Peter Ernst

Allogeneic bone marrow transplant is not better than autologous transplant for patients with relapsed Hodgkin's disease. European Group for Blood and Bone Marrow Transplantation.

PURPOSE To compare the results achieved with myeloablative therapy followed by either allogeneic bone marrow transplantation (alloBMT) or autologous bone marrow transplantation (ABMT) for patients with Hodgkins disease (HD). PATIENTS AND METHODS Of more than 1,200 patients with HD reported to the European Bone Marrow Transplantation (EBMT) registry, 49 underwent alloBMT. Of these, 45 with sufficient data were matched to 45 patients who underwent ABMT. The matching criteria were sex, age at time of transplantation, stage of disease at diagnosis, bone marrow involvement at diagnosis and at transplantation, year of transplantation, disease status at time of transplantation, time from diagnosis to transplantation, and conditioning regimen with or without total-body irradiation (TBI). RESULTS The 4-year actuarial probabilities of survival, progression-free survival (PFS), relapse, and non-relapse mortality were 25%, 15%, 61%, and 48% and 37%, 24%, 61%, and 27% after alloBMT and ABMT, respectively. The toxic death rate at 4 years was significantly higher for alloBMT patients (P = .04). For patients with sensitive disease at the time of transplantation, the 4-year actuarial probability of survival was 30% after alloBMT and 64% after ABMT (P = .007). This difference is mainly due to a higher transplant-related mortality rate after alloBMT (65% v 12%, P = .005). Acute graft-versus-host disease (aGVHD) > or = grade II was associated with a significantly lower risk of relapse, but also with a lower overall survival (OS) rate. CONCLUSION Based on this study, alloBMT from a human leukocyte antigen (HLA)-identical sibling donor does not appear to offer any advantage when compared with ABMT. A graft-versus-Hodgkin effect is associated with > or = grade II aGVHD, but its positive effect on relapse is largely offset by its toxicity. In most circumstances, alloBMT cannot be recommended for patients with HD.

Autologous versus allogeneic bone marrow transplantation for non-Hodgkin's lymphoma: a case-controlled analysis of the European Bone Marrow Transplant Group Registry data.

PURPOSE A case-controlled study of patients who reported to the European Bone Marrow Transplant Group (EBMTG) was performed to investigate the relative roles and efficacy of allogeneic (alloBMT) and autologous bone marrow transplantation (ABMT) in non-Hodgkins lymphoma. PATIENTS AND METHODS Of 1,060 patients who reported to the lymphoma registry, 938 patients underwent ABMT and 122 patients underwent alloBMT. A case-controlled study was performed by matching 101 alloBMT patients with 101 ABMT patients. The case matching was performed after the selection of the main prognostic factors for progression-free survival by a multivariate analysis. RESULTS The progression-free survival was similar in both types of transplants (49% alloBMT v 46% ABMT). The overall relapse and progression rate for the alloBMT patients was 23% compared with 38% in the ABMT patients. This difference was not significant statistically. In the lymphoblastic lymphoma subgroup, alloBMT was associated with a lower relapse rate than ABMT (24% alloBMT v 48% ABMT; P = .035). The progression-free survival, however, was not significantly different because patients with lymphoblastic lymphoma who underwent alloBMT had a higher procedure-related mortality (24% alloBMT v 10% ABMT; P = .06). A significantly lower relapse/progression rate was also observed in patients with chronic graft-versus-host disease (cGVHD) compared with those patients without (0% cGVHD v 35% no cGVHD; P = .02). Fourteen of 18 patients who had cGVHD also had lymphoblastic lymphoma. CONCLUSION This study suggests that ABMT and alloBMT for non-Hodgkins lymphoma are comparable, with the exception of lymphoblastic lymphoma in which a graft-versus-lymphoma effect may account for the lower relapse rate for patients who underwent alloBMT.

Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients

The efficacy and safety of oral fluconazole versus a polyene regimen in preventing mycoses in neutropenic patients was compared. Patients with haematological malignancy or bone marrow transplantation received as antifungal prophylaxis either fluconazole 200 mg daily or a regimen consisting of clotrimazole trouches 10 mg twice daily with mycostatin, 500,000 i.u. four times daily, benadryl and cepacol mouthwash. Ninety patients at risk for fungus infection were evaluable. Four of 42 patients (9.5 %; confidence interval 2 %–23 %) on fluconazole and 17 of 48 patients (35.4 %; confidence interval 22 %–52 %) (p<0.01) on the clotrimazole regimen developed a clinically significant fungal infection, including 3 (7.1 %) and 11 (22.9 %) patients respectively who had severe fungal infection, mainly pulmonary aspergillosis. Death directly due to a fungal infection within 100 days of the start of prophylaxis occurred in 2 of 42 patients (4.8 %) and 9 of 48 patients (18.8 %) respectively (p<0.06). Kaplan-Meier analysis showed that the chance of survival on fluconazole was statistically greater than for the clotrimazole regimen (p<0.04). A decrease of candidal colonisation of the gastrointestinal and genitourinary tracts occurred only in patients receiving fluconazole. No significant toxicity occurred. A 200 mg daily dose of fluconazole given to these patients thus appears to be well tolerated and to provide a protective effect against the development of fungal infection and death from severe fungal disease.

Bone Marrow Transplantation for Infantile Malignant Osteopetrosis

Purpose Most patients diagnosed with malignant osteopetrosis die during infancy or early childhood from hemorrhage and infection due to bone marrow failure. Allogeneic bone marrow transplantation (BMT) has been reported to provide curative therapy for this disorder. We report our experience with eight patients with malignant osteopetrosis who underwent BMT. Patients and Methods Between May 1987 and August 1992, eight children with malignant osteopetrosis underwent allogeneic BMT. Median age at BMT was 9 months (range, 2–36 months). Six patients received marrow from HLA-identical sibling donors, one from phenotypically matched father, and one from a one antigen mismatched father. BMT conditioning for all patients was busulfan 16 mg/kg and cyclophosphamide 200 mg/kg each administered over 4 days. Graft versus host disease (GVHD) prophylaxis included cyclosporin A in six patients or cyclosporin A and methotrexate in two patients. Results Six patients, including those who received bone marrow from their fathers, engrafted as documented by bone marrow biopsy showing an increase in osteoclasts in all cases and by chromosomal analysis in four patients. Two patients died without engraftment. Three out of six patients engrafted are alive and well at the follow-up of 48, 63, and 81 months. Serum calcium, alkaline, and acid phosphatase levels normalized within 2 months. These patients have full bone marrow reconstitution. Serial radiologic studies revealed bone marrow remodelling and a new nonsclerotic bone formation. Vision improved dramatically in the youngest patient. Conclusion BMT offers cure to patients with malignant osteopetrosis with reconstitution of bone marrow and correction of metabolic disturbances. In our experience, reversibility in neurosensory deficit is possible when BMT is done at an early age.

Systemic amphotericin B versus fluconazole in the management of antibiotic resistant neutropenic fever — preliminary observations from a pilot, exploratory study

A pilot exploratory study was undertaken to collect preliminary information relating to safety and overall outcome in using intravenous fluconazole (FLUC) for managing antibiotic resistant neutropenic fever (ARNF), with the objective of assessing feasibility of performing a larger prospective controlled study. Patients who were neutropenic from treatment for leukaemia or bone marrow transplantation, received either fluconazole (FLUC) or amphotericin B (AB). Eight of 16 patients (50%) on FLUC and 21 of 25 patients (84%) on AB defervesced; the mean time to defervescence was 11.0 +/- 10.0 days for FLUC compared to 7.7 +/- 6.3 days for AB, and a similar proportion in each treatment group defervesced within 5 days (50% vs. 52%), respectively. Six of 16 patients (37.5%) on FLUC and three of 25 patients (12%) on AB developed overt invasive fungal disease, including pulmonary aspergillosis (FLUC 4 cases, AB 2 cases) and invasive candidiasis (FLUC 2 cases, AB 0 cases). The mean time to these events was 19.5 +/- 13.4 (FLUC) and 9.0 +/- 3.6 (AB) days. The fungal related mortality rates were higher in the FLUC group: five of 16 patients (31%) vs. two of 25 patients (18%) died respectively; the time to fungal death was 43.2 +/- 18.2 (FLUC) and 25.0 +/- 18.4 (AB) days. This tendency towards a more favourable outcome in patients on AB may have been due to absence of prior fluconazole prophylaxis in patients subsequently receiving IV FLUC. Analysis of a small subgroup of patients who had all received prior prophylaxis with clotrimazole only, indicated that a greater number of patients subsequently receiving IV FLUC died from fungal disease (5/16 vs.0/6, P = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of Mesna and Dimesna After Simultaneous Intravenous Bolus and Infusion Administration in Patients Undergoing Bone Marrow Transplantation

