Isadore Brodsky

Conventional-Dose Chemotherapy Compared with High-Dose Chemotherapy plus Autologous Hematopoietic Stem-Cell Transplantation for Metastatic Breast Cancer

BACKGROUND We conducted a randomized trial in which we compared high-dose chemotherapy plus hematopoietic stem-cell rescue with a prolonged course of monthly conventional-dose chemotherapy in women with metastatic breast cancer. METHODS Women 18 to 60 years of age who had metastatic breast cancer received four to six cycles of standard combination chemotherapy. Patients who had a complete or partial response to induction chemotherapy were then randomly assigned to receive either a single course of high doses of carboplatin, thiotepa, and cyclophosphamide plus transplantation of autologous hematopoietic stem cells or up to 24 cycles of cyclophosphamide, methotrexate, and fluorouracil in conventional doses. The primary end point was survival. RESULTS The median follow-up was 37 months. Of 553 patients who enrolled in the study, 58 had a complete response to induction chemotherapy and 252 had a partial response. Of these, 110 patients were assigned to receive high-dose chemotherapy plus hematopoietic stem cells and 89 were assigned to receive conventional-dose chemotherapy. In an intention-to-treat analysis, we found no significant difference in survival overall at three years between the two treatment groups (32 percent in the transplantation group and 38 percent in the conventional-chemotherapy group). There was no significant difference between the two treatments in the median time to progression of the disease (9.6 months for high-dose chemotherapy plus hematopoietic stem cells and 9.0 months for conventional-dose chemotherapy). CONCLUSIONS As compared with maintenance chemotherapy in conventional doses, high-dose chemotherapy plus autologous stem-cell transplantation soon after the induction of a complete or partial remission with conventional-dose chemotherapy does not improve survival in women with metastatic breast cancer.

Immunoablative High-Dose Cyclophosphamide without Stem-Cell Rescue for Refractory, Severe Autoimmune Disease

