Undergoing Marrow Transplantation Research Articles

Marrow grafts from HLA-identical siblings for severe aplastic anemia: does limiting the number of transplanted marrow cells reduce the risk of chronic GvHD?

Twenty-one patients with severe aplastic anemia underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day × 4 days) and horse antithymocyte globulin (30 mg/kg/day × 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate combined with cyclosporine. The transplant protocol tested the hypothesis that the incidence of chronic graft-versus-disease (GVHD) could be reduced by limiting the marrow grafts to ≤2.5 × 108 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving a median of 4 (range 1–8) years after transplantation. Chronic GVHD developed in 16% of patients given ≤2.5 × 108 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GVHD.

Treatment and hematopoietic SCT in aplastic anemia

This edition of the journal Bone Marrow Transplantation is the dedicated to the diagnosis and treatment of aplastic anemia, a disease that has had an important role in developing SCT and maybe even modern hematology. This was borne out of a project to design algorithms for the diagnosis and treatment of this disease, comprising different clinical issues such as different age groups and disease severity, as well as strategies arising from the unavailability of a specific type of donor. Aplastic anemia is an orphan disease with an incidence of 1–2 patients per million inhabitants per year, and given the different paths in the algorithms this breaks down into even smaller distinct sub-entities. Without wishing to stress the common place of personalized medicine, these distinct situations require individualized attention. Often, the approach to patient care has to differ, be it while caring for the child or the older person being diagnosed with aplastic anemia, according to severity of the disease and response to initial treatment as well as depending on the availability or not of a matched donor. Given the difficulty to study rare diseases, we also designed these algorithms with the intention to standardize treatment and to record treatment outcome. Diagnostic procedures need to be standardized; congenital disease has to be ruled out in the young, hypoplastic myelodysplastic syndrome in the older patient and procedures are discussed in the chapter on the diagnosis of acquired aplastic anemia. Outcome of patients with aplastic anemia has greatly improved over the past decades and to a large part this is due to progress in supportive care, given that our currently used immunosuppressive and transplant regimens were developed in the 1970s. This progress includes treatment of infectious complications and transfusional support, among others. In younger patients, the primary decision in treatment is to choose between transplantation versus immunosuppression. We have learned recently through a randomized trial conducted at the National Institutes of Health that not all antithymocyte globulin regimens are equal.1 Standards for immunosuppression are to be found in the chapter on front line immunosuppressive treatment as well as current standards on upfront BMT with a sibling donor. Older patients with a donor are recommended to be treated with immunosuppression, but patients failing this treatment are candidates for BMT using a reduced intensity regimen containing fludarabine. Patients without a sibling donor failing immunosuppressive treatment may have an unrelated donor search initiated and may undergo marrow transplantation from an unrelated donor. Transplant rates in Europe for aplastic anemia continue to increase2 and this is mostly due to the increased use of unrelated donors following publications showing that outcomes with unrelated donors were similar to outcomes with sibling donors. The average age of patients with aplastic anemia is ~16 years, that is, half the patients are children, but the disease can occur in all age groups. There is a specific chapter on the management of aplastic anemia in children and also on the management of aplastic anemia in the older adults. The issue is rounded up by particular chapters on second- and third-line treatment options, including cord blood transplantation, transplantation from mismatched family donors (that is, haploidentical donors) and experimental immunosuppressive regimens including Campath. These specific protocols are detailed here to incite treating physicians to manage these patients according to common treatment protocols and to report outcomes in order for us to progress toward improved outcomes for these patients. All these chapters have been written by members of the aplastic anemia working party of the European Group for Blood and Marrow Transplantation and the algorithms are the fruits of many discussions held during our biannual group meetings. We hope to provide a platform for the reader that may help him in all clinical situations that can be encountered with these patients. For this reason, the working title of this project had been ‘the complete treatment algorithm’.

Should Methotrexate plus Calcineurin Inhibitors Be Considered Standard of Care for Prophylaxis of acute Graft-versus-Host Disease?

