Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT).

Peripheral blood cells are increasingly used in place of bone marrow as a source of hematopoietic stem cells for allogeneic transplantation. The relative efficacy of these 2 approaches is unknown. This retrospective multivariate analysis compared results of 288 HLA-identical sibling blood stem cell transplantations with results of 536 HLA-identical sibling bone marrow transplantations. No transplants were T-cell depleted. Median follow-up was 12 months, and analyses focused on 1-year outcomes. Recipients of blood stem cell transplants had more rapid recovery of neutrophils to at least 0.5 x 10(9)/L (median time to recovery, 14 days, compared with 19 days for marrow transplants; P <.001) and of platelets to at least 20 x 10(9)/L (median time, 18 days, compared with 25 days for marrow transplants; P <.001). There was no significant difference in the incidence of grades II to IV acute graft versus host disease (GVHD). The incidence of chronic GVHD was significantly higher after blood stem cell transplantation (1-year probability [95% confidence interval], 65% [56%-72%] compared with 53% [47%-59%]; P =.02) Relapse incidence in the 2 transplant groups did not differ significantly. Treatment-related mortality rates were lower and leukemia-free survival rates were higher with blood stem cell transplants in patients with advanced leukemia (acute leukemia in second remission or chronic myelogenous leukemia in accelerated phase) but not in early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in chronic phase). The median time from transplantation to hospital discharge was 23 days after blood stem cell transplantation and 28 days after bone marrow transplantation (P =.003). Further study with longer follow-up is necessary to definitively establish the role of blood stem cells for allogeneic transplantation, especially in patients with good-risk disease. (Blood. 2000;95:3702-3709)

HLA-identical sibling peripheral blood progenitor cell transplants (PBPCT).

Peripheral blood progenitor cells (PBPC) are being investigated as an alternative stem cell source in allogeneic transplantation. The current paper presents a 'state-of-the-art' review of HLA-identical sibling transplants (PBPCT). Medline search and meeting reports were used to identify the latest reports from the various transplant centers. The data are presented systematically with the goal of providing a basis for evidence-based medicine. This approach offered the opportunity to identify threshold CD34+ cell numbers for rapid engraftment, threshold CD3+ cell numbers to prevent acute GVHD, prognostic factors for various outcome parameters and are a strong indication that the infused CD3+ cell dose might influence chronic graft-versus-host disease (GVHD), the most controversial and concerning aspect in allogeneic PBPCT. The value of systematic reviews for future clinical research planning is emphasized.

Haematological recovery after high-dose consolidation chemotherapy with peripheral blood progenitor cell rescue: the effects of the mobilization regimen and post-transplant growth factors.

PURPOSE: Peripheral blood progenitor cells (PBPC), mobilized by chemotherapy, growth factors (GF) or the combination of these modalities are currently used in most autologous transplants settings. Patient selection factors and infused cell numbers have been related to the rate of haematological recovery after transplant (p-Tx). The effect of the mobilization regimen on haematological recovery has rarely been reported and is addressed herein. The value of p-Tx GF use is also evaluated. METHODS: A literature review identified studies reporting both mobilization results and haematological recovery (time to ANC > 0.5 or 1.0 x 10(9)/1 and PLT > 20 or 50 x 10(9)/1). The studies are listed in tables showing the mobilization regimen, disease, infused CD34+ cell and CFU-GM dose, p-TX GF use and haematological recovery. The ranges of recovery times for each transplant setting are summarized in a figure in addition to the ranges of recovery times using GF after autologous bone marrow transplants in controlled studies. RESULTS: Transplantation of cells mobilized by G-CSF results in faster haematological recovery than transplantation of cells mobilized by GM-CSF. This difference disappears when chemotherapy is included in the mobilization regimen. GF have minimal effect on haematological recovery after transplantation of PBPC mobilized by chemotherapy plus GF and some effect on neutrophil recovery after transplants of PBPC mobilized by GF only. CONCLUSIONS: Recovery after PBPC transplantation depends on the mobilization method and is best predictable when mobilization occurs with chemotherapy plus GF. In this situation, the value of post-transplant growth factors is questionable. Careful choice of the mobilization method, including optimal timing of leucapheresis and patient selection factors, determine the leucapheresis yield and thus the rate of haematological recovery.

Guidelines for efficient peripheral blood progenitor cell collection.