This study was undertaken to examine the pharmacokinetics of mesna and its dimer form, dimesna, in the plasma and urine of patients undergoing bone marrow transplantation who received 130 mg/kg of mesna divided intravenously into a 30‐mg/kg bolus dose followed immediately by 100 mg/kg infused over 12 hours for uroprotection. The relationship between and urinary excretion of mesna and dimesna also was examined by comparing the data obtained in patients who developed hemorrhagic cystitis versus those who did not. Blood and urine samples were collected at different time intervals after administration, and the plasma or urine was analyzed by liquid chromatography with electrochemical detection. Dimesna was analyzed in these samples after reduction back to mesna with sodium borohydride. The concentration—time data of mesna exhibited the characteristics of the two‐compartment model well, and the mean ± SD values of the distributive phase half‐life (t1/2α), postdistributive phase half‐life (t1/2β), volume of distribution of the central compartment (Vdc), volume of distribution at steady state (Vdss), volume of distribution during the postdistributive phase (Vdβ), total clearance (Cl), and mean residence time (MRT) observed were 0.12 ± 0.15 hours, 2.12 ± 1.61 hours, 0.324 ± 0.336 L/kg, 1.09 ± 1.18 L/kg, 2.09 ± 3.0 L/kg, 0.755 ± 0.507 L/hr · kg, and 6.77 ± 0.72 hours, respectively. The mean ± SD values of t1/2 and MRT of dimesna were 1.29 ± 0.6 hours and 6.68 ± 1.05 hours, respectively, and the ratio of the area under the concentration—time curve (AUC) of mesna to that of dimesna was 1.21 ± 0.57. The fractions of dose excreted in urine in the form of mesna and dimesna in 20 hours (fu) were 0.361 ± 0.15 and 0.482 ± 0.25, and the renal clearance (ClR) values were 0.244 ± 0.201 L/hr · kg and 0.157 ± 0.156 L/hr · kg, respectively. The urinary excretion of mesna in these patients was higher than that required for uroprotection for the whole duration of infusion, and there was no significant difference in the pharmacokinetics of mesna between patients who developed hemorrhagic cystitis and those who did not. This was not the case with dimesna, in which patients with hemorrhagic cystitis excreted in urine less than 50% of the amount of dimesna excreted by those without hemorrhagic cystitis.

Engraftment failure following bone marrow transplantation in children with thalassemia major using busulfan and cyclophosphamide conditioning.

Thirteen children older than 3 years of age with beta-thalassemia major underwent allogeneic bone marrow transplantation (BMT) from a full human leukocyte antigen (HLA) matched sibling donor in a single institution. These patients received busulfan (Bu). 16 mg/kg followed by cyclophosphamide (Cy) 200 mg/kg for conditioning. Eight of the 13 patients (Group 1) engrafted and have a median age of 13 years (range 5-15 years). The five patients (Group 2) who failed to engraft have a median age of 6 years (range 3-8 years). The association with the following factors was found to be statistically significant: age (older in Group 1), duration of nadir of white blood count (WBC) of < or = .1 x 10(9)/L (longer in Group 1), and the dose of Bu administered to each patient calculated on the basis of body surface area (higher dose in Group 1). The high rate of engraftment failure (5 out of 13) may be related to the suboptimal systemic exposure of Bu in younger children leading to inadequate bone marrow ablation when the standard dose of 16 mg/kg is used.

