Long-term follow-up of allogeneic bone marrow transplantation for patients with chronic phase chronic myeloid leukemia prepared with a regimen consisting of cyclophosphamide, cytarabine and single-dose total body irradiation conditioning.

We evaluated long-term toxicities and outcomes in 96 patients with chronic phase chronic myeloid leukemia treated with a single bone marrow allograft regimen. Conditioning was cytosine arabinoside, cyclophosphamide (120 mg/kg) and single fraction total body irradiation (500 cGy). Median follow-up was 12.8 years (0.4-19.9 years). Graft failure occurred in one patient, nonfatal veno-occlusive disease in 13 patients (14%). Overall incidences of acute (a) and chronic (c) graft-vs-host disease (GVHD) were 77 and 63%. The 100-day and 1-year transplant-related mortality (TRM) were 1 and 9.2%, respectively, with no change through 5 years. Five- and 10-year event-free survival rates were 56 and 49%, overall survival (OS) rates 72 and 70%, respectively. Forty patients have relapsed: 8 cytogenetic (20%), 10 hematologic (25%) and 22 molecular (55%). Most have been salvaged with donor-leukocyte infusion, second transplants and/or imatinib therapy. Survival was worse for patients transplanted >2 years from diagnosis (10-year OS 56 vs 78%, P=0.01), for patients over 50 years old (10-year OS 44 vs 75%, P=0.05) and for patients without cGVHD (10-year OS 53 vs 86%, P<0.001). This regimen resulted in successful engraftment, low risk of TRM and long-term survival. In an era when imatinib is first line therapy, this regimen offers a potentially low-toxicity, highly successful alternative in the event of poor imatinib response.

Acute intestinal graft-versus-host disease in a syngeneic bone marrow transplant recipient.

BACKGROUND: We report a case of intestinal graft-versus-host disease (GVHD) in a syngeneic bone marrow transplant patient. METHODS: Several days after receiving a bone marrow transplant from his identical twin for treatment of non-Hodgkin's lymphoma, a 47-year-old man developed a skin rash and diarrhea. RESULTS: A colonic biopsy on day +15 revealed characteristic changes of acute intestinal GVHD. Molecular studies (microsatellite DNA and HLA sequence-specific primer polymerase chain reaction analyses) confirmed the genotypic identity of donor and host and the improbability of transfusion-associated GVHD. CONCLUSION: This case illustrates that pathological evidence of GVHD does not absolutely require the presence of genetic differences between host and donor and questions existing concepts about the nature of cyclosporine-induced GVHD.

Quality of life following bone marrow transplantation: a comparison of patient reports with population norms.

All surviving patients who had received an allogeneic bone marrow transplant at the Princess Margaret Hospital were asked to participate in a health-related quality of life (HQL) study using the Medical Outcomes Survey-Short Form 36 (MOS SF-36), the Satisfaction with Life Domains Scale-Bone Marrow Transplantation (SLDS-BMT) and a current symptoms checklist. The main objective was to compare the health status of BMT survivors with age-adjusted population norms. Of the 251 patients contacted, 93% returned questionnaires. The median follow-up after BMT was 40 months, ranging from 1-253 months. On average, survivors had some diminished HQL relative to the health status of the population in general. Time since transplant had a significant influence on HQL; those less than 3 years from transplant experienced considerable impairment while those who had survived beyond this point were indistinguishable from the normal population in most domains and significantly better in certain psychosocial aspects of health. Many patients still reported symptoms months after BMT; some were mildly affected while others experienced more troublesome symptoms. However, 81% of patients were satisfied with the HQL outcome that they had achieved and 94% would recommend a transplant for someone in similar circumstances.

Abnormal thyroid stimulating hormone (TSH) levels in adults following allogeneic bone marrow transplants.

Thyroid function abnormalities in 270 adult patients post-BMT are described. Various conditioning regimens were used and the effects of three TBI and one chemotherapy only based regimens are compared. The overall incidence of elevated TSH is 8.9; 3.8, 7.2 and 16.7% in those patients who received 300, 500 and 1200 cGy respectively and 11.7% in those who received BuCy conditioning. Three cases (1.1%) of clinial hypothyroidism were observed. Compensated hypothyroidism defined as an elevated TSH in the presence of normal T3, T4 levels and transient in some cases, was the most common finding. All but four cases occurred in the first 2 years after BMT. In the remaining four, three occurred in patients with chronic GVHD. The results reported here show a lower prevalence than observed in most other reviews, particularly for children. A trend was observed with increasing radiation doses. The results are not significantly different from those we observed in the BuCy regimen.

Detection of donor cell derived acute myelogenous leukaemia in a patient transplanted for chronic myelogenous leukaemia using fluorescence in situ hybridization.

