require novel therapeutic approaches. A risk-adapted approach should be followed in determining treatment options for patients with PR REF and REL HL.

Natural history of pulmonary complications in children after bone marrow transplantation.

We sought, in children after bone marrow transplantation (BMT), (1) to determine the natural history and incidence of pulmonary complications, (2) to evaluate the diagnostic yield of fiberoptic bronchoscopy and bronchoalveolar lavage (BAL); and (3) to determine the effect of bronchoscopy with lavage on patient outcome. The study design was a retrospective review in a tertiary care university hospital of all children undergoing BMT over a 5-year period. Patients were separated into 2 study groups: children with and without pulmonary complications. Pulmonary complications were defined as new or persistent pulmonary infiltrates on chest radiograph or chest computed tomography scan, respiratory symptoms, hypoxemia, or hemoptysis. Three hundred sixty-three pediatric patients underwent BMT between January 1, 1995, and December 31, 1999. Ninety patients (25%) developed pulmonary complications and were evaluated with bronchoscopy and BAL. Patients with pulmonary complications had a higher mortality (65% versus 44%; P < .01). The median posttransplantation survival for children with pulmonary complications was 258 days, compared with 1572 days in patients without pulmonary complications. The incidence of pulmonary complications was increased in patients with allogeneic BMT (P < .01). The time-dependent onset of severe (grade III to IV) graft-versus-host disease increased the relative risk of pulmonary complications by 2.0 (95% confidence interval, 1.1-3.7; P = .02). Pulmonary complications increased the time-dependent relative risk of mortality by 3.5 (95% confidence interval, 2.5-4.8). The diagnostic yield of bronchoscopy with lavage was 46% in patients undergoing BAL. Diagnostic bronchoscopy did not enhance either 30- or 100-day survival. Pathogen identification did not decrease mortality (P = .45). Pulmonary complications occur in 25% of children undergoing BMT and increase the risk of death in the first year after BMT. Although pathogen identification does not confer a survival advantage, rigorous, prospective screening may allow for earlier identification of pathogens and thereby provide a benefit to this uniquely vulnerable population.

Long-term follow-up after autologous hematopoietic stem cell transplantation for low-grade non-Hodgkin lymphoma.

Autologous hematopoietic stem cell transplantation (AHSCT) in low-grade non-Hodgkin lymphoma (NHL) can result in a prolonged remission, although most patients eventually relapse and die of their disease. We report long-term outcomes of AHSCT for patients with relapsed low-grade NHL. Between May 1983 and 2001, 67 patients with relapsed or refractory stage III and IV low-grade NHL received an AHSCT at the University of Minnesota at a median of 2.3 years (range, 0.4-15.2 years) after diagnosis. At transplantation, 62 patients (92%) were in complete remission (CR) (6%) or partial remission (PR) (86%); 5 (8%) had resistant disease; and 9 (14%) had transformed to a higher-grade NHL. After AHSCT, 32 (49%) of 65 evaluable patients achieved CR, and 26 (40%) achieved PR. Overall survival (OS) was 50% (95% confidence interval [CI], 38%-62%) at 4 years and 33% (95% CI, 20%-46%) at both 10 and 18 years, whereas progression-free survival (PFS) was 28% (95% CI, 17%-39%) at 4 years, 18% (95% CI, 8%-28%) at 10 years, and 14% (95% CI, 4%-25%) at 18 years. Transplant-related mortality in the first 100 days was 3% (95% CI, 0%-7%). Relapse occurred in 62% (95% CI, 48%-75%) at 4 years and 72% (95% CI, 56%-87%) at 10 years. Eleven patients (16%) developed myelodysplastic syndrome/acute myeloid leukemia 1 to 8 years after AHSCT, and 3 (5%) developed solid tumors. In multiple regression analysis, the International Prognostic Index (IPI) score at transplantation was the most significant predictor for both OS and PFS. The median OS has not been reached in patients with an IPI score of 0 or 1 at transplantation (20 of 35 survive 2 to 18 years after AHSCT), whereas it was 2.3 and 1.6 years for IPI scores of 2 and 3, respectively ( P = .002). A good response (CR/PR) to AHSCT (relative risk [RR], 0.4; 95% CI, 0.2-0.9; P = .04) and age <50 years (RR, 0.5; 95% CI, 0.2-0.8; P = .01) were also independently significant predictors of good OS and PFS. We present mature follow-up data (median follow-up, 8 years; range, 2-18 years) of patients undergoing AHSCT for relapsed low-grade NHL and demonstrate extended OS and PFS. Very long-term remissions were seen in nearly 20% of patients. AHSCT remains promising, especially for patients with sensitive relapse and lower IPI scores. Recurrent lymphoma after AHSCT remains the major problem, and prolonged survival is further tempered by a significant risk of post-transplantation second malignancies, including myelodysplastic syndrome/acute myeloid leukemia and solid tumors.