In a rapidly developing field, one can always anticipate that different interpretations of similar data will coexist. Stem cell transplanters can be a contentious lot, especially in the absence of controlled randomized trials. Thus, although improvements in the basic understanding of acute graft-versus-host disease (aGVHD) has led to many testable hypotheses in the management of GVHD, there remains little consensus regarding the most effective and least toxic approach to GVHD prevention. In the 1980s, the comparison would have been between cyclosporine-based regimens and ex vivo T cell depletion (TCD). Although ex vivo TCD is still used in some settings, pharmacologic-based therapy and in vivo TCD with serotherapy now predominate. This review is meant to highlight the advantages and disadvantages of the "standard of care" and assess the prospects for future regimens that may be more effective.

Twenty Year Follow up of Survivors of Childhood Acute Lymphoid Leukemia: A Report from the Childhood Cancer Survivor Study (CCSS).

Background: Survival for ALL has improved substantially: current five-year survival rates are approximately 80% yet survivors continue to experience late medical and social effects.Objective: To report rates of mortality and second neoplasm (SN) and selected social outcomes from a large cohort of childhood ALL survivors.Methods: Five year survivors of ALL (n=4151) diagnosed < age 21, from 1970–1986 were compared to population rates or a sibling control group (n=3899) for mortality, SN, education, marriage, health insurance and employment.Results: Survivors and siblings were 53% and 48% male; median ages were 26 and 31yrs respectively. Survivors had a mean age of 6 yrs (range 0–20) at diagnosis and had a mean follow-up of 22 yrs (range 16–34). Sixty two percent received chemotherapy (CT) + radiation therapy (RT), 5.2% underwent marrow transplant with CT +/− RT, while 27% received CT only. Among 5yr survivors, 417 deaths occurred; cumulative mortality was 12% at 25 yrs. Recurrent ALL accounted for 67% of deaths, while 13% (n=55) died of SN. Standardized mortality rate (95% confidence intervals) for malignant SNs was 14.0 (10.7–17.9). Survival at 25 yrs was 94% for patients who never reported relapse and 59% for patients who reported a relapse (p<0. 001). For patients treated between 1970–1974, 1975–1979 and 1980–1986, 15-yr survival from cohort entry improved from 85% to 90% to 92%, (p< 0. 001). Improvement was seen both in non-relapsed (94%, 95% and 97% respectively, p= 0.015) and relapsed survivors (41%, 62% and 70% respectively, p< 0. 001) for the same era. 199 SNs (excluding non-melanoma skin cancer) occurred among 185 survivors; 52% occurred in the CNS. 89% of all SNs occurred in RT patients. Cumulative incidence at 25 yrs was 9% and the standardized incidence rate was 5.6 (95% CI 4.8–6.4). Age standardizing to siblings aged 25–49, rates for high school completion among survivors and siblings were 93% and 97%, respectively, with college graduation rates of 41% and 52% (p< 0.001, for education overall). 35% of survivors never married, compared to 21% siblings (p<0.001), 97% of survivors reported ever working vs. 100% of siblings (p<0.001), rate of health insurance was lower for survivors (86%) vs. siblings (90%), p<0.001. Comparison of rates for selected social outcomes among survivors who did or did not experience a recurrence are reported in Table-1.Conclusion: In the largest long-term follow-up study of its kind, the CCSS cohort demonstrated a significant improvement in survival over time among 5-yr survivors of ALL with and without history of relapse. Death after cohort entry was due most commonly to ALL, although SNs contributed substantially. HS graduation rates for survivors were comparable to the sibling cohort, but the rates were significantly lower for college graduation and for marraige. Although lower than siblings, majority of survivors reported being employed and having health insurance. There was no significant difference between the survivors of relapsed and non-relapsed ALL, with respect to their socioeconomic outcomes.Rates (percentage), Age Standardized to SiblingsSiblingNon-relapseRelapsep-value Relapse vs. NonHS grad979397College grad524141.78*Never married213446.10Ever employed1009897.07Health Insurance908688.86* p for rows 1 & 2

Prospective evaluation of Candida species colonization in hospitalized cancer patients: impact on short-term survival in recipients of marrow transplantation and patients with hematological malignancies.