The recurrence of leukaemia following allogeneic bone marrow transplantation appears to develop rarely in donor cells. However, the standard method for assigning the origin of recurrence, metaphase analysis, can be unreliable. We have applied the technique of fluorescence in situ hybridization (FISH) directly on archival Wright stained bone marrow slides obtained from a patient who developed acute myelogenous leukaemia (AML) following allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukaemia (CML). Using a chromosome-specific DNA probe we linked a chromosomal aberration, previously detected by conventional metaphase analysis, directly to morphologically identifiable blast cells. In this way we were able to assess cell-lineage involvement of the secondary leukaemia and assign a donor origin.

Secondary malignancies after bone marrow transplantation in adults.

PURPOSE: The records of 557 consecutive adult recipients of allogeneic-related and -unrelated and syngeneic bone marrow transplants (BMTs) were reviewed to determine the incidence of secondary cancers. PATIENTS AND METHODS: Four hundred fifty-six patients were transplanted for acute lymphocytic leukemia (ALL; n = 79), acute myelogenous leukemia (AML; n = 182), and chronic myelogenous leukemia (CML; n = 195); 42 patients were transplanted for aplastic anemia (AA) and 59 for a variety of other hematologic and nonhematologic disorders, malignant and nonmalignant. Conditioning regimens included high-dose chemotherapy with or without total-body irradiation (TBI). Statistical analyses determined the cumulative incidence of developing a secondary cancer and elucidated the associated risk factors. Complete records (1 to 24 years of follow-up) on all patients were available. RESULTS: Nine patients developed 10 secondary cancers for a cumulative actuarial risk of 12% (95% confidence interval [CI], 4.3 to 23.0) 11 years after transplant. The age-adjusted incidence of secondary cancer was 4.2 times higher than that of primary cancer in the general population. Eight of the 10 were epithelial in origin and three were cutaneous. TBI and acute graft-versus-host disease (GVHD) with a severity > or = grade II were associated with the development of any secondary cancer. On the other hand, chronic GVHD was a risk factor only for the development of secondary skin neoplasms. CONCLUSION: Adult recipients of BMT face a significant risk of developing a secondary malignancy. Their risk is similar to that of other patients with hematologic malignancies who are treated with chemoradiotherapy only. Epithelial tumors, rather than the more commonly reported Epstein-Barr virus (EBV)-associated lymphomas, were most common. The fact that we did not routinely use T-cell-depleted marrow grafts nor anti-T-cell immunoglobulin for the treatment of acute GVHD may explain this variance.

Pneumatosis intestinalis with free air mimicking intestinal perforation in a bone marrow transplant patient.

A case of pneumatosis intestinalis with perforation is reported in a patient after bone marrow allograft for chronic myeloid leukemia. Risk factors included the transplant, prolonged immunosuppression and neutropenia, graft-versus-host disease, extended use of corticosteroids, infection and lower gastrointestinal endoscopic biopsy. The literature is reviewed and a management plan for patients presenting with this complication is discussed.

Cyclosporine as possible prophylaxis for obstructive airways disease after allogeneic bone marrow transplantation.

The objective of this study was to evaluate the impact of cyclosporine (cyclosporin A; CyA) prophylaxis for graft-versus-host disease (GVHD) on the development of obstructive airways disease (OAD) after allogeneic bone marrow transplantation (BMT) in leukemic patients. Patients with normal pulmonary function tests (PFTs) prior to BMT were followed with serial PFTs for the development of OAD. Follow-up PFTs were performed at 3, 6, 9, and 12 months, and thereafter at consecutive yearly intervals. Obstructive airways disease was defined as FEV1 less than 80 percent, ratio of FEV1 over the forced vital capacity (FEV1/FVC) less than 80 percent of predicted, maximal midexpiratory flow rate at 50 percent vital capacity less than 65 percent of predicted, or residual volume greater than 120 percent of predicted. In the period prior to CyA prophylaxis for GVHD development (March 1983 to September 1986), 17 (39 percent) of the 44 patients undergoing BMT developed OAD, compared with 2 (4 percent) of 45 in the post-CyA period (September 1986 to March 1990) (chi 2 = 17; p < 0.00005). Age, sex, type of leukemia, severity of GVHD, histocompatibility status, presence of acute GVHD, and sex mismatch between donor and recipient were not associated with development of OAD. Although chronic GVHD was associated with OAD in univariate analysis, a multivariate logistic regression analysis showed that the only significant independent predictor for OAD was the use of CyA. We conclude that CyA is protective against the development of OAD after BMT in leukemic patients.

Pregnancy after BMT: three case reports.

A case of successful pregnancy after BMT in a 24-year-old woman with ALL, conditioned with CY, L-asparaginase, methylprednisolone and total body irradiation (TBI) is reported. A second case of two spontaneously aborted pregnancies in a woman transplanted for ALL at the age of 29 years using CY and TBI conditioning and a third case, this time a successful pregnancy in a woman transplanted for AML at age 27 years using CY and TBI conditioning are also described. There are now 6 successful live births after TBI reports of, versus 16 following regimens in which no TBI is used. This is the first report of a successful pregnancy reported in a female transplanted when older than 25 years using any TBI-containing regimen.

Long-term sequelae after recovery from cytomegalovirus pneumonia in allogeneic bone marrow transplant recipients.