Late mortality in survivors of autologous hematopoietic-cell transplantation: report from the Bone Marrow Transplant Survivor Study.

We assessed late mortality in 854 individuals who had survived 2 or more years after autologous hematopoietic cell transplantation (HCT) for hematologic malignancies. Median age at HCT was 36.5 years, and median length of follow-up was 7.6 years. Overall survival was 68.8% +/- 1.8% at 10 years, and the cohort was at a 13-fold increased risk for late death (standardized mortality ratio [SMR] = 13.0) when compared with the general population. Mortality rates approached those of the general population after 10 years among patients at standard risk for relapse at HCT (SMR = 1.1) and in patients undergoing transplantation for acute myeloid leukemia (AML; SMR = 0.9). Relapse of primary disease (56%) and subsequent malignancies (25%) were leading causes of late death. Relapse-related mortality was increased among patients with Hodgkin disease (HD; relative risk [RR] = 3.6), non-Hodgkin lymphoma (NHL; RR = 2.1), and acute lymphoblastic leukemia (ALL; RR = 6.5). Total body irradiation (RR = 0.6) provided a protective effect. Nonrelapse-related mortality was increased after carmustine (RR = 2.3) and with use of peripheral blood stem cells (RR = 2.4). Survivors were more likely to report difficulty in holding jobs (RR = 9.4) and in obtaining health (RR = 7.7) or life insurance (RR = 8.4) when compared with siblings. Although mortality rates approach that of the general population after 10 years in certain subgroups, long-term survivors of autologous HCT continue to face challenges affecting their health and well-being.

Successful hematopoietic stem cell transplantation for Fanconi anemia from an unaffected HLA-genotype-identical sibling selected using preimplantation genetic diagnosis.

The only proven cure for Fanconi anemia (FA)-associated bone marrow failure is successful allogeneic hematopoietic stem cell transplantation (HSCT). However, HSCT with donors other than HLA-identical siblings is associated with high morbidity and poor survival. Therefore, we used preimplantation genetic diagnosis (PGD) to select an embryo produced by in vitro fertilization (IVF) that was unaffected by FA and was HLA-identical to the proband. The patient was a 6-year-old girl with FA and myelodysplasia previously treated with oxymetholone and prednisone. After her parents underwent 5 cycles of IVF with intrauterine transfer of 7 embryos over a span of 4 years, successful pregnancy ensued. Twenty-eight days after delivery, the patient underwent transplantation with her newborn sibling donor's HLA-identical umbilical cord blood hematopoietic stem cells (HSCs). Neutrophil recovery occurred on day 17 without subsequent acute or chronic graft-versus-host disease. Currently, 2.5 years after transplantation, the patient is well and hematopoiesis is normal. In summary, we have described the first successful transplantation, using IVF and PGD, of HSCs from a donor selected on the basis of specific, desirable disease and HLA characteristics. The medical, legal, and ethical issues involved with this approach are discussed.

Autoimmune haemolytic anaemia complicating haematopoietic cell transplantation in paediatric patients: high incidence and significant mortality in unrelated donor transplants for non-malignant diseases.