High-dose cytotoxic therapy followed by autologous stem-cell transplantation has been proposed as a novel treatment for severe autoimmune disease [1, 2]. This approach was prompted by autoimmune animal models that demonstrated marked improvement or complete eradication of autoimmune disease after syngeneic marrow transplantation [3, 4]. In addition, allogeneic marrow transplantation (performed chiefly for aplastic anemia) has been reported to eradicate concurrent autoimmune disease [5, 6]. Allogeneic marrow transplantation is not routinely used to treat autoimmune disease because of substantial associated morbidity and mortality. Although interest in the use of high-dose cytotoxic therapy followed by autologous stem-cell transplantation to treat autoimmune disease is increasing, disease progresses or relapses early in many patients [7, 8]. It is unclear whether reappearance of the disease after autologous transplantation results from failure of high-dose therapy to eradicate autoaggressive lymphocytes, reinfusion of autoaggressive lymphocytes with the autograft, or renewed challenge from the autoantigen [7, 8]. However, the success of syngeneic transplantation in animal models and allogeneic transplantation in patients with autoimmune diseases suggests that high-dose cytotoxic therapy may be sufficient to eradicate autoaggressive lymphocytes [8]. We previously found that the immunoablative doses of cyclophosphamide used for transplantation can induce durable, complete remission (median follow-up > 10 years) without stem-cell rescue in most patients with severe aplastic anemia [9]. Because most cases of aplastic anemia result from immune suppression of hematopoiesis [10], high-dose cyclophosphamide without the addition of other cytotoxic immunosuppressive agents seems to ablate the autoaggressive lymphocytes. We also reported that high-dose cyclophosphamide spared hematopoietic stem cells because full hematopoietic recovery occurred [9]. Hematopoietic stem cells express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide, and are therefore resistant to the cytotoxic effects of cyclophosphamide [11, 12]. We investigated the efficacy of high-dose cyclophosphamide without stem-cell rescue in patients with various severe autoimmune diseases. Methods Treatment Schedule Our study was approved by the institutional review boards of Johns Hopkins University and Hahnemann University. After giving informed consent, eight patients (Table 1 and Table 3) with refractory autoimmune disorders received cyclophosphamide (50 mg/kg of body weight per day) intravenously for 4 consecutive days. Granulocyte colony-stimulating factor therapy (5 g/kg per day) was started 6 days after the last dose of cyclophosphamide and was continued until the absolute neutrophil count reached 109 cells/L. Inclusion in the study required failure of two previous therapies. Patients were excluded if their cardiac ejection fraction was less than 0.45, their serum creatinine level was greater than 176.8 mol/L, or they were older than 70 years of age. Red blood cell transfusions were administered to patients with a hematocrit less than 0.25, and platelet transfusions were given to patients with platelet counts less than 20 109 cells/L or clinically significant bleeding. Complete remission required the absence of any clinical or serologic evidence of disease. Complete remission from lupus nephritis was defined as fewer than 10 dysmorphic erythrocytes per high-powered field, absence of cellular casts, and excretion of less than 1 g of protein per day without doubling of the serum creatinine level [13]. For patients with systemic lupus erythematosus, daily activity indices [14] were measured at 3-month intervals. Table 1. Patient Characteristics and Response to High-Dose Cyclophosphamide Table 3. Table 1. Continued Selected Case Reports Patient 1 was a 64-year-old man with a 35-year history of rheumatoid arthritis treated with prednisone and gold. The Felty syndrome had been diagnosed 3 years earlier when the patient developed a perirectal abscess and profound neutropenia (neutrophil count < 0.2 109 cells/L). Examination of bone marrow showed hypercellularity with myeloid maturation arrest. The patient was treated with myeloid growth factors and steroids but showed no response. He required frequent hospitalizations for recurrent infections. Before the patient received high-dose cyclophosphamide, he was positive for antineutrophil antibodies, the neutrophil count was 0.1 109 cells/L, the rheumatoid factor level was elevated, complement levels were depressed, and the Karnofsky score [15] was 40%. The patient tolerated high-dose cyclophosphamide well and had few side effects other than alopecia; he achieved a neutrophil count greater than 0.5 109 cells/L by day 15, and infections (perirectal abscess, pneumonia, and sinusitis) that were present at the time of treatment resolved. Two units of red blood cells and five platelet transfusions were required. The patient is in complete remission 21 months after treatment and has normal peripheral blood counts, has normal complement levels, and is negative for antineutrophil antibodies. He has not been receiving any immunosuppressive agents for more than 15 months. Patient 6 was a 23-year-old woman in whom lupus was diagnosed at 12 years of age after she presented with the Raynaud phenomenon and stomatitis. She later developed severe proteinuria, hyperlipidemia, polyarthralgia, and an extensive skin rash. Renal biopsy performed 4 years before initiation of high-dose cyclophosphamide therapy showed membranous nephropathy. The patient required hospitalization for lupus flares three to four times per year despite treatment with methylprednisolone (4 mg/d), hydroxychloroquine (400 mg/d), azathioprine (150 mg/d), and pulse-dose cyclophosphamide. Before high-dose cyclophosphamide therapy began, the hematocrit was 0.27, the leukocyte count was 2.8 109 cells/L, the platelet count was 278 109 cells/L, and the erythrocyte sedimentation rate was 104 mm/h. Anti-DNA antibodies were present at a titer of 1:320, the C3 level was 0.41 g/L, and the 24-hour urine protein level was 2 g. The patient tolerated high-dose cyclophosphamide well; side effects were alopecia and febrile neutropenia. A neutrophil count greater than 0.5 109 cells/L was reached on day 18, and only six units of red blood cells and three platelet transfusions were needed. The patient is in continuous complete remission 12 months after treatment; the erythrocyte sedimentation rate is 20 mm/h, no anti-DNA antibodies are present, the C3 level is 1.49 g/L, and the 24-hour urine protein level is 86 mg. Immunosuppressive therapy has been tapered to 1 mg of prednisone daily. Results High-dose cyclophosphamide was well tolerated and was associated with rapid hematologic recovery in all eight patients despite their poor medical condition at time of treatment. Four patients were hospitalized for complications of their autoimmune disease, and four patients were being treated for active infections at the time of cyclophosphamide therapy; the median Karnofsky score was 40% (range, 20% to 70%). The median time to achievement of a neutrophil count greater than 0.5 109 cells/L was 17 days (range, 11 to 22 days), and the median time to the last platelet transfusion was 16 days (range, 12 to 33 days). All patients experienced complete alopecia, and six patients required antibiotics for febrile neutropenia. No patient developed hemorrhagic cystitis or mucositis. Patients 2 and 4 eventually died of complications of autoimmune disease. Patient 2, who was treated for autoimmune hemolytic anemia, died of complications of immune thrombocytopenic purpura, which was not present when she was treated with high-dose cyclophosphamide. Autoimmune hemolytic anemia remained in complete remission until the patients death, 16 months after cyclophosphamide therapy. Patient 4 achieved brief remission of immune thrombocytopenic purpura and died of her disease 8 months later. Six patients remain alive, and five (patients 1, 3, 6, 7, and 8) have no symptomatic manifestations of their disease. In addition, four patients have no laboratory or clinical evidence of disease (Table 2). Patient 3, who has the Evans syndrome, shows continued improvement in blood counts; prednisone therapy is being tapered to 10 mg every other day. Patient 3 has been independent of transfusion for more than 10 months and has a normal hemoglobin level and a platelet count of 66 109 cells/L. One of the patients with lupus achieved complete remission; the other still has clinical and serologic evidence of the disease but continues to improve 14 months after treatment. Patient 7, who has the Felty syndrome, is in complete remission 3 months after cyclophosphamide therapy. Patient 10, who has chronic inflammatory demyelinating polyneuropathy, had progressive upper- and lower-extremity paralysis and was unable to walk. Plasmapheresis, intravenous immunoglobulin, and pulse-dose cyclophosphamide therapy had proven ineffective. Three months after therapy with high-dose cyclophosphamide, he has no neurologic manifestations, is not receiving immunosuppressive therapy, and can walk normally. Table 2. Laboratory Results* Discussion Most immunoablative therapy for severe autoimmune disease uses autologous stem-cell rescue after high-dose therapy with cyclophosphamide in combination with other immunosuppressive agents [8]. Although our study was small and the follow-up was relatively short, the results indicate that high-dose cyclophosphamide alone can be effective therapy for some patients with severe autoimmune disease. In addition, our study confirms that high-dose cyclophosphamide (50 mg/kg per day for 4 days) spares hematopoietic stem cells; the kinetics of bone marrow recovery after high-dose cyclophosphamide therapy without stem-cell rescue are similar to those of engraftment after autol

