Impact of admission body weight and chemotherapy dose adjustment on the outcome of autologous bone marrow transplantation.

We performed a retrospective analysis of 473 consecutive adult patients undergoing autologous bone marrow transplantation for hematologic malignancies between 1988 and 1995. The analysis examined whether significant deviation from ideal body mass index is associated with a decrease in event-free survival (EFS), an increase in nonrelapse mortality (NRM) including late toxicities and second malignancies, or relapse. Chemotherapy dosing in underweight and overweight patients is administered based on the relationship of admission body weight (ABW) to ideal body weight (IBW). Doses were adjusted for obesity; however, the adjustment did not obviate increased risk for NRM. Patients were categorized into five groups according to the relationship of ABW to age-adjusted body mass index (aBMI) as a percent of actual BMI, as follows: group I, 70-79%; group II, 80-99%; group III, 100-119%; group IV, 120-139%; and group V, 140-199% aBMI. When body weight was expressed as percent BMI adjusted for age, there was a significantly increased risk for NRM in groups I and IV (p = 0.03 and 0.02, respectively). A trend toward greater NRM in group V (p = 0.10) was also noted. Multivariate analysis confirmed that the risk of NRM for extremely underweight and overweight patients is almost three times that of patients close to ideal body weight. Age-adjusted BMI was an independent predictive factor for NRM but not associated with increased relapse. We determined that dose adjustment could be safely used without significant increase of relapse. In patients with significant deviation of BMI from aBMI, dose adjustment and possible weight normalization should be considered.

Granulocyte colony-stimulating factor-induced comobilization of CD4- CD8- T cells and hematopoietic progenitor cells (CD34+) in the blood of normal donors.

The feasibility of transplantation of HLA-matched hematopoietic progenitor cells from the blood of normal donors given granulocyte colony-stimulating factor (G-CSF) has been reported recently. In the current study, the changes in T-cell subsets as well as CD34+ cells were determined in one blood volume leukapheresis products of six normal individuals given G-CSF. Examination of the T-cell subsets in the leukapheresis products showed three different patterns: one in which a discrete population of CD4- CD8- alphabeta T cells was found in addition to the typical CD4+ and CD8+ T cells in the unfractionated as well as in high- and low-density cells; a second in which the discrete population of CD4- CD8- alphabeta T cells was predominant only in the low-density fractions; and a third in which a discrete population of CD4- CD8- T cells was not observed. The median yield of CD4- CD8- T cells was about fourfold to fivefold higher than the calculated number present in one blood volume (5L) from normal individuals. The ratios of CD34+ cells to CD4+ and CD8+ T cells, and of CD4- CD8- T cells to CD4+ and CD8+ T cells, were highest in the low-density fractions. These fractions suppressed the mixed leukocyte, and may ameliorate graft-versus-host disease as compared with unfractionated cells.

Influence of age on the outcome of 500 autologous bone marrow transplant procedures for hematologic malignancies.

PURPOSE: To determine the effect of age on the outcome of autologous bone marrow transplantation (ABMT) and/or peripheral-blood progenitor-cell (PBPC) transplantation. PATIENTS AND METHODS: A retrospective analysis was performed on 500 consecutive patients who ranged in age from 1 to 65 years (median, 40) with non-Hodgkin's lymphoma (NHL), Hodgkin's disease (HD), multiple myeloma (MM), or acute nonlymphoblastic leukemia (AML) who underwent autologous hematopoietic-cell transplant procedures at Stanford University Medical Center. RESULTS: The actuarial 5-year event-free survival (EFS) rate was 44%, the relapse rate 47%, and the regimen-related mortality (RRM) rate 8.6%. Disease status at time of transplantation, categorized as either minimal or advanced disease, was the strongest predictive factor for EFS (relative risk (RR) for advanced-disease group, 1.8; P < .0003) and relapse rate (RR for advanced-disease group, 1.9; P < .0004). Patients with minimal or advanced disease had an EFS rate of 48% and 30% and relapse rates of 43% and 72%, respectively. The EFS rate of patients less than 50 years verus > or = 50 years of age was 46% versus 34% (P = .03). Cox regression analysis showed that age was predictive for EFS (RR for patients 50 to 65 years, 1.4; P = .03). The actuarial RRM rate for these age groups was 7.4% versus 12.7% (P = .07), respectively. Multivariate analysis demonstrated that age (odds ratio [OR] for patients 50 to 65 years, 1.9; P < .05) and period of transplantation (OR for most recent years [1991 to 1995], 0.6; P = .06) were the most predictive factors for RRM. CONCLUSION: Although age greater than 50 years is associated with an inferior outcome following autologous hematopoietic-cell transplantation, it does not appear to be warranted to limit this potentially curative procedure based solely on age. The upper age limit of high-dose therapy with autologous progenitor-cell and/ or bone marrow support remains to be defined.