Haemolytic anaemia is a recognized complication of haematopoietic cell transplantation (HCT) and can result from alloimmune- or autoimmune-derived antibodies. Unlike alloimmune haemolytic anaemia, autoimmune haemolytic anaemia (AIHA) is poorly understood, particularly in the paediatric population where only case reports have been published. Between January 1995 and July 2001, 439 consecutive allogeneic HCT were performed in paediatric patients at the University of Minnesota, 31% (n = 136) from related donors (RD) and 69% (n = 303) from unrelated donors (URD). Nineteen cases of AIHA were identified with documented significant haemolysis and a positive direct antiglobulin test. All cases of AIHA occurred in URD transplants, yielding a cumulative incidence of AIHA post-transplant of 6% at 1 year. Patients transplanted for non-malignant disease, particularly metabolic diseases, had a higher incidence of AIHA post-HCT when compared with patients transplanted for malignancies (RR 4.2 95% CI 1.2-15.4, P = 0.01). Mortality was high in our series of 19 patients with 10 (53%) dying following the onset of AIHA, three as a direct consequence of haemolysis. Fifty per cent of deaths occurred from infection while on immunosuppressive therapy to treat haemolysis. Alternative treatment strategies were employed, with the majority of patients demonstrating disease refractory to traditional steroid therapy.

Response of 443 patients to steroids as primary therapy for acute graft-versus-host disease: comparison of grading systems.

Acute GVHD remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). In a retrospective analysis, the response of 443 HSCT patients who received prednisone, 60 mg/m2, for 14 days followed by an 8-week taper, as initial therapy for acute GVHD from 1990 through 1999 at a single institution was examined. Median patient age was 29.0 years (range, 0.3-60.3 years), with 40% of patients <20 years old. Patients received HSCT from 201 related (189 matched sibling/12 partially matched) and 242 unrelated (130 HLA-A, B, DRB1 matched/112 partially matched) donors. GVHD score was measured and outcomes compared using the Minnesota, Consensus, and International Bone Marrow Transplant Registry (IBMTR) grading systems. Prior to initiation of steroid therapy, severe (grades III-IV) acute GVHD was observed in 57 (13%) patients (Minnesota or Consensus grading) and in 192 (43%) patients (IBMTR grading). At day 28 of treatment, overall improvement was observed in 55% of patients, with durable (> or = 28 days) complete response observed in 35% and partial response observed in 20% of patients. Patients with acute lower gastrointestinal GVHD (+/- other organ involvement) had lower response rates. In multivariate logistic regression analysis, recipients of related donor grafts and recipients of GVHD prophylaxis other than methotrexate alone had the highest likelihood of overall response. Initial Minnesota GVHD grade or Consensus GVHD grade was not associated with significant differences in overall response, whereas patients with an initial IBMTR grade of B or C had a higher likelihood of response. Chronic GVHD developed in 42% of patients by 1 year after HSCT. The probability of survival at 1 year after initiation of steroid therapy was 53% (95% confidence interval, 48%-58%). In Cox regression analysis, factors associated with better survival included patients' youth, receipt of related or HLA-matched unrelated grafts, and administration of GVHD prophylaxis other than T-cell depletion in all 3 grading systems. Lower initial GVHD grade (I-II or A-B) led to better survival. These data suggest that steroids provide an active but inadequate therapy for acute GVHD, especially with higher grade GVHD. More effective prophylaxis and therapy for acute GVHD is needed for mismatched unrelated donor recipients and for those with severe GVHD.

Early antithymocyte globulin therapy improves survival in patients with steroid-resistant acute graft-versus-host disease.

Second-line therapies for steroid-resistant acute GVHD have been used with limited success. We have reviewed the responses of 79 hematopoetic stem cell transplant (HSCT) patients uniformly treated from 1990-1998 with equine antithymocyte globulin (ATG) for steroid-resistant acute GVHD, defined as progression of acute GVHD after 4 days of treatment with prednisone or no improvement of acute GVHD after 7 days of treatment with prednisone. Patients received HSCT from 34 related (32 matched sibling/2 partially matched) and 45 unrelated (14 HLA-A, -B, -DRB1 matched/31 partially matched) donors. Prior to ATG therapy, severe (grade III-IV) GVHD was observed in 34 patients (43%). Organs involved included skin in 81% of patients, lower GI tract in 52%, upper GI tract in 28%, and liver in 11%. Treatment consisted of 1-5 courses (median, 2 courses) of ATG (15 mg/kg per dose bid x 5 days) given for a median of 16 days (range, 5 to 44 days) after the onset of GVHD. All patients continued to receive prednisone, 60 mg/m2 per day (or methylprednisolone IV equivalent), plus CSA (75%) or tacrolimus (4%). At day 28 of treatment, overall improvement was observed in 54% of patients; durable (> or = 28 days) complete response was observed in 20% of patients, and partial response was observed in 34% of patients. In multivariate analysis, patients with CML or a malignant disease other than acute leukemia had a greater likelihood of overall response than did those with nonmalignant diseases. Patients with acute skin GVHD (with or without other organ involvement) responded most frequently. Chronic GVHD developed in 51% of patients by 1 year after HSCT. One patient developed EBV lymphoproliferative disease. For the entire cohort, the probability of survival at 1 year was 32% (95% CI, 22%-42%). In multivariate analysis, factors associated with better survival included earlier onset of acute GVHD, shorter time from initial treatment for GVHD to treatment with ATG, and the use of non-T-cell-depleted stem cell grafts. These data suggest that treatment with ATG can be an active therapy, especially in patients with skin GVHD and early signs of steroid resistance.