Most hematogenous candidiasis originates from endogenous host flora. The impact of clinically prominent Candida colonization on short-term mortality (<or=14 weeks) was prospectively studied in 193 hospitalized patients from 1998 to 1999. Clinically prominent colonization included yeasts isolated from all sterile body sites and >50 colonies of Candida from non-sterile sites. Fourteen (7.1%) patients were granulocytopenic (ANC <or=100/microl). Nineteen (9.8%) had undergone marrow transplantation, 26 (13.5%) had a hematologic malignancy and 129 (66.5) had non-hematologic cancer. Candida isolates (216) were collected form 210 specimens. Fifty-three (27.5%) patients died; 25 (19.4%) with solid tumors, compared to 16 (61.5%) with hematological malignancy, and 11 (57.9%) BMT recipients (P < 0.001). No deaths were seen in patients with AIDS, and one (7.7%) in a patient with a benign condition (P < 0.001). Twenty-six (29.2%) patients with respiratory tract, 13 (23.2%) with gastrointestinal tract, and three (14.3%) with genitourinary tract colonization died. In patients with multiple-site colonization, mortality was significantly higher (45.5%) (P < 0.05). Mortality was higher in patients with C. glabrata (52.9%) and C. krusei (75%) colonization than with C. albicans (24.1%) (P < 0.025). This study shows that patients with hematologic cancer and recipients of marrow transplant with Candida colonization of multiple body sites, and colonization with C. glabata or C. krusei have poor survival.

Non-endocrine late complications of bone marrow transplantation in childhood: part I.

Non-endocrine late complications of bone marrow transplantation in childhood: part I.

Can we make some general recommendations regarding immune recovery after hematopoietic reconstitution preceded by ablative therapy?

Children undergoing marrow transplantation have compromised immune systems for variable periods of time after transplant. A number of methods have been utilized to assess recovery of the immune system. Four recommendations are made in regards to the testing that should be done, when the testing should be done, when immunizations should be provided and when antibiotic and other infection prophylaxis can be reduced.

Bone marrow transplantation for paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired clonal disorder of the haemopoietic stem cells for which the only curative treatment is bone marrow transplantation. There are few reports on the use of allogeneic transplantation for PNH, and nearly all of them include only a few patients. Between September 1978 and December 1997, 16 patients underwent marrow transplantation for PNH at the Hospital Saint Louis. The 5-year survival rate for the 16 patients was 58 +/- 13%. Two factors, an absolute neutrophil count >1.0 x 109/l and haemoglobin level >9 g/dl at transplant, were found to be statistically associated with a better outcome.

Gentamicin and tobramycin pharmacokinetics in pediatric bone marrow transplant patients.

To describe the pharmacokinetic parameters of gentamicin and tobramycin in pediatric bone marrow transplant patients. Retrospective medical record review. Pediatric bone marrow transplant unit in a university teaching hospital. Pharmacokinetic parameters (apparent volume of distribution [Vd] in L/kg, half-life [t1/2] in h, elimination rate constant [ke] in h-1, clearance [Cl] in mL/min/1.73 m2 and mL/min/kg) calculated from serum concentrations. Thirty-three patients aged 15 years or less who underwent bone marrow transplant and received gentamicin or tobramycin. Mean pharmacokinetic parameters were Vd 0.32 +/- 0.07 L/kg, t1/2 2.32 +/- 0.65 h, Cl 1.71 +/- 0.53 mL/min/kg, and Cl 86.2 +/- 24.5 mL/min/1.73 m2. Factors such as disease state, type of marrow graft, gender, or exposure to cyclosporine had no significant effect on pharmacokinetic parameters. Linear regression indicated a weak relationship between serum creatinine (SCr) and Cl in mL/min/kg (r = 0.59), but no relationship was found between SCr and Cl in mL/min/1.73 m2, between age and apparent Vd, or between SCr and apparent Vd. Models for estimating Cl and Ke developed by multiple regression were somewhat predictive (r = 0.7). Required calculated maintenance dosages to obtain therapeutic concentrations were 8, 7, and 6 mg/kg/d in children 6 or younger, 7-12, and 13-15 years, respectively. The mean Cl and apparent Vd for all ages are similar to those reported in pediatric oncology patients who had not undergone marrow transplantation. Children 6 years or younger had lower than expected Cls and larger apparent Vds than did the older children. Dosages estimated to be necessary to achieve therapeutic concentrations were 6-8 mg/kg/d.