Preemptive ganciclovir administration based solely on asymptomatic pulmonary cytomegalovirus infection in allogeneic bone marrow transplant recipients: long-term follow-up.

The use of ganciclovir at the time of cytomegalovirus (CMV) infection but before disease onset has been termed "preemptive" therapy. This preemptive ganciclovir administration has been shown to be an effective method for preventing severe CMV disease after allogeneic bone marrow transplantation (BMT), but the optimal method of CMV surveillance is not clear. The purpose of this study was to evaluate effectiveness, side effects, and long-term outcome of preemptive ganciclovir therapy in allogeneic BMT recipients when ganciclovir is prescribed solely on the basis of CMV detection in day +35 bronchoalveolar lavage (BAL). In a consecutive cohort of 202 HLA-matched recipients of sibling donor marrow transplantations, 163 received prospective BAL and were given preemptive ganciclovir if CMV-positive; 39 had disqualifying complications and were not eligible for BAL. Over the 36-month follow-up, CMV disease occurred in 21 (10%) of the 202 BMT recipients; there was one CMV-related death. In the 60 subjects (37% of the total 163) who received preemptive ganciclovir based on positive CMV-BAL, two (3%) developed CMV disease during the first 120 days post-BMT and two more developed late disease. Among the 103 BAL-negative subjects, CMV disease occurred in eight (8%) during the first 120 days and in three (3%) at > 120 days. Forty-three percent of all CMV disease occurred either before day +35 BAL (four cases) or at late times after BMT (five cases). The negative predictive value of BAL was 91%, allowing for the occurrence of 52% of all CMV disease in subjects considered CMV-BAL-negative. Nevertheless, using this treatment method, no significant differences in neutropenia rates or in 36-month survival were noted in the high-risk group having pulmonary CMV infection (compared with the group without pulmonary CMV). Thus, a strategy of preemptive ganciclovir based on a single BAL can reduce the complications caused by CMV; however, improved surveillance methods are necessary to eliminate all CMV disease.

Multiple cycles of high dose chemotherapy supported by hematopoietic progenitor cells as treatment for patients with advanced malignancies.

BACKGROUND: Retrospective studies suggest that dose intensity is an important determinant of outcome in the treatment of patients with a variety of malignant diseases such as breast cancer, ovarian cancer, and lymphoma. Unfortunately, these results have not been clearly substantiated in prospective randomized trials. One problem with these studies may be that the degree of dose escalation is not sufficient to result in an improved outcome because the chemotherapy doses are limited by hematopoietic toxicity. In an attempt to deliver more dose-intensive therapy, the feasibility of the administration of multiple cycles of high dose chemotherapy with hematopoietic progenitor cell and growth factor support was investigated in patients with advanced malignancies. METHODS: Nineteen patients with metastatic breast cancer and six patients with refractory non-Hodgkin's lymphoma were initially treated with etoposide (VP-16) (2 gm/m2) and granulocyte-colony stimulating factor (G-CSF). Peripheral blood hematopoietic progenitor cells were collected by leukapheresis and cryopreserved as the patients' leukocyte counts recovered from the nadir induced by VP-16. Patients were then treated with four cycles of mitoxantrone (18 mg/m2), thiotepa (150-200 mg/m2) and cyclophosphamide (4500-5000 mg/m2) as a 48-72 hour continuous infusion followed by infusion of one-quarter of their progenitor cells 48 hours later. All patients also received G-CSF (5 micrograms/kg/day) until engraftment. RESULTS: A total of 88 of a planned 100 cycles of therapy were administered to these 25 patients. The median time to recovery of an absolute neutrophil count of 500/microliters or greater was 13-14 days (range, 7-18 days) and time to recovery of a platelet count of 20,000/microliters or greater was 13-14 days (range, 7-16 days) after the initiation of each cycle of chemotherapy. The median number of platelet transfusions required after each cycle was 2-3 (range, 0-18 transfusions) and the number of erythrocyte transfusions was 4 (range, 0-10). The most common toxicity was diarrhea. Prophylactic intravenous antibiotics were administered to avoid fever with neutropenia. Two patients developed interstitial pneumonitis and one patient died. One heavily pretreated patient failed to engraft after the first cycle. Reversible veno-occlusive disease of the liver developed in one patient after the fourth cycle of therapy. Four patients progressed while on therapy. Eight patients were disease free and 13 patients had a partial response or had a positive bone scan as the only evidence of disease at the completion of therapy. Seven patients, two with lymphoma and five with breast cancer (28%), remain progression free with a median follow-up of 24.7 months (range, 17-28 months). CONCLUSIONS: Support with hematopoietic progenitor cells and growth factors allows the timely administration of repetitive cycles of high dose chemotherapy, resulting in a significant increase in dose intensity with acceptable toxicity.