Cerebral X-linked adrenoleukodystrophy: the international hematopoietic cell transplantation experience from 1982 to 1999.

Cerebral X-linked adrenoleukodystrophy (X-ALD) is a disorder of very-long-chain fatty acid metabolism, adrenal insufficiency, and cerebral demyelination. Death occurs within 2 to 5 years of clinical onset without hematopoietic cell transplantation (HCT). One hundred twenty-six boys with X-ALD received HCT from 1982 to 1999. Survival, engraftment, and acute graft-versus-host disease were studied. Degree of disability associated with neurologic and neuropsychological function and cerebral demyelination were evaluated before and after HCT. Complete data were available and analyzed for 94 boys with cerebral X-ALD. The estimated 5- and 8-year survival was 56%. The leading cause of death was disease progression. Donor-derived engraftment occurred in 86% of patients. Demyelination involved parietal-occipital lobes in 90%, leading to visual and auditory processing deficits in many boys. Overall 5-year survival of 92% in patients with 0 or 1 neurologic deficits and magnetic resonance imaging (MRI) severity score less than 9 before HCT was superior to survival for all others (45%; P <.01). Baseline neurologic and neuropsychological function, degree of disability, and neuroradiologic status predicted outcomes following HCT. In this first comprehensive report of the international HCT experience for X-ALD, we conclude that boys with early-stage disease benefit from HCT, whereas boys with advanced disease may be candidates for experimental therapies.

Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival.

The potential benefits of unrelated donor marrow transplantation are offset by the immunologic complications of graft-versus-host disease (GVHD) and infection. Therefore, we used cryopreserved umbilical cord blood (UCB) as a strategy to reduce the risks of GVHD and treatment-related mortality (TRM) and improve survival. Data on 102 patients (median age 7.4 years) who received transplants between 1994 and 2001 for the treatment of malignant (n = 65; 68% were high-risk patients) and nonmalignant (n = 37) diseases were evaluated. Log-rank tests and Cox regression analyses were used to determine the effects of various demographic, graft-related, and treatment factors on engraftment, GVHD, TRM, relapse, and survival. As of October 15, 2001, the median follow-up was 2.7 years (range, 0.3-7.2). Incidences of neutrophil and platelet engraftment were 0.88 (CI, 0.81-0.95) and 0.65 (CI, 0.53-0.77), respectively. Notably, incidences of severe acute and chronic GVHD were 0.11 (CI, 0.05-0.17) and 0.10 (CI, 0.04-0.16), respectively. At 1 year after transplantation, proportions of TRM and survival were 0.30 (CI, 0.21-0.39) and 0.58 (CI, 0.48-0.68), respectively. In Cox regression analyses, CD34 cell dose was the one factor consistently identified as significantly associated with rate of engraftment, TRM, and survival. Despite the low incidence of GVHD, the proportion of patients with leukemia relapse at 2 years was 0.17 (CI, 0.00-0.38) and 0.45 (CI, 0.28-0.61) for patients with standard and high-risk disease, respectively. There is a high probability of survival in recipients of UCB grafts that are disparate in no more than 2 human leukocyte antigens (HLAs) when the grafts contain at least 1.7 x 10(5) CD34(+) cells per kilogram of recipient's body weight. Therefore, graft selection should be based principally on CD34 cell dose when multiple UCB units exist with an HLA disparity of 2 or less.