Successful program to prevent aspergillus infections in children undergoing marrow transplantation: use of nasal amphotericin.

Aspergillus infections in the pediatric bone marrow transplant (BMT) patients are usually fatal. We began the use of a prophylactic nasal spray of amphotericin in 1990. This nasal spray was provided in addition to low-dose intravenous amphotericin. During the time of this study, the number of fatal cases of aspergillus in the pediatric BMT population was reduced significantly from 13.8% to 1.8% (P < 0.0025) thereby suggesting that the use of nasal amphotericin in this population helps to prevent fatal aspergillus infections. The lack of significant side-effects and the ease of administration make this a very helpful preventive measure in the supportive care of pediatric bone marrow transplant patients.

A Pilot Study of Continuous Infusion Ara-C in Combination with rhG-CSF in Relapsed Childhood Acute Myeloid Leukemia

Relapse in acute myeloid leukemia (AML) following intensive chemotherapy bears a bad prognosis. We treated 18 children with relapsed AML on two separate protocols that included continuous infusion (CI) of cytosine arabinoside (ara-C) (total dose 4gr-6gr/m2) over 96120 hours. In an attempt to increase the fraction of blasts in S-phase and render them more sensitive to cell-cycle specific agents such as ara-C, 10 patients received Smcg/kg rhG-CSF twice daily beginning 48 hours before and continuing through the duration of the CI ara-C (POG #9192 study). The percentage of cells is S phase before and after G-CSF administration was determined. In a second group of patients (n = 8) who received ara-C alone, endogenous concentrations of G-CSF and serial blood counts were measured (St Jude's R4 study). The rationale of the St Jude's R4 was to optimize the schedule of the second course of ara-C at a time when the patient's endogenous G-CSF concentration was increased and thus maximize the percent of cells captured in S phase.Four out of 8 patients receiving CI ara-C alone and 4 out of 10 patients receiving CI ara-C with rhG-CSF achieved a complete remission (CR) after 1 cycle of therapy. Four patients in CR underwent marrow transplantation (2 allogeneic and 2 autologous). Cell cycle analysis of blast cells cultured in vitro with or without G-CSF showed a two fold increase in the percentage of cells in S phase (P = 0.03) whereas cells obtained from patients before and after G-CSF administration showed no difference in cell cycling. Correlation between G-CSF concentrations and ANC showed a negative association indicating that the regulatory mechanisms for G-CSF production remained intact. In our relatively small series, CI ara-C achieved a CR rate of 44% with rhG-CSF having no effect on the remission rate. Although in vitro rhG-CSF increased the percentage of blasts in S phase significantly, in vivo effects were not observed. Larger studies with combinations of different hematopoietic growth factors and cell-cycle active drugs are needed to evaluate the role of these cytokines in the therapy of recurrent AML.

Tacrolimus and minidose methotrexate for prevention of acute graft- versus-host disease after matched unrelated donor marrow transplantation

Thirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (i.v.) by continuous infusion from day -2, converted to oral at four times the i.v. dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given i.v. on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last i.v. dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

Tacrolimus and Minidose Methotrexate for Prevention of Acute Graft-Versus-Host Disease After Matched Unrelated Donor Marrow Transplantation

