Infectious complications in neutropenic patients. Clinical-laboratory correlations.

Thirty-four patients undergoing bone marrow transplantation or remission induction for acute non-lymphocytic leukemia were the subjects of a study to determine whether outcome of infection (survival, death) could be related to total complement (TC), complement components, or C-reactive protein (CRP). Serum samples were obtained when the neutropenic patients became febrile, and at intervals thereafter. Significant differences were found between final total serum complement levels, the C3 component of complement, and the C-reactive protein. Multivariate logistic regression demonstrated a significant relationship between the final C3 complement and C-reactive protein levels and the outcome of infection. Changes between initial and final values were also predictive of outcome, suggesting that the magnitude and direction of changes in these measurements may assist the clinician in assessing the success of his prescribed antibiotic therapy. Our data suggest that a test battery comprising serial TC, C3, and CRP measurements may have more predictive potential than each test performed independently.

A multicenter trial to document the efficacy and safety of a rapidly excreted analog of hydroxyethyl starch for leukapheresis with a note on steroid stimulation of granulocyte donors.

Currently, the frequency of granulocyte donation is limited by the prolonged circulation of hydroxyethyl starch (HES). We conducted a Phase I, uncontrolled, multicenter trial to evaluate both the efficacy and safety of a rapidly excreted low-molecular-weight analog of HES (LMW-HES). Seventy-five donors underwent 179 centrifugation leukapheresis procedures using LMW-HES as the red-cell-sedimenting agent. The efficacy of LMW-HES was established by harvesting adequate numbers of leukocytes. Most granulocyte concentrates contained at least 20 X 10(9) neutrophils when 8 l of blood was processed from donors optimally stimulated with steroids. The safety of LMW-HES was documented by the detection of almost no clinically significant adverse effects. In only 1.7 percent of procedures did donors require special attention, and only 1 of 179 procedures (0.6%) was permanently discontinued. Results of laboratory studies were usually normal or their values decreased transiently (approximately 15-25%) as a consequence of plasma volume expansion (dilution). Based on previous experience with HES, LMW-HES and HES perform comparably during leukapheresis. When commercially available, use of this new, rapidly excreted analog should permit more frequent leukapheresis donation.

Oral manifestations of bone marrow transplantation.

Bone marrow protection by transplantation permits the administration of large doses of antitumor drugs and radiation. Severe oral complications occur in about 70% of patients who have had allogeneic bone marrow transplants and to a lesser degree in patients who have had autologous and syngeneic transplants. Oral complications consist of mucositis, salivary gland dysfunction, loss of resiliency of perioral tissues, periodontal disease, and caries. Pre- and post-transplant oral care aimed at plaque control, control of dental pathology, and hydration of oral tissues are important factors in support therapy of bone marrow transplant patients.

Oral contraceptives and cancer: a perspective.

PIP: This article argues against widespread use of oral contraceptives (OCs) from 2 perspectives: OC's inpact on the risk of developing certain types of cancers, and the moral issues involved in the pill's abortifacient action. It is predicted that recent studies linking OC use with increased risk of breast and cervical cancer will lead many women to discontinue pill use in favor of sterilization, IUD use, or abortion. It is also anticipated that the pharmaceutical companies will manufacture OCs with a lower hormone content, which will result in a higher failure rate (and a consequent rise in the abortion rate) and produce a greater dependence on the microabortifacient effects of OCs. Promoters of natural family planning are urged to educate couples about the carcinogenic potential of OC use and to point out that there may be further longterm effects not yet manifested. Although contraceptive practice can rarely be influenced by explanations of the ways artificial contraception perverts marital sexuality, explanation of the abortifacient action of OCs and the IUD may be effective among both Catholics and non-Catholics who oppose abortion but see nothing wrong with contraception.^ieng

High-dose cytoreductive therapy with autologous bone marrow transplantation in advanced malignancies.

Twenty-one patients with advanced malignancies received high-dose chemotherapy and/or radiotherapy followed by autologous bone marrow infusion. Eighteen patients (85.7%) had fever greater than or equal to 100 degrees F for a median of 6 days; 14 of these patients required broad-spectrum antibiotics for a median of 13 days. Nineteen patients (90.5%) had a granulocyte count less than 500/mm3 for a median of 11 days. Thrombocytopenia (platelet count less than 50,000/mm3) was observed in 18 patients (85.7%) for a median of 14 days. Mucositis and diarrhea were not common, occurring in six (28.6%) and seven (33.3%) patients, respectively. Of the 21 patients studied, 16 were evaluable for tumor response; there were four complete responses and four partial responses, and two patients who showed no change for variable times. Two patients have unmaintained remissions for greater than 2 years. Our response rate (complete plus partial) is 50%. Our study shows that high-dose cytoreductive therapy can be given with moderate toxicity when combined with autologous bone marrow infusion. Because responses in this group of patients are generally of short duration, we believe that patients with advanced malignancies who have had less exposure to therapy or who have a high likelihood of disease recurrence should be considered for high-dose cytoreductive therapy with autologous transplantation.