Hemostatic effects of tranexamic acid and desmopressin during cardiac surgery.

Background Desmopressin-induced release of tissue plasminogen activator from endothelial cells may explain the absence of its hemostatic effect in patients undergoing cardiac surgery. Prior administration of the antifibrinolytic drug tranexamic acid might unmask such an effect, and combination therapy might thereby improve postoperative hemostasis. Methods and Results A double-blinded design randomly allocated 163 adult patients undergoing coronary revascularization, valve replacement, both procedures, or repair of atrial septal defect to four treatment groups: placebo, tranexamic acid given as 10 mg/kg over 30 minutes followed by 1 mg. kg−1. hr−1 for 12 hours initiated before skin incision, desmopressin given as 0.3 μg/kg over 20 minutes after protamine infusion, and both drugs. One surgeon performed all operations. Blood loss consisted of mediastinal tube drainage over 12 hours. Follow-up visits sought evidence of myocardial infarction and stroke. Desmopressin decreased neither the 12-hour blood loss nor the amount of homologous red cells transfused. Tranexamic acid alone significantly reduced 12-hour blood loss, by 30%1 (mean, 318 versus 453 ml; Conclusions Desmopressin exerts no hemostatic effect, with or without prior administration of antifibrinolytic drug. Prophylactic tranexamic acid alone appears economical and safe in decreasing blood loss and transfusion requirement after cardiac surgery.