AbstractThirty adults with leukemia or lymphoma undergoing marrow transplantation from HLA-compatible unrelated donors received tacrolimus (FK506), a new immunosuppressive macrolide lactone, and minidose methotrexate to prevent acute graft-versus-host disease (GVHD). The group had a median age of 36 years (range 21 to 49 years). Twenty-four patients had advanced disease, and 11 were resistant to conventional therapy. Tacrolimus was administered at 0.03 mg/kg/d intravenously (IV) by continuous infusion from day -2, converted to oral at four times the IV dose following engraftment, and continued through day 180 posttransplant. Methotrexate 5 mg/m2 was given IV on days 1, 3, 6, and 11. All patients engrafted. Grades 2-4 GVHD occurred in 34% (95% CI, 17% to 52%), and grades 3-4 GVHD in 17% (95% CI, 3% to 31%). Mild renal toxicity was common before day 100; 63% of patients had a doubling of creatinine, and 52% had a peak creatinine greater than 2 mg/dL, but only one patient was dialyzed. The median last IV dose of tacrolimus was 53% of the scheduled dose, and the median oral dose on day 100 was 41% of that scheduled. Overall survival at 1 year was 47% (95% CI, 27% to 66%). We conclude that tacrolimus can be combined safely with minidose methotrexate, and the combination has substantial activity in preventing acute GVHD after unrelated donor marrow transplantation.

Cutaneous mucor infection treated with wide excision in two children who underwent marrow transplantation

Cutaneous mucor infection developed in two children who had undergone bone marrow transplantation for treatment of leukemia. One infection occurred before transplantation, and the other occurred during the period of profound neutropenia after transplantation. Both children were treated with an extensive wide excision of the infected area, and there was no evidence of mucor along the resected edges of tissue. Both patients received extensive treatment with either amphotericin (case 1) or amphotericin and itraconazole (case 2). These two cases represent aggressive management of cutaneous mucor infections, which is believed to be required for the successful completion of a marrow transplantation procedure.

The Significance of HLA-DRB1 Matching on Clinical Outcome After HLA-A, B, DR Identical Unrelated Donor Marrow Transplantation

Despite matching for serologically defined HLA-A, B, DR antigens, acute graft-versus-host disease (GVHD) is a major complication contributing to increased morbidity and mortality in patients who undergo marrow transplantation from unrelated donors. The extent to which unrecognized mismatching for alleles that encode DR1-DR18 contribute to the increased risk of acute GVHD and overall survival is unknown. We analyzed 364 patients and their HLA-A, B, DR serologically matched donors to determine whether molecular typing of DRB1 alleles can allow more accurate donor/recipient matching and thereby improve clinical outcome after marrow transplantation. DRB1 alleles were typed by sequence-specific oligonucleotide probe hybridization methods. Selected alleles were confirmed by DNA sequencing. Of the 364 pairs, 305 were matched and 59 were mismatched for DRB1. The probability of moderate to severe acute GVHD was .48 for the matched and .70 for the mismatched patients. Compared with mismatched patients, the estimated relative risk (RR) of GVHD for matched patients was .58 (95% confidence interval [CI], .40 to .85). DRB1 matching decreased the risk of transplant-related mortality (RR, .66; 95% CI, .44 to .97) and was associated with decreased overall mortality (RR, .71; 95% CI, .51 to 1.0). Therefore, matching DRB1 alleles of the donor and recipient decreases the risk of acute GVHD and improves survival after unrelated marrow transplantation. These results indicate that prospective matching of patients and donors for DRB1 alleles is warranted.

Morbidity using subcutaneous ports and efficacy of vancomycin flushing in cancer.