In recent years peripheral blood progenitor cells (PBPC) have increasingly been used to support hematological recovery after high-dose chemotherapy treatment. PBPC are collected by leukopheresis after mobilization by chemotherapy and/or hematopoietic growth factors. Efficient mobilization and correct timing of leukopheresis is essential to minimize the number of leukophereses required for collection of sufficient PBPC for transplantation. Mobilization efficiency is influenced by various factors and recruitment of cells can be assessed by cell assays and FACS analysis. Target values of cells required for rapid hematological reconstitution after high-dose chemotherapy have been reported, but threshold values for various conditions still need to be established. CD34+ selection of the leukopheresis is of value for tumor cell purging and may be important for reduction of relapse rate of solid tumors and hematological malignancies.

Dose-escalating induction chemotherapy supported by lenograstim preceding high-dose consolidation chemotherapy for advanced breast cancer. Selection of the most acceptable regimen to induce maximal tumor response and investigation of the optimal time to collect peripheral blood progenitor cells for haematological rescue after high-dose consolidation chemotherapy.

BACKGROUND: In advanced breast cancer high-dose consolidation chemotherapy with haematological rescue has resulted in prolonged disease free and overall survival in a small percentage of patients. Maximal reduction of the tumor burden by intensive induction treatment preceding the high-dose chemotherapy may favor that outcome. The aims of this study were to find a rapid highly effective induction regimen with acceptable toxicity and to examine the optimal time for peripheral blood progenitor cell (PBPC) collection for haematological rescue. SUBJECTS AND METHODS: Twenty-four patients received 4 cycles of FAC chemotherapy (5-FU, adriamycin, cyclosphamide), each followed by 10 micrograms/kg/d of lenograstim (glycosylated rHuG-CSF) s.c. day 2 to 11. Chemotherapy was administered at 4 dose intensity levels with 6 patients including at each level (level 1: 500(F)/50(A)/500(C) mg/m2/3wk, level 2: 500/50/500 mg/m2/2wk, level 3: 500/75/500 mg/m2/2wk, m2/2wk, level 4: 500/75/1000 mg/m2/2wk d1 i.v.). In addition lenograstim (10 micrograms/kg/d s.c.) was administered for a period of 10 days before (period X) and after (period Y) chemotherapy. In 16 patients (4 at each dose intensity level) assessment of PBPC was performed during period X and Y as well as during cycle 1 and 4. A single apheresis to collect PBPC was planned during chemotherapy cycle 1. RESULTS: The best response was obtained at dose intensity level 3 (all 6 patients responded, 3 of them achieved CR) with acceptable toxicity. Peak circulating numbers of total CFC/ml blood were median 5819 (period X), 4635 (cycle 1), 3807 (cycle 4) and 3519 (period Y) and occurred concurrently with peak circulating numbers of CD34+ cells. The and median 3.76 x 10(6)/kg CD34+ cells. Three patients received high-dose consolidation chemotherapy with PBPC support. Recovery of ANC > 0.5 x 10(9)/l occurred on median day 11 and of platelets > 20 x 10(9)/l on median day 10. CONCLUSION: Dose intensity level 3 is the best usable induction regimen in this study. The optimal time for apheresis is either during lenograstim before chemotherapy treatment or during the first cycle of chemotherapy. Rapid haematological recovery was obtained by reinfusion of PBPC as sole source of support in the patients receiving high-dose consolidation chemotherapy.

Urinary-derived monocyte-colony stimulating factor (P-100) following treatment with carboplatin and etoposide in small cell lung cancer (SCLC).

BACKGROUND: The hematopoietic growth factor P-100 is a monocyte-colony stimulating factor purified from human urine and has been reported to reduce neutropenia following chemotherapy. In this study the effect and toxicity of P-100 was evaluated in 26 patients receiving intensive chemotherapy for SCLC. STUDY DESIGN: Chemotherapy consisted of four 28 day cycles of carboplatin (C) 600 mg/m2 i.v. on day 1 of cycle 1 + 2 and 300 mg/m2 i.v. on day 1 of cycle 3 + 4 and etoposide (E) 120 mg/m2 i.v. on day 1-3 of each cycle. Patients were randomised to receive P-100 for ten days following chemotherapy during either the first or second cycle. 12 Patients received P-100 with the first and 12 with the second cycle. For each group cycles with P-100 were compared to cycles without P-100. RESULTS: P-100 was well tolerated but no significant differences between cycles with and without P-100 were seen in the administered chemotherapy dose, depth and duration of neutropenia, number of blood or platelet transfusions, WHO grade 3-4 infection or requirement for intravenous antibiotics. Of 24 evaluable patients 14 (58.3%) achieved CR and 4 (16.6%) PR. Patients achieving CR received radiotherapy. The median time to progression was 169 days (range 38-995+ days) and the median survival time was 305 days (range 42-1052+ days). Three patients are alive after 2 years (11.5%), 2 without relapse (7.7%). Alopecia, nausea and vomiting occurred in all patients but no treatment related deaths occurred. CONCLUSION: In this study P-100 did not significantly influence the myelotoxicity associated with carboplatin-etoposide chemotherapy in the treatment of SCLC.

