Unrelated donor bone marrow transplantation for chronic myelogenous leukemia: a decision analysis

BACKGROUND: Chronic myelogenous leukemia (CML) is an indolent but ultimately fatal disease. Because the natural history of CML varies and quality of life with CML may be excellent until shortly before death, deciding whether and when to pursue unrelated donor bone marrow transplantation is often difficult. OBJECTIVE: To compare early transplantation, delayed transplantation, and no transplantation for patients with chronic-phase CML on the basis of discounted, quality-adjusted life expectancy. DESIGN: A markov model comparing different strategies was constructed. This model considers patient age, quality of life, risk aversion, and the competing risks for CML progression and transplant toxicity. SETTING: Therapeutic decision at the time of diagnosis of CML. PATIENTS: The base case is a 35-year-old patient with intermediate-prognosis CML. Younger and older patients with better and worse prognoses are also evaluated. INTERVENTION: Early transplantation, delayed transplantation, and no transplantation. MEASUREMENTS: Quality-adjusted, discounted life expectancy. RESULTS: For patients with newly diagnosed CML, transplantation within the first year provides the greatest quality-adjusted expected survival, although this benefit decreases with increasing patient age. For a 35-year-old patient with intermediate-prognosis CML, transplantation within the first year results in 53 more discounted, quality-adjusted years of life expectancy than does no transplantation. This finding is robust even with varying baseline assumptions. CONCLUSIONS: These results support the use of early unrelated donor bone marrow transplantation for most patients with CML.     

Unrelated donor bone marrow transplantation for Fanconi anemia

This paper describes the approach taken at the University of Queensland to broaden the scope of curriculum design to involve rural general practitioners, medical students and rural health care consumers. A form of nominal group process in serial telephone teleconferences was used, with a group of rural general practitioners, to develop and pilot curriculum content, learning strategies and assessment methods. Medical students assisted in the evaluation of the curriculum and representatives of rural organisations were consulted about the value of hosting medical students in rural communities. The three groups made significant contributions to the project. The results will be trialed for the entire year 6 cohort (240 students) in 1995 and will form the basis of the planned rural practice term in the new graduate course.     

Unrelated donor bone marrow transplantation for children with acute leukemia

PURPOSE: To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS: Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS: The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION: URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.     

Association between pretransplant interferon-alpha and outcome after unrelated donor marrow transplantation for chronic myelogenous leukemia in chronic phase

Treatment options for patients diagnosed with chronic myelogenous leukemia (CML) in chronic phase (CP) who lack a suitable related donor for marrow transplantation include hydroxyurea, interferon-alpha (IFN-alpha), or transplantation from an unrelated donor (URD). Most studies support the view that treatment with IFN-alpha results in prolonged survival compared with hydroxyurea therapy. Some patients are offered URD transplantation as a second-line treatment; however, the impact of pretransplant IFN-alpha on the outcome of URD transplantation is uncertain. To address this question, we evaluated the effect of pretransplant IFN-alpha therapy in 184 patients undergoing URD transplantation for CML in CP at a single center. Of the 184 patients, 114 did not receive IFN-alpha, whereas 22, 23, and 25 patients received IFN-alpha for, respectively, 1 to 5, 6 to 12, and more than 12 months before transplant. Pretransplant IFN-alpha therapy administered for > or = 6 months was associated with an increased risk of severe (grades III-IV) acute graft-versus-host disease (GVHD; relative risk [RR], 3.0; 95% confidence interval [CI], 1.4 to 6.2; P = .004) and mortality (RR, 2. 1; 95% CI, 1.3 to 3.5; P = .003) relative to less than 6 months or no IFN-alpha therapy. Increased mortality occurred between 100 and 365 days after transplant (P = .005), was limited to patients with severe acute GVHD, and was due to chronic GVHD refractory to immunosuppressive therapy. Other variables associated with mortality included HLA-DRB1 or DQB1 (but not HLA-A or B) mismatched donors, age greater than 50 years, weight > or = 110% of ideal body weight, and the absence of cytomegalovirus (CMV) or fungal prophylaxis. For patients treated with IFN-alpha for less than 6 months before transplant, who were < or = 50 years of age, received a HLA-A, B, DRB1, and DQB1 matched URD transplant, and received CMV and fungal prophylaxis after transplant (n = 48), survival was 87% +/- 5% at 5 years. These data provide a rationale for immediate transplantation in preference to extended treatment with IFN-alpha when the patient is < or = 50 years of age and has an HLA-compatible unrelated volunteer donor.     