Effects of trimethoprim on folate metabolism in man

Recent studies have demonstrated a synergistic effect of dihydrofolate reductase (DHFR) inhibitors and sulfonamides in the therapy of chronic urinary tract infections and malaria. Trimethoprim (TMP) (Ro‐56846, Hoffmann‐LaRoche) has 10,000 times more inhibitory effect on bacterial DHFR than on mammalian DHFR. Folate metabolism was evaluated in 10 normal patients treated with TMP alone for 4 weeks and 14 patients with chronic genitourinary infections treated with TMP and sulfonamides for periods up to 2 years. Parameters under study were complete blood count, bone marrow examination, serum and red blood cell folate levels, formiminoglutamic acid (FiGlu) excretion, and lobe counts of circulating neutrophiles. In order to measure folate activity a mutant strain of L. casei resistant to TMP was developed (Hitchings and Burchall, Burroughs Wellcome & Co. [U.S.A.] Inc.). In the short‐term group 1 patient developed thrombocytopenia and another anemia associated with transitional megaloblastosis, while 5 patients excreted FiGlu and all had significant elevation of lobe counts. When the drug was stopped these abnormalities disappeared in 2 weeks. One patient ingesting the combination of drugs demonstrated thrombocytopenia and leukopenia which disappeared when citrovorum factor was given despite continued administration of drugs. The dose of citrovorum factor needed to ensure hematologic normalcy was 400 µg. It is concluded that TMP has mild inhibitory effects On folate metabolism in man at the tissue level which can be overcome by administration of reduced folates.

Effect of clinical outcomes data on intensive care unit utilization by bone marrow transplant patients

OBJECTIVE To determine if a program to educate referring physicians as to the poor outcome of mechanically ventilated bone marrow transplant patients would result in a change in intensive care unit (ICU) utilization. DESIGN Retrospective chart review. SETTING Medical ICU at an urban university hospital. PATIENTS Patients undergoing bone marrow transplantation in the interval before (n = 236) vs. the interval after (n = 144) a physician education program. INTERVENTIONS Two separate educational programs were conducted for oncologists and intensivists to review the findings of an earlier study demonstrating the outcome of bone marrow transplant patients in the ICU. MEASUREMENTS AND MAIN RESULTS The results demonstrated that this physician education intervention did not result in a change in the utilization of medical ICU resources by these patients. Comparing the time periods before and after the intervention, there were no statistically significant differences in the proportion of patients who were admitted to the medical ICU, the proportion who received mechanical ventilation, or the medical ICU lengths of stay. Similarly, the two groups did not differ regarding the 100-day survival rate of all bone marrow transplant patients studied, all bone marrow transplant patients admitted to the medical ICU, or all bone marrow transplant patients intubated. CONCLUSION Simple educational interventions are not a powerful mechanism by which to alter the practice of physicians regarding the utilization of scarce and expensive resources, even when the physicians generally agree that the use of those resources results in dismal patient outcomes.

Disseminated intravascular coagulation—a complication of chemotherapy in acute myelomonocytic leukemia

This is the first reported case of disseminated intravascular coagulation (DIC) occurring as a complication of chemotherapy in acute myelomonocytic leukemia. The DIC was successfully treated with heparin. Chemotherapy was continued, and a complete objective hematologic remission was obtained.

Familial occurrence of breast cancer is associated with reduced natural killer cytotoxicity

SummaryA factor in the incidence of spontaneous neoplasms in mice is the endogenous level of natural cell-mediated cytotoxicity (1, 2). These immunosurveillant or host defense mechanisms are probably under the control of multiple gene products (3, 4) including interferons. We studied natural killer (NK) cytotoxicity using peripheral blood mononuclear cells from 59 normal individuals with either a high (17) or low (42) familial incidence of breast cancer. The K562 cell line was used as target in51Cr release assays. Three effector: target ratios (6.2 : 1, 25 : 1, and 50 : 1) were studied in quadruplicate using 3, 4 and 5-h incubations. Significantly lower natural killer activity (p<0.002) was detected in normal individuals with high familial incidences of breast cancer compared to individuals with low incidences in each of the three separate assays (50 : 1). The same conclusion was reached whether the data were expressed in terms of lytic units per 107 blood mononuclear cells or as % specific51Cr released. Thus, a relationship was observed between the occurrence of breast cancer in closely related family members and low natural cell-mediated cytotoxicity. This result suggests that defects in NK activity may play a role in the initiation of human breast tumors. However, prospective studies will be necessary to establish whether low NK cell activity is a risk factor for breast cancer.