An improved method for T-cell depletion of allogeneic histoincompatible donor bone marrow.

Acute graft-versus-host disease (GVHD) following allogeneic bone marrow transplantation is the most significant limiting factor preventing the widespread application of transplant therapy in acute leukemia and aplastic anemia. GVHD is mediated by T cells that contaminate harvested marrow in proportions ranging from 5-50% of the mononuclear cell population. T cell depletion (TCD) of large volumes of human marrow by E-rosetting for 24 h at 4 degrees C with modified sheep erythrocytes achieves removal of greater than or equal to 97% of all T cells, as judged by cytofluorographic analysis of the T-depleted bone marrow population with a broad panel of anti-T cell monoclonal antibodies, and abrogates functional T cell activity. Although T-depleted bone marrow cell recoveries were 2 logs below total harvested buffy coat cell numbers, the TCD mononuclear population was more than 99% viable and was enriched twofold for Ia+ cells as judged by cytofluorographic analysis. This method is at least the equivalent of those employing lectin column or monoclonal antibody/complement lysis techniques and is simpler to perform. Successful engraftment of adult patients can safely be obtained with as few as 4 X 10(8) total mononuclear cells following the 24-h procedure suggesting that prolonged or repeated T-depletion procedures do not interfere with stem cell engraftment. Preliminary results suggest that this method of TCD may ameliorate GVHD in histoincompatible transplants.

Graft-versus-host reaction following blood product transfusion.

The observation of graft-versus-host (GVH) reaction after platelet transfusion in a patient with Hodgkin's disease led us to analyze 38 reported cases in the literature, to outline prognostic factors and to characterize patients at risk. Overall mortality was 68 percent. It was higher among children (76 percent) than among adults (62 percent), and among patients with Hodgkin's disease and immune deficiency syndromes (88 percent) than among those with leukemias (23 percent, p less than 0.005). Following blood transfusions from normal donors, mortality was higher (88 percent) than after transfusions from donors with chronic myelocytic leukemia (25 percent, p less than 0.05). Minimal lymphocyte doses necessary to cause GVH reaction are in excess of 10(7)/kg. Adults seem more resistant to homografts than do children, and the host's cellular immune status is of major prognostic importance. Lymphocytes from donors with chronic myelocytic leukemia may be deficient, and after a threshold dose, the number of lymphocytes transfused does not correlate with clinical outcome. Effective prophylactic measures do exist for this complication but satisfactory therapy does not.

Adjuvant adriamycin and cis-diamminedichloroplatinum (cis-platinum) in primary osteosarcoma.

Twelve consecutive patients with osteosarcoma who were without evidence of metastases were treated with Adriamycin and cis-platinum in an adjuvant fashion. The primary lesion was in the distal femur in five patients, proximal tibia in three, and one each in the proximal femur, proximal humerus, sacrum, and a previously irradiated orbit. Surgery consisted of amputation in eight, limb-salvage procedures in two, and regional resections in the patients with orbital and sacral lesions. Postoperatively, Adriamycin at 30 mg/m2/d, for three days alternated every three weeks with cis-platinum, 100 mg/m2, once daily or 60 mg/m2/d, for two days i.v. drip forced i.v. fluid diuresis. Adriamycin was given to a total dose of 540 mg/m2. Ten of 12 patients remain continually disease-free with a median time on study of 23+ months (range 12+-41+ months). Local recurrences, without evidence of metastatic disease, occurred in the patient with the orbital lesion and the patient who underwent the regional resection for the lesion of the proximal humerus at 20 and 17 months from diagnosis, respectively. Nine patients are off all chemotherapy from 6+ to 33+ months (median 22+ months). Administration of cis-platinum was limited to eight courses because of renal and ototoxicity. Despite appreciable toxicity, this chemotherapeutic regimen appears to be a highly effective adjuvant in the management of primary nonmetastatic osteosarcoma.

Reversal of possible marrow graft rejection with plasma exchange therapy.

A patient with severe aplastic anemia underwent bone marrow transplantation from her HLA identical sister after a prolonged transfusion history and clinical evidence of shortened red cell and platelet survival. Following the transplant, she exhibited minimal graft vs. host disease which resolved, and was discharged with normal blood counts. Because of falling hemoglobulin, platelets and white blood cell counts 8 weeks following the transplant, graft rejection was suspected. High dose steroid therapy apparently had no effect, since the hematologic parameters continued to fall. She underwent two plasma exchanges, after which all hematologic parameters returned to normal, and she continues to exhibit normal parameters seven months after the transplant. Although other explanations for the reversal of the apparent graft rejection can be considered, the case is presented to call attention to the possibility that plasma exchange, by possibly removing circulating inhibitors of bone marrow function, may be useful and simple method for dealing with graft rejection.