Rhinocerebral zygomycosis following bone marrow transplantation in chronic myelogenous leukaemia. Report of a case and review of the literature

We report on a man suffering from chronic myelogenous leukaemia treated by allogeneic bone marrow transplantation who, in the late post-transplantation phase, developed a hyperacute fatal invasive rhinocerebral zygomycosis. The origin of the ascending infection was the sinus sphenoidalis from which fungal hyphae spread to the central nervous system via the skull and the dura mater. The first symptoms of this severe infection were cerebral convulsions and a bilateral total amaurosis. The isolation of the pathogen from post mortem tissue was not successful. The present case is compared with previous reports of zygomycoses after bone marrow transplantation.     

Unrelated bone marrow transplantation in a Wiskott-Aldrich syndrome patient sharing two HLA-extended haplotypes with the donor

OBJECTIVE: To determine the distribution and amount of elastic fibers in the dermis of clinically normal dogs and dogs with dermatoses, particularly solar dermatitis. DESIGN: Skin specimens from 7 anatomic sites were obtained from 19 clinically normal dogs after euthanasia to evaluate the normal distribution of elastic fibers. Biopsy specimens also were obtained from 34 dogs with dermatoses, including 16 with solar dermatitis. Tissue sections were stained with H&E, Verhoeff-van Gieson, and periodic acid-Schiff. ANIMALS: 19 clinically normal dogs and 34 dogs with dermatoses. PROCEDURE: Numbers of elastic fibers were graded subjectively. Comparisons between clinically normal dogs and dogs with dermatoses were made. RESULTS: Normal elastic fibers were present in low numbers in the dermis of adult dogs, regardless of anatomic site or presence or severity of dermatitis. Condensed elastotic material was visualized in only 2 dogs with solar dermatitis. In both dogs, the elastotic material was Verhoeff-van Gieson and periodic acid-Schiff stain positive but was not visible with H&E stain. The most frequent histopathologic finding in the dermis of dogs with solar dermatitis was superficial dermal fibrosis. CONCLUSIONS: The dermis of clinically normal dogs does not contain abundant elastic fibers. Alterations of elastic fibers in dogs with solar dermatitis are rare. Superficial dermal fibrosis may be a better indicator of solar damage.     

Infusion of donor peripheral blood mononuclear cells to treat relapse after transplantation for chronic myelogenous leukemia

Until recently, the only curative therapy for patients with chronic myelogenous leukemia (CML) who relapse after allogeneic bone marrow transplantation (BMT) has been second allogeneic BMT. Recently, donor mononuclear cells have been given to patients with relapsed CML to induce a potent graft-versus-leukemia reaction and re-establish complete remissions in the majority of patients without the need for a second transplant. The extraordinary success of donor mononuclear cell infusions shows that it is possible to manipulate and harness the graft-versus-leukemia (GVL) reaction for clinical benefit. The identity of the effector cells and target antigens is unclear, but intensive investigation is beginning to define the complex cytokine and cellular interactions that mediate GVL reactivity. Current clinical trials are investigating strategies that will retain and enhance the GVL effects while limiting toxicity from this therapy. Ultimately, the ability to harness the GVL potential of allogeneic donor cells without excessive toxicity from graft-versus-host disease will be a central challenge in BMT and cellular immunotherapy.     

Donor leukocyte transfusion as treatment for relapsed chronic myelogenous leukemia after allogeneic bone marrow transplantation