An evaluation of totally implanted venous access systems inserted in 163 consecutive children with cancer is reported. From 1988 to 1994, 180 subcutaneous ports were inserted in children more than 1 year old. Initial diagnosis was acute leukaemia (n = 79), non-Hodgkin's lymphoma (n = 33), and solid tumour (n = 51). Median age was 85 months. All venous procedures were performed through the device. Chemotherapy was either moderate (n = 13) or intensive (n = 119) or very intensive (n = 48), including 16 patients undergoing marrow transplantation. Cumulative venous access totalled 55,770 patient days with a mean of 305 days/subcutaneous port. The cause of device removal was, end of treatment (n = 111), death due to malignancy (n = 20), catheter related infection (n = 7), and occlusion of the system (n = 4). Mechanical complications occurred in 19 ports; 16 were due to clots, of which 14 were cleared with instillation of urokinase. Documented infectious episodes occurred in 47 ports, recurred once in 14, and twice in five cases. Among these infections, 47 were septicaemic; 31 due to Staphylococcus epidermidis. Twenty seven of initial septic episodes were considered to be catheter related; the rate was 15%/subcutaneous port or 0.05/100 catheter days. Risk factors for the development of a first infection were age below 4 years and the time of use. Since February 1993, vancomycin (50 micrograms/ml) has been given and this has reduced the rate of S epidermidis infection from 26/83 subcutaneous port to 4/97. Life table analysis showed that the infection free interval for staphylococcus was significantly better after this technique ws initiated (log rank rest=0.02). Time saved was approximately 30minutes/patient/week compared with external catheters, or 45 hours/month for the cohort of children treated. Subcutaneous ports in paediatric cancer patients are reliable, safe, and durable and may offer an attractive alternative to external catheters for prolonged venous access and intensive treatment.

Treatment combined with bone marrow transplantation for advanced neuroblastoma: An analysis of patients who were pretreated intensively with the protocol of the study group of Japan

One hundred and ten patients with advanced neuroblastoma were treated with the protocol of the Study Group of Japan between January 1985 and March 1991. Patients received six cyclic courses of regimen A1, consisting of cyclophosphamide (1,200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (40 mg/m2), and cisplatin (90 mg/m2). Primary tumors and regional lymph node metastases were removed some time during the first six cycles of regimen A1. After six cycles of A1, the patients were divided into three groups. Patients in group 1 received alternating treatment with regimen B (cyclophosphamide and ACNU) and intensified A1, and those in group 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in group 3 were treated with supralethal therapy and bone marrow transplantation (BMT). Event-free survival rates at five years were 38.8% in the chemotherapy group (groups 1 and 2) and 50.0% in the transplant group (group 3). Because of the study design that was not in truly randomized fashion and because of the small number of patients in each risk group, it is indicated, though not concluded, that the transplant group had a better prognosis than the chemotherapy group in the cases with stage III disease or with amplified N-myc oncogene, based on the statistical calculations. Differences in survival rates for patients who underwent BMT when complete remission (CR) was achieved and for those who achieved CR but who did not undergo marrow transplant were statistically insignificant. BMT-related death occurred in 3 of 31 cases (9.7%) undergoing marrow transplant, and the causes of the death included hemorrhagic pneumonia, myocardial disturbance and hemorrhagic uremia.

Acute cholecystitis after autologous bone marrow transplantation for acute myeloid leukemia

We investigated the incidence of acute cholecystitis in patients with acute myeloid leukemia (AML) undergoing autologous bone marrow transplantation in complete remission. Thirty-five consecutive acute myeloid leukemia patients were given oral busulfan 4 mg/kg/day for 4 days and IV cyclophosphamide 50 mg/kg/day for 4 days followed by reinfusion of autologous bone marrow purged with 4-hydroperoxycyclophosphamide. Five of 35 patients developed clinical evidence of acute cholecystitis, manifested by fever, nausea, vomiting, right-upper-quadrant pain, and abdominal guarding, within 18 days after autologous bone marrow infusion. Ultrasonography and CT scans of the abdomen supported the diagnosis of cholecystitis. Three patients underwent cholecystectomy, while two patients were treated medically; all recovered uneventfully. A review of 338 consecutive bone marrow transplant patients who underwent marrow transplantation for a variety of diseases and were treated with other high-dose cytotoxic regimens during the same time period revealed significantly fewer cases of cholecystitis, i.e. two, (p < 0.0001). Five of 35 AML patients undergoing autologous bone marrow transplant using busulfan, cyclophosphamide, and purged bone marrow developed evidence of acute cholecystitis. These findings suggest that the busulfan/cyclophosphamide preparative regimen may be associated with acute cholecystitis. The true incidence of this injury and its pathogenesis remain to be elucidated.