Effects of cytosine arabinoside on unseparated bone marrow and peripheral blood cells and on specimens enriched for myeloblasts and promyelocytes.

Myeloblast and promyelocyte enriched preparations and the original unseparated specimens were compared in regard to the phosphorylation of cytosine arabinoside (ara C) and the retention of ara CTP as well as the effects of ara C on the clonogenic cells. The immature cell-enriched preparations have a significantly higher rate of ara C phosphorylation, while retention of ara CTP is not significantly different from that of the unseparated cells. No correlation was found between the measured parameters of ara C metabolism and the drug's effects on the clonogenic cells in either cell population.

Polymorphonuclear neutrophil function in malignant lymphomas and effects of splenectomy.

Granulocyte (PMN) directional locomotion (migration) in vitro and in vivo, resting nitroblue tetrazolium (NBT)-reduction and adherence to nylon wool of polymorphonuclear neutrophils (PMN) were assayed in 7 patients with Hodgkin's disease (HD) and in 11 patients with non-Hodgkin's lymphoma (NHL) prior to therapy. In most patients with HD, NBT-reduction was increased and in all directional locomotion was markedly decreased both in vitro and in vivo. In addition to being depressed, accumulation of PMN into skin chambers in patients with HD correlated with the peripheral blood count (r = 0.95). In vitro directional migration of PMN in NHL was depressed in half the patients, but increased in the in vivo assay. After splenectomy, PMN-adherence tended to increase and NBT-reduction to decrease. These findings are compatible with a constant cellular defect of PMN in HD, whereas in NHL abnormal PMN function is more likely mediated by extracellular factors. Abnormal PMN function may correlate with clinical susceptibility to infection in malignant lymphomas.

Granulocyte transfusions: current status.

Since granulocyte transfusions first became widely used in clinical medicine, there have been advances in the treatment of acute leukemia and improvement in prevention and management of infection in neutropenic patients. Improved understanding now exists concerning prognosis of infections in such patients, and advances have been made in procurement of granulocytes. Granulocyte transfusions should be given for specific indications, and used adjunctively to other established antiinfective therapy. Once initiated, transfusions should be given in adequate doses at daily intervals (at least) with ongoing evaluation and periodic reassessment of the whole antiinfective program. Serious complications of granulocyte transfusion therapy are relatively rare, but the physician should be prepared to manage them intelligently. Research continues in discerning exactly how granulocyte transfusion work, in preservation of granulocytes, and in delineation of immunologic phenomena affecting the efficiacy of such therapy. Granulocyte transfusions will continue to be important in the management of acute leukemia, and other reversible bone marrow failure states, and in marrow transplantation and autotransplantation.

Reversal of cyclophosphamide induced neutropenia by hypertransfusion and androgen therapy.

We injected 300 mg/kg Cyclophosphamide i.p. into female AKR mice and rendered them reversably neutropenic. Group A was hypertransfused; Group B received 5 mg Nandrolone decanoate i.m. q.d X 2; and Group C received both. Group D served as a control. White blood cell counts were followed every other day for 10 days. The nadirs seen on all groups appeared on day 5. At day 10 counts in Groups A, B, and D had returned to normal, while the pattern of granulocyte decline and recovery in Group C was significantly faster than that seen in other groups, returning to normal at day 8. Hypertransfusion and androgen administration together significantly ameliorated drug-induced leukopenia, suggesting synergism. Thus manipulation of the stem-cell compartment may be clinically feasible.

Chemotherapy of nonirradiated malignant gliomas. Phase II: study of the combination of methyl-CCNU, vincristine, and procarbazine.

Twenty-eight adult patients with nonirradiated malignant gliomas of the brain were administered a combination of methyl-CCNU (130 mg/m2, p.o., day 1), vincristine (2 mg/m2, i.v., day 1) and procarbazine (100 mg/m2, p.o., days 2 to 15) (MVP), scheduled to be given at successive 6 week intervals. Nineteen (67.9%) were not responsive to MVP and 9 (32.1%) were. Of 16 who had previous partial resection of their tumors, 8 (50%) responded to MVP and 8 (50%) did not. Of 12 who had previous biopsy, only 1 (8.3%) responded. Overall 1-year survival rate for the 28 patients was 28.6%. Major side effects of MVP were leukopenia, thrombocytopenia, pulmonary emboli, and thrombophlebitis, detected mainly during the first 20 to 24 weeks of treatment.