We reviewed 4 cases of high-grade transitional-cell carcinoma (TCC) of the urinary tract with solitary pulmonary metastases that were studied by transthoracic needle aspiration biopsy cytology. There were two grade II and two grade III TCCs. The two grade II tumors yielded, in needle aspirates, syncytial tumor-cell clusters showing ill-defined, granular cytoplasm and slightly pleomorphic nuclei with inconspicuous nucleoli. In one case the tumor-cell cluster showed a focal acinar arrangement, mimicking cells of an adenocarcinoma. In both cases the electron microscopy (EM) study of aspirated tumor cells revealed epithelial cells with well-formed cell junctions, intracytoplasmic vesicles, apical short microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial neoplasm. The two grade III TCCs yielded, in needle aspirates, pleomorphic malignant cells singly and in small clusters, showing well-defined, granular cytoplasm and pleomorphic nuclei containing prominent nucleoli, suggesting a poorly differentiated adenocarcinoma or an anaplastic large-cell carcinoma. By EM examination the aspirated tumor cells from one case revealed well-formed cell junctions, intracytoplasmic vesicles, poorly formed microvilli, and focal interdigitation of lateral cell membranes, suggesting a urothelial differentiation. In the other case the tumor cells were pleomorphic cells with occasional cell junctions and no ultrastructural features as seen in the other 3 cases of TCC. The tumor cells from the two grade II TCCs showed strong immunopositive reaction with keratin 7 antibody and weakly positive reaction with carcinoembryonic antigen antibody (CEAA), while those of the two grade III TCCs displayed only a weak and focal immunopositive staining with keratin 7 antibody and strong reaction with CEAA.     

Recurrent annular erythema in juvenile chronic myelogenous leukaemia

Juvenile chronic myelogenous leukaemia (JCML) is a rare haematological malignancy of myelomonocytic lineage that affects patients less than 4 years of age and is known as an entity different from adult-type chronic myelogenous leukaemia. In JCML, skin manifestations are relatively common but most of them have been reported as a non-specific eruption, which histologically may show changes resembling neurofibromatosis or xanthogranuloma. We present a 2-year-old boy with JCML who developed a recurrent annular erythema in which leukaemic infiltrates were confirmed histologically, even though his bone marrow examination suggested that be remained in haematological remission.     

Autologous transplantation for the treatment of chronic myelogenous leukemia

There is evidence that benign, Ph-negative hematopoietic progenitors persist in the marrow and blood of some patients with chronic myelogenous leukemia (CML). A number of pilot studies using purged and unpurged marrow or peripheral blood autografts have demonstrated that autologous transplantation can result in transient cytogenetic responses in CML. Although not curative, this procedure may be associated with longer-than-expected patient survival and represents an alternative treatment for patients ineligible for allogeneic transplantation and not responding to interferon-alpha therapy. Several novel approaches are being developed to improve graft purging and eliminate residual leukemia post-transplantation. Such approaches may allow for long-term restoration of Ph-negative hematopoiesis following the procedure.     

Minimal residual disease after allogeneic bone marrow transplantation for chronic myeloid leukaemia: a metaphase-FISH study

Metaphase-FISH was adopted for the detection of proliferating Philadelphia-positive (Ph+) residual leukaemic cells in 25 patients with chronic myeloid leukaemia treated with allogeneic bone marrow transplantation (BMT). Patients were followed up during their clinical remission for 4-50 months (median 17 months) after BMT. 80 bone marrow samples were studied. For most of the cases no fewer than 1000 metaphases were analysed. Six patients (24%) showed residual Ph+ cells during the first 6 months and two others by the end of the first year after BMT. Three patients relapsed during the study and in two of them residual Ph+ cells were detected during the first 6 months after BMT. In 17 patients no Ph+ cells were detected at any stage of follow-up and 16 (94.1%) of them continue in complete clinical and haematological remission. Our results indicate that metaphase-FISH is a reliable tool in the quantitation of proliferating residual leukaemic cells. We suggest that consecutive findings of equal amounts of residual leukaemic cells do not necessarily predict a relapse. However, their presence calls for follow-up at shorter intervals where an increasing number of these cells predicts an ensuing relapse.     

Related donor liver transplant for veno-occlusive disease following T-depleted unrelated donor bone marrow transplantation

The results of a study of Inter-Alpha-Trypsin Inhibitor (ITI) polymorphism in 281 blood samples are reported in this paper. These samples were taken from healthy individuals of both sexes, unrelated and resident in the Province of Cadiz. The frequency of ITI*1 was 0.617 and of ITI*2 was 0.383. The probability of exclusion in paternity testing was 0.18.     