The clinical course of cytomegalovirus (CMV) pneumonia in seven consecutive bone marrow transplant (BMT) recipients during a 24-month period was studied. Retrospective analysis of clinical data on the recipients with CMV pneumonia during the illness and prospective follow-up of those who recovered from the pneumonia was performed. Those who had CMV as the sole pathogen and with lymphocytosis in the BAL or the peripheral blood during the illness recovered from the pneumonia. On the contrary, those who had mixed bacterial or fungal infection with peripheral lymphopenia died. Persistent lymphocytosis in the BAL and the peripheral blood, in the absence of CMV infection, was observed in the survivors. Two subsequently developed restrictive lung disease and two had relapse of their primary malignancy. These data suggest that CMV pneumonia in BMT patients is associated with significant long-term sequelae. The phenomenon of persistent lymphocytosis in the BAL and the peripheral blood, in the absence of CMV infection, supports Grundy's hypothesis that CMV pneumonia in BMT recipients is an immunopathologic condition.

Long-term results of bone marrow transplantation for patients with AML, ALL and CML prepared with single dose total body irradiation of 500 cGy delivered with a high dose rate.

One hundred and sixty-six patients between the ages of 12 and 48 years with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) underwent allogeneic bone marrow transplantation following single fraction total body irradiation (TBI) of 500 cGy from a cobalt source. Patients also received one of three chemotherapeutic regimens according to their diagnosis or disease status at time of transplant. The median follow-up was 67 months with a range of 33-120 months. The actuarial 5-year event-free survival (EFS) for the subgroup of patients with good risk disease (first complete remission AML and ALL or first chronic phase CML) was 43% with an actuarial relapse rate at 5 years of 26%. Patients with poor risk disease (other than first remission AML and ALL or other than first chronic phase CML) had an EFS at 5 years of 15% with a relapse rate of 62%. Disease status at the time of transplantation was the most important factor predicting outcome in this patient population. We conclude that preparation of good risk patients with chemotherapy and single fraction TBI of 500 cGy at a dose rate of 42-91 cGy/min resulted in EFS and relapse rates similar to those observed by centers using fractionated radiotherapy schedules, without a concomitant increase in toxicity, in particular interstitial pneumonitis and cataracts.

Cytomegalovirus pneumonia in allogeneic bone marrow transplantation. An immunopathologic process?

Recent literature suggests that CMV pneumonia is an immunopathologic process. This case report summarizes the clinical course of a patient which supports this hypothesis. The patient is the recipient of an allogeneic BMT who recovered from an episode of CMV pneumonia that occurred about two months after the transplant. Despite recovery from the viral infection, follow-up BALs revealed persistent lymphocytosis in an apparent asymptomatic patient. He subsequently developed BOOP about four months after the initial CMV infection. These observations suggest that the viral infection may have resulted in the activation of the host's cell-mediated response and provides evidence to support the hypothesis that CMV pneumonia is an immune-mediated process.

Cutaneous and mucosal neoplasms in bone marrow transplant recipients.

Fifty-six long-term survivors of bone marrow allografts were followed for a minimum of 40 months after bone marrow transplantation (BMT) to determine the frequency of secondary malignancies. The 56 patients included ten with severe aplastic anemia (SAA), 16 with acute myeloblastic leukemia (AML), 11 with acute lymphoblastic leukemia (ALL), and 19 with chronic myelogenous leukemia (CML). All patients received a preparative regimen combining high-dose chemotherapy with total body irradiation (TBI). Three patients developed a malignancy of the skin or oral mucosa. Two were diagnosed as squamous cell carcinoma and one as a malignant melanoma. All three patients had chronic graft versus host disease (GvHD) and were treated for prolonged periods with immunosuppressive medications. The lesions of all patients developed in areas involved by chronic GvHD.

Small-airways disease in recipients of allogeneic bone marrow transplants. An analysis of 11 cases and a review of the literature.

In a retrospective review of 116 consecutive allogeneic bone marrow transplants (BMT), severe obstructive airways disease was identified in 11 patients. Lung pathology demonstrated bronchiolitis in 9 patients and physiologic studies showed small-airways disease consistent with bronchiolitis in the other 2. None of the 5 patients with associated infection survived, while 3 of the 6 patients without an identified pathogen stabilized or improved. Analysis of the 11 cases presented and all 25 cases reported in the literature (1982 to 1985) supports the conclusion that graft-versus-host disease is a major risk factor for bronchiolitis in BMT recipients. Among the proposed mechanisms for the development of bronchiolitis after allogeneic BMT, the 2 most likely are graft-versus-host disease directly causing bronchiolitis, and increased immunosuppressive therapy given for graft-versus-host disease predisposing to viral bronchiolitis. The available evidence would suggest that it is prudent to obtain serial pulmonary function tests even in asymptomatic patients post-BMT, and particularly in those with chronic graft-versus-host disease, in the hope that early detection will allow for early intervention that will arrest or reverse the progression of the obstructive airways disease.