Simultaneous Fibrinogen and Platelet’ Survival with [75Se]Selenomethionine in Man

Summary. Simultaneous fibrinogen and platelet survivals were determined with a cohort label, [75Se]selenomethionine, in patients with hepatocellular disease and abnormal serial thrombin times (STT) and in control patients. The fibrinogen survival curves were divided into an anabolic and catabolic phase. In a control group maximum labelling of fibrinogen (anabolic phase) occurred within 24 hr and mean fibrinogen survival (catabolic phase) was 7.8 ± 2.8 days. Patients with hepatocellular disease fell into two groups, those with short fibrinogen survivals and those with normal fibrinogen survivals. In general, the more abnormal the STT the shorter the fibrinogen survival. The anabolic phase of the curve was also abnormal in that there was delay in incorporation of label in these patients.

High dose cyclophosphamide for severe refractory myasthenia gravis

Myasthenia gravis (MG) exemplifies autoimmune disease. Most patients require immunomodulating treatment, including steroids, chemotherapy, or intravenous immunoglobulin (Ig), in addition to anticholinesterase treatment. Drachman et al 1 published the beneficial effects of high dose cyclophosphamide in three patients with severe refractory myasthenia. We recount our experience of three myasthenic patients treated in a similar way. All patients participated in studies approved by the Drexel University College of Medicine and signed informed consent. These three patients with severe (class IVb) refractory MG includes all patients treated. Patients received cyclophosphamide 50 mg/kg (adjusted ideal body weight)/day over four consecutive days. Patients received antibacterial, antiviral, and antifungal prophylaxis. Haemorrhagic cystitis prophylaxis included Mesna and forced diuresis. Packed red cells and platelets were transfused to maintain haemoglobin ⩾8.5 g/dL and platelets ⩾10 × 109/L, respectively. Patients received filgrastion (G-CSF) (5 μg/kg/day) starting day 10 until their absolute neutrophil count (ANC) reached 10 × 109/L for two consecutive days. Patient 1 was diagnosed with seronegative MG at 30 years of age by a positive tensilon test and a decremental response on repetitive stimulation. Initial treatment included pyridostigine and plasmapheresis, but worsening symptoms prompted thymectomies at 12 and 18 months later. Her thymic pathology revealed thymic hyperplasia. Additional treatment with …

Frequency of veno-occlusive disease of the liver in bone marrow transplantation with a modified busulfan/cyclophosphamide preparative regimen

Veno-occlusive disease (VOD) of the liver is a major complication of hone marrow transplantation (BMT). The overall frequency of VOD has ranged from 20 to 30%, with a mortality rate > 40%, as reported by centers utilizing cyclophosphamide (Cy) and total body irradiation (CyTBI) or various chemotherapeutic regimens, including the busulfan (Bu) (4 mg/kg for 4 days) and Cy (50 mg/kg for 4 days) (BuCy4) combination. Since 1986, Hahnemann University (HU) has primarily used the BuCy2 regimen, i.e., Bu (4 mg/kg for 4 days) followed by Cy (60 mg/kg for 2 days). We reviewed 74 consecutive patients who received either an autologous or allogeneic BMT for various malignancies from January 1986 through October 1988 to determine the frequency of VOD. Seven of 74 consecutive patients met clinical criteria for VOD, for a total frequency of 9.5%. Fifty-five patients were conditioned with various other regimens. Only 5 of the patients conditioned with BuCy2 developed VOD (9.1%.). This is less than the 25% reported frequency of VOD in patients who received CyTBI (1,000 rads) and less than the 24% reported frequency of VOD in patients who received BuCy4. Only one of seven patients who developed VOD died from the disease. One patient died of sepsis after the VOD had almost completely resolved. The remaining five completely recovered. We conclude that the total Cy dose, and not Bu, is the major factor in the occurrence of VOD in Bu/Cy BMT preparative regimens, and the BuCy2 regimen reduces the frequency of VOD in autologous and allogeneic graft recipients when compared to CyTBI or the BuCy4 regimens.