Subhash C. Gulati

Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as Adjunct Therapy in Relapsed Hodgkin Disease

OBJECTIVE To determine the clinical and economic effects of granulocyte macrophage colony-stimulating factor (GM-CSF) as adjunct therapy in relapsed or refractory Hodgkin disease. DESIGN A randomized, double-blind, phase III clinical trial. SETTING A tertiary referral center. PATIENTS Twenty-four patients (twelve of whom were controls) treated with high-dose chemotherapy and autologous bone marrow transplantation. MAIN RESULTS The 12 patients treated with GM-CSF, when compared with placebo recipients, had shorter periods of neutropenia (median duration of an absolute neutrophil count of less than 1000 cells/mm3, 16 days compared with 27 days; P = 0.02), shorter periods of platelet-transfusion dependency (median duration, 13.5 days compared with 21 days; P = 0.03), and shorter hospitalizations (median hospital stay, 32 days compared with 40.5 days; P = 0.004). Other clinical outcomes, such as frequency and severity of toxicities, development of pneumonia or infection, in-hospital death, and response rate were similar in the two groups. Actuarial long-term disease-free survival was 64% for patients treated with GM-CSF and 58% for patients who received placebo after 32 months of follow-up (P = 0.15). The group treated with GM-CSF had lower total charges after infusion of autologous marrow than the placebo group (median in-hospital charges,

Pregnancy after bone marrow transplantation.

39,800 compared with

ECONOMIC ANALYSIS IN PHASE III CLINICAL CANCER TRIALS

62,500; P = 0.005) because of lower post-infusion charges for room and board, antibiotic therapy, transfusions, laboratory tests, and physical therapy visits. CONCLUSIONS Administration of GM-CSF was associated with acceleration of myeloid and platelet recovery and was cost effective in the treatment of patients with relapsed Hodgkin disease who received intensive chemotherapy.

Role of cytokines in healing chronic skin wounds

PURPOSE To evaluate the occurrence of pregnancy after bone marrow transplantation (BMT). DESIGN Medline literature review of reported pregnancies in the BMT population published in the English language. RESULTS Multiple case reports and a few series studies showed more than 250 offspring from BMT recipients. CONCLUSION BMT patients receive high-dose chemotherapy and often radiation, as well. These agents are associated with gonadal dysfunction and the fertility of patients after BMT is of concern because BMT patients are often young people who wish to resume a normal quality of life, which for many patients involves the desire to have children. Our experience with the successful pregnancy of one of our BMT patients led to the investigation of reported cases that showed numerous other births. The issue of counseling BMT patients about fertility, pregnancy complications, and potential birth defects is becoming increasingly complex and warrants further investigation.

Abnormal Liver Function in Patients Undergoing Autologous Bone Marrow Transplantation for Hematological Malignancies

Randomized phase III clinical trials provide important information on the efficacy of new pharmaceutical agents for cancer patients. Policy makers are showing increased interest in both economic and clinical data on new agents in order to approve pharmaceuticals for widespread use, and clinical trials have been viewed as the proper setting to evaluate these outcomes for new agents. With the recent approval of new pharmaceutical agents that have high costs, early assessments of economic benefit have taken on larger importance to physicians and patients. The integration of economic and clinical analysis in phase III clinical trials raises methodological and practical issues related to study design, collection of data on resource utilization, and generalizability of data to other settings. In this paper, we review these issues and discuss their relationship to clinical trials for new pharmaceutical products.

Improving the Role of Hematopoietic Support for High-Dose Cytotoxic Therapy

In the chronic wound, the normal cascade of inflammation, granulation and reconstruction phases of healing is interrupted. Cytokines are now known to orchestrate different biochemical mediators resulting in the restoration of the healing phases. Growth factors may play a significant role in stimulating wound repair by stimulating growth and proliferation. Since growth factors stimulate a variety of functions depending on cell type and wound stage and since wound-healing defects may occur at any phase of healing, a mixed combination of growth factors would be predicted to be more effective than a single factor. Factors that may modulate the action of growth factors include electrical stimulation, weight bearing, debriding and ischemia.

p53 gene mutation in the bone-marrow of a patient with diffuse mixed cell type lymphoma at diagnosis predicting eventual progression to large cell lymphoma.