Assessment of tumour vascularity as a prognostic factor in lymph node negative invasive breast cancer.

The association between tumour vascularity and relapse was examined in 93 patients with lymph node negative (LNN) invasive breast cancer. Factor VIII-related antibody was used to stain the microvessels. Vascularity was defined by the number of vessels per field counted in the area of highest vascular density at 100 x magnification. These vascular counts were divided into three groups of vascular density (group I: < 67, group 2: 68-100, group 3: > 101 vessels/field). Cross-tabulation analysis revealed a significant relationship between vascular density and tumour grade (P = 0.027). No association was found between vascularity and tumour size, tumour type, age or menopausal status. Survival analysis showed no association between vascularity and relapse-free (P = 0.92) or overall survival (P = 0.99). Significant associations between tumour grade and relapse-free (P = 0.0048) and overall survival (P = 0.0064) and between tumour size at the cut off of 15 mm diameter and relapse-free (P = 0.0097) and overall survival (P = 0.0271) were found. When grade was taken into account the effect of tumour size became non-significant (P = 0.059). Our results suggest that assessment of vascularity is not an independent prognostic factor in LNN invasive breast cancer.

[Ambulatory continuous intravenous infusion of fluorouracil: a feasible palliative form of chemotherapy]. / Ambulante continue intraveneuze infusie van fluorouracil: een haalbare palliatieve chemotherapie.

A study to evaluate the feasibility and toxicity of outpatient continuous intravenous infusion of fluorouracil (5-FU) was initiated at the department of Medical Oncology of the University Hospital of Utrecht. To this purpose a subcutaneous drug delivery system (Port-a-Cath) was implanted in 36 patients with various advanced cancers. Of these patients 83% had received prior chemotherapy (including 5-FU in 62%). Ambulatory continuous-infusion pumps were used to administer 5-FU in a dosage of 300 mg/m2/24 h. The treatment was continued until tumour progression was seen, and it was interrupted in case of toxicity grade 2 or more (WHO criteria). A Port-a-Cath was implanted 37 times in the 36 patients. The main complications of this infusion system were pneumothorax (2/37), arrhythmia (1/37), catheter sepsis (2/37) and thrombosis (2/37); they were easily managed. The toxicity and feasibility of this treatment were evaluable in 30 patients. They received a median of 44 g 5-FU (range 11-136, 5 g, mean 281 mg/m2/24 h) during a median infusion time of 12 weeks (range 4-32 w). Side effects were encountered in 70% of the patients and consisted of the hand-foot syndrome (14/30), nausea and vomiting (8/30), diarrhoea (8/30) and stomatitis (7/30). The toxicity was completely reversible after a short interruption of the chemotherapy. The treatment was tolerated well, and good palliation was attained in 22 of 30 patients. The best response was seen in patients with colon and breast cancer. We conclude that continuous infusion of 5-FU is a reliable outpatient chemotherapy even in this category of patients.

Testicular cancer with enlarged mediastinal lymph nodes: a diagnostic pitfall.

A patient with embryonal cell carcinoma restricted to the left testicle, without retroperitoneal but with mediastinal lymph node enlargement and highly elevated serum alpha-fetoprotein levels, is presented (T1N4M0). Because stage III of the disease was presumed, he received chemotherapy, which was unfortunately complicated by a bleomycin-induced pneumonitis. At re-evaluation after chemotherapeutic treatment, it appeared that the tumor marker level had decreased exponentially after the operation and that the mediastinal lymph node enlargement was due not to metastatic disease but to sarcoidosis. The necessity of calculating the half-life of tumor markers after operation and histological examination of the mediastinal lymph nodes prior to chemotherapy in such cases, is discussed.