Enrichment of bone marrow and blood progenitor (CD34+) cells by density gradients with sufficient yields for transplantation.

We have evaluated the use of iso-osmolar Percoll density gradients to enrich CD34+ hematopoietic progenitor cells and to reduce T cells for purposes of bone marrow or mobilized peripheral blood cell transplantation (BMT or PBCT). Samples from 12 normal BM donors and 11 patients undergoing mobilization of PB cells using chemotherapy and G-CSF were placed over a five-step density gradient from 40 to 50% Percoll. In BM, low-density fractions 1 to 3 (40 to 45% Percoll) accounted for 3% of starting nucleated cells with a 10- to 20-fold enrichment of hematopoietic progenitors (CD34+ cells) and a 20-fold reduction of CD4+ and CD8+ T cells. In PB, fractions 1 to 3 accounted for 20 to 30% of the starting nucleated cells with a five-fold enrichment of hematopoietic progenitors. Based on these values, such populations have been used for clinical transplantation using a single apheresis. The reduced cell numbers in the low-density fractions can facilitate tumor purging, and the reduced T cell numbers present in the marrow may ameliorate graft-vs.-host disease.

Transplantation of enriched and purged peripheral blood progenitor cells from a single apheresis product in patients with non-Hodgkin's lymphoma.

High-dose chemotherapy with or without radiotherapy followed by autologous transplantation of hematopoietic progenitor cells is an effective treatment for patients with high-risk or relapsed non-Hodgkin's lymphoma. Chemotherapy and/or hematopoietic growth factors have been used to mobilize progenitor cells in the peripheral blood for transplantation. However, the mobilized blood cell products have been found to be frequently contaminated with tumor cells, and techniques have not been developed to purge tumor cells from these products. In addition, the minimum number of hematopoietic progenitor cells required for engraftment has not yet been fully elucidated. We treated 21 patients with a single infusion of cyclophosphamide (4 g/m2) followed by daily administration of granulocyte colony-stimulating factor (G-CSF). After recovery of the white blood cell count, a single 3-hour apheresis collection was performed. The apheresis product was then applied to a discontinuous Percoll gradient. The low-density fractions resulting from this separation procedure were enriched for CD34+ progenitor cells (total cell yield, 19.5%; CD34+ cell recovery, 81.2%). These enriched cellular products were treated with a panel of anti-B cell or anti-T cell monoclonal antibodies and complement in an effort to remove residual tumor cells. After treatment of the patient with myeloablative therapies, the enriched and purged cells were reinfused. Hematologic recovery was rapid, with median neutrophil engraftment in 10 days [absolute neutrophil count (ANC), greater than 0.5 x 10(9)/L] and 11 days (ANC, greater than 1.0 x 10(9)/L). Median platelet transfusion independence required 13 days. The rapidity of multilineage engraftment correlated with the number of CD34+ cells per kilogram that were infused. Patients who received more than 2 x 10(6) CD34+ cells per kilogram had rapid hematologic engraftment, whereas those patients transplanted with less than 2 x 10(6) CD34+ cells per kilogram had slower platelet recovery. Modeling studies using a lymphoma cell line with a t(14; 18) chromosomal translocation demonstrated the successful removal of tumor cells assayed using the polymerase chain reaction (PCR) after the processing and purging. Four of the 21 patients had PCR-detectable lymphoma cells in the bone marrow and peripheral blood; however, the enriched and purged blood products reinfused in all four did not contain detectable tumor cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Subcutaneous low dose arabinosyl-cytosine and oral idarubicin in high risk adult acute myelogenous leukemia.