Effect of Repeated Dosing on the Pharmacokinetics of Oral Fluconazole in Bone Marrow Transplant Patients

We examined the pharmacokinetics of fluconazole in 11 bone marrow transplant patients after multiple oral daily dose of 200 mg of this drug. Blood was sampled at different intervals on day 1, day 13, and day 27. No dose was given on day 2, day 14, and day 28 to allow the concentration—time data to be collected over 48 hours. The 24 hour urine was also collected, and fluconazole was analyzed in both plasma and urine by a high performance liquid chromatography. The plasma concentration—time data were best described by the one‐compartment model with first‐order absorption. The overall inter‐day change and the difference between day 1 and day 27 in the rate constant for absorption (ka), peak plasma concentration (Cmax), trough plasma concentration (Cmin), time‐to‐peak (tmax), area‐under‐the‐curve 0–24 (AUC0–24), rate constant for elimination (ke), mean residence time after oral administration (MRTor), and fraction of the dose excreted unchanged in urine 24 hours (fu24) were significant (P ≤ 0.0029 and P ≤ 0.01, respectively). However, the difference between day 1 and day 13 was significant (P ≤ 0.05) only in ka, tmax, Cmax, Cmin, and AUC0–24, and between day 13 and day 27 was significant (P ≤ 0.05) only in ka, Cmin, ke, and MRTor. There was no significant inter‐day change in the renal clearance. The significant (P ≤ 0.05) increases in Cmax, Cmin, and AUC0–24 after the dose given on day 13 as compared with day 1, and in Cmin on day 27 as compared with day 13 indicate that, in contrast to volunteers, the steady state condition was not reached on day 13 and possibly not on day 27 in these patients. This perhaps should be taken into account when prescribing fluconazole to seriously ill patients.

Multiple myeloma: A review of 92 cases at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

A review of 92 cases of multiple myeloma (66 males and 26 females) seen at the King Faisal Specialist Hospital and Research Centre from October 1975 through December 1987 revealed the age for affected patients ranged from 23 to 90 years (mean, 56 years). Six percent of the patients were less than 40 years old at the time of diagnosis. Bone pain was the most common presenting symptom in our patients (80%), most frequently involving the back. Anemia was the initial finding in 74%, followed by plasmacytoma (22.8%), hypecalcemia (19.6%), and renal insufficiency (18.5%). Skeletal survey abnormalities were seen in 92.4% of the cases, with osteolytic lesions as the predominant finding. Serum protein electrophoresis showed a monoclonal paraprotein in 78% of the cases, of which 55.5% were the IgG class. Free light chains were detected in the urine of 20 patients. The median survival time for all patients was 68 months. Twenty patients died of renal failure and/or infection. The combination of melphalan and prednison was used for treatment in 37 patients, while 31 patients received the M2 protocol and 19 patients received different therapy such as VCEP (vindesine, cyclophosphamide, VP 16 and prednisone), MPV (melphalan, prednisone, and vincristine) or high-dose melphalan. Five patients either refused treatment or died before treatment could be started.

Bone marrow transplantation in patients with Fanconi anemia: experience with cyclophosphamide and total body irradiation conditioning regimen.

Eleven patients with Fanconi anemia (FA) underwent bone marrow transplantation (BMT) between March 1985 and May 1990 in a single institution. Ten patients received bone marrow from healthy full human leukocyte antigen (HLA) matched siblings and one patient from her father (one antigen mismatch). Ten patients were conditioned with cyclophosphamide (Cy) at a dose of 5 mg/kg per day for 4 days followed by total body irradiation (TBI) for a total of 600 cGy over 3 days. Six of the 11 patients are alive and have normal reconstitution of their bone marrow. Median follow-up was 72 months (range 42-84). Three of the 10 patients who received Cy and TBI (two HLA compatible, one antigen mismatch) had graft failure. Five patients developed at least grade III acute graft-versus-host disease (GVHD). The rates of graft failure and GVHD are, however, still significantly high. Modification of the conditioning regimen and GVHD prophylaxis is needed to improve the outcome.