Autologous bone marrow transplantation (AuBMT) is an accepted treatment modality for patients with high-risk or relapsed hematological malignancies. Hepatotoxicity, in particular veno-occlusive disease (VOD), is a significant complication of this therapy. The purpose of this study was to determine the clinical relevance of abnormal liver function in the patients who received high-dose cytotoxic therapy and AuBMT for hematological malignancies at Memorial Sloan Kettering Cancer Center. Medical records of 180 consecutive patients between 1984 and 1991 treated with cytotoxic chemotherapy and AuBMT for acute myelogenous leukemia, non-Hodgkins lymphoma, and Hodgkins disease were reviewed. Forty-six patients (26%) developed jaundice with bilirubin > 4 mg/dl. These patients had a 43% toxic death rate compared to an 11% toxic death rate in patients with lower bilirubins (p < 0.001). The main etiology of hyperbilirubinemia was VOD of the liver noted in 22 of the 180 patients (12%). Other etiologies of jaundice included hepatitis, sepsis with multiorgan dysfunction, cholecystitis, and recurrent disease. Hyperbilirubinemia of various etiologies is a significant complication of AuBMT. Several new strategies are under investigation to decrease the toxicity of intensive therapy.

The Role of GM-CSF in Chronic Infections

Dose intensification of cytotoxic drugs is now being evaluated in several trials. Various methods are available to manage the hematopoietic toxicity. Hematopoietic growth factors can be used alone and/or in combination with hematopoietic stem cell rescue. Patients undergoing autologous stem cell transplantation (AuSCT) have their own bone marrow and/or peripheral blood used for hematopoietic engraftment. In several malignancies, the bone marrow is involved with tumor, and in such situations, the success of AuSCT may improve if hematopoietic elements are enriched (positive selection) or if contaminating cancer cells are purged by negative selection. In patients undergoing allogeneic bone marrow transplantation, T lymphocytes, from donor cells, contribute to the development of graft-versus-host disease (GVHD), which can result in major morbidity and mortality. The incidence of GVHD has decreased with selective purging of T lymphocytes, but further modifications are needed to improve hematopoietic engraftment. Methods for purging hematopoietic stem cells are discussed, with emphasis on the therapeutic role of purging. Growing stem cells from a small amount of bone marrow presents a new possibility. Furthermore, genetic engineering can enhance immune surveillance and decrease drug resistance. Analysis of the clinical trials utilizing various doses of cytotoxic therapy with proper methods of hematopoietic rescue will help avoid unnecessary dose escalation and help decide the optimum use of cancer treatment modalities.

Important issues in high dose chemotherapy and stem cell transplantation

Mutations of the p53 tumor suppressor gene have been used as molecular genetic markers of disease and serve as a prognostic indicator in various malignancies including non-Hodgkins lymphoma (NHL). Alterations in the p53 gene were investigated in a bone marrow sample from a NHL patient admitted for autologous bone marrow transplantation. Diffuse mixed small and large cell NHL, was initially diagnosed which eventually progressed to large cell lymphoma at relapse following poly-chemotherapy. A sequential technique of polymerase chain reaction-mediated single-strand conformational polymorphism (PCR-SSCP) of the p53 gene revealed a shift in one band of exon 6 in the bone marrow, collected at the time of initial diagnosis. No mutations were detected in exons 5, 7, 8 and 9. Direct sequencing of exon 6 detected a single base change from G to C resulting in an amino acid substitution from glycine to histidine. Results of this study and data reviewed from other publications suggest that the missense p53 mutation seen in this patient at the time of diagnosis may perhaps have been used to predict the eventual outcome of the disease. This could, therefore, serve as an important genetic disease marker particularly in bone marrow or peripheral blood samples initially collected and cryopreserved for future possible autologous transplantation.

Pharmacological Elimination of Tumor Cells Contaminating Normal Human Bone Marrow Using PTT-119

Significant progress has been made in understanding wound healing. Various growth factors interact in a complex manner resulting in eventual wound healing. GM-CSF, platelet derived growth factor, tumor necrosis factor, alpha and various angiogenesis factors may have a significant role and in the future, may have to be combined for the maximum benefit in wound healing.