In order to further explore low dose chemotherapy for high risk acute myelogenous leukemia (AML), low dose Ara-C and oral idarubicin (LAI) were given to 33 patients of 24-84 (median 66) years with AML after myelodysplastic syndrome (MDS) (12 patients), refractory AML (13 patients), and AML with contraindications to intensive chemotherapy (8 patients). Patients received 1 to 4 cycles of Ara-C 10 mg/m2 q 12 h s.c. inject. on days 1-14 and idarubicin 20 mg/m2/d orally days 3, 4, 5. Three Three patients attained complete remission, four patients partial remission and one patient minor response, whereas 11 patients succumbed to early mortality from hemorrhage (two patients) and/or infections (10 patients). Three of 13 patients with heavily pretreated refractory AML went into remission compared to 3/12 with AML after MDS and 1/8 with AML and contraindications against intensive treatment. Median duration of CR is 102 (70-488 +) days. Thirty-two of 33 patients developed grade 4 hematological toxicity requiring platelet transfusions. The non-hematologic toxicity was acceptable. LAI provides a standardized therapeutic option especially for heavily pretreated patients with AML.

Response of osteosarcoma and Ewing sarcoma to preoperative chemotherapy: assessment with dynamic and static MR imaging and skeletal scintigraphy.

In 15 osteosarcomas and six Ewing sarcomas, response to preoperative chemotherapy was assessed with magnetic resonance (MR) imaging without and with gadolinium diethylenetriaminepentaacetic acid (DTPA) enhancement and with dynamic Gd-DTPA studies, and the results were compared with the scintigraphic findings. All studies were obtained prior to and following preoperative chemotherapy. Static MR imaging was of little value for assessment of response; reduction in signal intensity within soft-tissue masses on the T2-weighted spin-echo images indicated response with a sufficient degree of accuracy (71%) but low sensitivity, whereas an increase in signal intensity after Gd-DTPA administration indicated zones of viable tissue with low specificity. With three-phase skeletal scintigraphy, the findings in the perfusion and blood-pool phases were of no value, whereas the findings in the osseous phase allowed the prediction of response with an accuracy of 73.7%. Of all techniques employed, dynamic MR imaging had the highest degree of accuracy (85.7%) and was superior to scintigraphy, particularly in patients who were receiving intraarterial chemotherapy.

Musculoskeletal neoplasms: static and dynamic Gd-DTPA--enhanced MR imaging.

Static and dynamic magnetic resonance imaging studies were performed in 69 patients with bone and soft-tissue tumors. T1-weighted spin-echo (SE) imaging after intravenous administration of gadolinium diethylenetriaminepentaacetic acid (DTPA) improved the differentiation of necrotic from viable areas; the contrast-to-noise ratio (C/N) between tumor and muscle was an average of 44% lower compared with that in T2-weighted SE imaging. The C/N between tumor and bone marrow or fatty tissue was 43% and 37% lower, respectively, compared with that in nonenhanced T1-weighted SE imaging. Dynamic changes of signal intensity (SI) after Gd-DTPA enhancement were assessed with fast low-angle shot imaging. Of malignant tumors, 84.1% exhibited slopes higher than 30% per minute; 72% of benign tumors showed slopes lower than 30% per minute. The dynamic technique enabled assessment of the malignant potential of a tumor with some overlap (accuracy, 79.7%). Necrotic areas and peritumorous edema showed significantly lower and more gradual increases in SI than adjacent neoplastic tissue.