Dosing of thioTEPA for myeloablative therapy

High-dose thioTEPA is used frequently in myeloablative regimens for marrow transplantation, but the need for dose adjustments in obese patients has not been explored. We determined the pharmacokinetics of thioTEPA and its metabolite TEPA during first-dose infusion of thioTEPA 150-250 mg/m2 given daily for 3 days in combination with busulfan and cyclophosphamide, and evaluated the results for correlations with toxicity and dosing strategies. The study included 15 adults undergoing marrow transplantation for hematologic malignancies. Plasma samples were obtained at various times over a 24-h period, and concentrations of thioTEPA and TEPA were measured by gas chromatography. At 22-24 h after initiation of a 4-h infusion, the mean +/- SE plasma concentration of thioTEPA was 124 +/- 63 ng/ml, while that of TEPA was 235 +/- 69 ng/ml. For CFU-GM and BFU-E growth in vitro, the IC50(s) of thioTEPA were 83 ng/ml and 16 ng/ml, respectively, and the IC50(s) of TEPA were 141 ng/ml and 47 ng/ml, respectively. Using a two-compartment model, the mean thioTEPA Vc was 47.4 +/- 4.7 1/m2, t1/2 alpha 19 +/- 5 min, t1/2 beta 3.7 +/- 0.5 h, and plasma clearance 302 +/- 21 ml/min per m2. The mean AUCs were 6.9-16.2 mg h/1 for thioTEPA and 8.9-21.2 mg h/1 for TEPA, while the mean peak concentrations were 0.95-2.08 micrograms/ml for thioTEPA and 0.88-1.90 micrograms/ml for TEPA. There was a significant association of grades 2-4 maximum regimen-related toxicity (RRT) with TEPA peak > 1.75 micrograms/ml and with combined thioTEPA and TEPA AUC > 30 mg h/1 (5/6 vs 0/9, P = 0.01 for both comparisons), suggesting that drug exposure was an important determinant of toxicity and, potentially, efficacy. ThioTEPA Vc correlated best with adjusted body weight (r = 0.74, P = 0.0015). In an evaluation of 74 adults receiving thioTEPA 750 mg/m2 in combination with busulfan and cyclophosphamide, the maximum RRT for patients at ideal weight was significantly greater than that for obese patients dosed on ideal weight (mean RRT grade 1.7 vs 1.0, P = 0.004) but did not differ from the maximum RRT for obese adults dosed on actual or adjusted weights. We recommend that for obese patients thioTEPA be dosed on adjusted body weight. Measurements at time-points after 24 h are needed to determine when thioTEPA and TEPA concentrations are below myelosuppressive levels and safe for marrow infusion.

Brain abscess following marrow transplantation: experience at the Fred Hutchinson Cancer Research Center, 1984-1992.

The etiology of brain abscess in patients undergoing marrow transplantation at the Fred Hutchinson Cancer Research Center in Seattle was assessed in a retrospective review. Fifty-eight patients with histology- or culture-proven brain abscess diagnosed between January 1984 and March 1992 were identified. A fungus was isolated in 92% of cases. Aspergillus species were the most prevalent fungi (58% of cases), and Candida species were second in frequency (33%); sporadic cases were caused by Rhizopus, Absidia, Scopulariopsis, and Pseudallescheria species. Bacteria were involved in fewer than 10% of cases. There was no appreciable variation from year to year in the incidence of brain abscess over this period. Aspergillus brain abscess was associated with concomitant pulmonary disease (87% of cases), whereas candida brain abscess often occurred in association with fungemia (63% of cases) or neutropenia (63%). Mortality was high (97%); the risk of death was unrelated to etiology or therapeutic regimen. Since the etiology of brain abscess in patients undergoing marrow transplantation is primarily fungal, the development of better antifungal therapeutic and/or prophylactic modalities is warranted.