Unrelated living donor kidney transplants

Recent linkage studies in the spontaneously hypertensive rat (SHR) suggest that a blood pressure regulatory gene or genes may be located on rat chromosome 1q. To investigate this possibility, we replaced a region of chromosome 1 in the SHR (defined by the markers D1Mit3 and Igf2) with the corresponding chromosome segment from the normotensive Brown-Norway (BN) strain. In male SHR congenic rats carrying the transferred BN chromosome segment, 24-hour average systolic and diastolic blood pressures were significantly lower than in male progenitor SHR. Polymerase chain reaction genotyping using 60 polymorphic microsatellite markers dispersed throughout the genome confirmed the congenic status of the new strain designated SHR.BN-D1Mit3/Igf2. These findings provide direct evidence that a blood pressure regulatory gene exists on the differential segment of chromosome 1 that is sufficient to decrease blood pressure in the SHR. The SHR.BN-D1Mit3/Igf2 congenic strain represents an important new model for fine mapping and characterization of genes on chromosome 1 involved in the pathogenesis of spontaneous hypertension.     

Successful donor leukocyte infusion for chronic myeloid leukemia relapsing in accelerated phase after T cell-replete unrelated marrow transplantation

A 47-year-old man relapsed with accelerated phase CML 19 months after a T cell-replete unrelated BMT. Three donor leukocyte infusions (DLI) from the original donor resulted in durable complete hematological and cytogenetic remission. Moderate GVHD developed but was steroid responsive. This report suggests that DLI can be administered safely to patients relapsing after unmodified unrelated allografts. In the patient described, DLI exerted an antileukemic effect sufficiently potent to reverse accelerated phase disease.     

Effect of bcr-abl oligodeoxynucleotides on the clonogenic growth of chronic myelogenous leukaemia cells

Two-dimensional echocardiographic (2-D) planimetry and the Doppler pressure half-time (PHT) method have been used to estimate mitral valve area (MVA) in patients with mitral stenosis (MS). Recently, the proximal isovelocity surface area (PISA) method has been shown to be accurate for calculating MVA. The purpose of this study was to compare the PISA method with previous methods. Thirty patients with MS were studied; 17 had pure MS, 4 combined mild MR, 6 combined mild AR, and 3 combined MR and AR. Color Doppler flow mapping was performed at an aliasing (blue-red interface) velocity of 14 cm/sec using the zero-baseline shift. MVA was calculated as 2 x 3.14 x R2 x 14 x (theta/180) / PFV, where R is the distance from aliasing to orifice, 14 is the aliasing velocity, theta is the internal angle of the mitral valve, and PFV is the peak flow velocity at the mitral orifice. MVA was also calculated using the 2-D and PHT methods, and compared with the PISA method. MVA calculated using the PISA method correlated well with the 2-D (r=0.90, p < 0.01, SEE = 0.18 cm2) and PHT methods (r=0.82, p < 0.01, SEE = 0.24 cm2). Compared with the 2-D method, the standard error of the estimate of the PISA method was - 0.14+/-0.18 cm2 and the percent error was -10.4+/-18.9%. Compared with the PHT method, the standard error of the estimate of the PISA method was + 0.01+/-0.24 cm2 and the percent error was +3.4+/-34.6%. MVA calculated using the PISA method correlated well with the 2-D and PHT methods in patients with pure MS or with MS combined mild regurgitation. The PISA method may be useful for calculating MVA as an alternative method.     

Allogeneic bone marrow transplant for chronic myelogenous leukemia in a patient with multiple sclerosis

A novel Clostridium bifermentans strain toxic to mosquito larvae on ingestion was isolated from a soil sample collected from secondary forest floor. This strain was designated as serovar paraiba (C. b. paraiba) according to its specific H antigen. Clostridium bifermentans paraiba is most toxic to Anopheles maculatus Theobald larvae (LC50 = 0.038 mg/liter), whereas toxicity to Aedes aegypti (Linn.) (LC50 = 0.74 mg/liter) and Culex quinquefasciatus Say (LC50 = 0.11 mg/liter) larvae was 20 and 3 times lower, respectively. The toxicity to An. maculatus larvae is as high as that of Bacillus thuringiensis serovar israelensis. C. b. paraiba was also found to exhibit significant per os insecticidal activity toward adult Musca domestica (Linn.).