Barry Meisenberg

High-dose chemotherapy and autologous bone marrow support as consolidation after standard-dose adjuvant therapy for high-risk primary breast cancer.

PURPOSE We studied high-dose cyclophosphamide, cisplatin, and carmustine (CPA/cDDP/BCNU) with autologous bone marrow support (ABMS) as consolidation after standard-dose adjuvant chemotherapy treatment of primary breast cancer involving 10 or more axillary lymph nodes. PATIENTS AND METHODS One hundred two women with stage IIA, IIB, IIIA, or IIIB breast cancer involving 10 or more lymph nodes at surgery were registered; 85 were eligible, treated, and assessable. Patients were treated with four cycles of standard-dose cyclophosphamide, doxorubicin, and fluorouracil (CAF), followed by high-dose CPA/cDDP/BCNU with ABMS. RESULTS Actuarial event-free survival for the study patients at a median follow-up of 2.5 years is 72% (95% confidence interval, 56% to 82%). Comparison to three historical or concurrent Cancer and Leukemia Group B (CALGB) adjuvant chemotherapy trials selected for similar patients showed event-free survival at 2.5 years to be between 38% and 52%. Therapy-related mortality was 12%; pulmonary toxicity of variable severity occurred in 31% of patients. Quality-of-life evaluations indicate that patients are functioning well without major impairments. CONCLUSION High-dose consolidation with CPA/cDDP/BCNU and ABMS after standard-dose CAF results in a decreased frequency of relapse in patients with high-risk primary breast cancer compared with historical series at the median follow-up of 2.5 years. Evaluation in a prospective, randomized trial is warranted and currently underway.

Sequential prophylactic oral and empiric once-daily parenteral antibiotics for neutropenia and fever after high-dose chemotherapy and autologous bone marrow support.

PURPOSE We studied the effectiveness of prophylactic oral ciprofloxacin and rifampin on fever prevention in patients undergoing autologous bone marrow transplantation (ABMT) for breast cancer. Furthermore, we evaluated the toxicity and efficacy of empiric once-daily vancomycin and tobramycin for febrile neutropenia. PATIENTS AND METHODS Ninety-nine assessable women received prophylactic ciprofloxacin and rifampin after high-dose chemotherapy (HDC) for advanced or high-risk primary breast cancer supported with either bone marrow and peripheral-blood progenitor cells (PBPCs) or bone marrow purged with chemotherapy and monoclonal antibodies. Neutropenic fever was treated with empiric once-daily vancomycin and tobramycin. Patients were compared with historic controls treated with the identical HDC and bone marrow support regimen. RESULTS In patients treated with bone marrow and PBPCs, the incidence of fever during neutropenia was reduced by ciprofloxacin and rifampin from 98% to 57%. Documented infections were reduced from 42% to 13% (P < .01) and bacteremia from 18% to 0% (P < .001). In purged bone marrow recipients, the overall infection rate decreased from 74% to 17% (P < .001), and bacteremia from 29% to 7%. (P = .02). No patient developed breakthrough bacteremia or sepsis syndrome while on study. Serum creatinine level greater than 1.8 g/dL was noted in 7% of controls and 10% of study patients. Increased ototoxicity was not encountered with the higher peak concentrations of vancomycin and tobramycin. CONCLUSION The therapeutic strategy of ciprofloxacin and rifampin followed by once-daily vancomycin and tobramycin markedly reduced the incidence of infection and virtually eliminated bacteremia in both purged and nonpurged bone marrow recipients. Once-daily vancomycin and tobramycin was safe and effective and, because of the ease of use, facilitates outpatient management of ABMT patients.

FDG PET/CT findings in acute adult mononucleosis mimicking malignant lymphoma

We report a case of acute Epstein–Barr virus (EBV) infection in which the clinical syndrome and pattern of F‐18‐2‐fluoro‐2‐deoxy‐d‐glucose (FDG) uptake mimicked malignant lymphoma. A 53‐yr‐old man presented with 2 wk of high fevers, night sweats, sinus congestion and severe fatigue. The patient was treated for 1 wk with broad‐spectrum antibiotics for acute sinusitis without any improvement. Persistence of fevers and presence of abnormal lymphadenopathy seen on the abdominal computed tomography (CT) were concerning lymphoma with B symptoms. FDG positron emission tomography (PET) showed avid FDG uptake in numerous abdominal/pelvic nodes, liver, spleen and bone marrow. These findings were highly suspicious for lymphoma. Patient underwent a pelvic lymph node biopsy which showed large granular lymphocytes that were predominantly T cells. Bone marrow biopsy showed diffuse infiltration with plasmocytoid cells that were not kappa lambda restricted. Additional diagnostic workup became available showing positive EBV IgM titers and negative IgG levels indicating acute infectious mononucleosis. Lymph node biopsy stained positively with EBV‐encoded RNA. We concluded that patient’s abnormal FDG PET was most likely secondary to acute EBV infection. After 2 months, follow‐up FDG PET/CT showed marked improvement in lymphadenopathy and decreased hypermetabolic activity in the liver and spleen. Other than EBV, there are many other FDG‐avid non‐malignant conditions that may lead to false‐positive PET scans. FDG accumulates in inflamed and infected lesions with increased glucose metabolism. This case underscores the importance of maintaining a broad differential and restricting use of PET scans for staging.

A phase I trial of recombinant human interleukin-1β (OCT-43) following high-dose chemotherapy and autologous bone marrow transplantation

We studied the effects of escalating doses of recombinant human IL-1β in patients receiving high-dose chemotherapy and ABMT for metastatic breast cancer or malignant melanoma. Sixteen patients received IL-1β, 4 to 32 ng/kg/day administered subcutaneously for 7 days beginning 3 h after bone marrow infusion. Three patients at the highest dose level also received G-CSF following completion of IL-1β. All patients completed the 7 days of therapy. The majority of patients experienced chills and fever following one or more injections, and seven had severe pain at the injection site. There was one episode of hypotension and one episode of transient confusion at the highest dose level; other significant toxicity was not identified. Recovery of neutrophils to >0.5 × 109/l and platelet transfusion independence occurred at a median of 23 and 22 days, respectively, which was comparable to historical controls. The mean number of bone marrow colony-forming unit granulocyte–macrophage (CFU-GM) per 105 mononuclear cells on day +21 post-ABMT was more than twice that of control patients or patients receiving G-CSF or GM-CSF. A linear correlation was found between the dose of IL-1β and endogenous concentrations of several cytokines. These patients also displayed significantly higher concentrations of endogenous G-CSF compared to historical controls receiving GM-CSF. While IL-1β was moderately toxic and had no effect on recovery of peripheral blood counts after ABMT, the increased number of bone marrow CFU-GM suggests that the addition of G- or GM-CSF to a short course of IL-1β may accelerate hematologic recovery.

Effects of granulocyte‐macrophage colony stimulating factor produced in Chinese hamster ovary cells (regramostim), Escherichia coli (molgramostim) and yeast (sargramostim) on priming peripheral blood progenitor cells for use with autologous bone marrow after high‐dose chemotherapy

Abstract: Peripheral blood progenitor cells (PBPCs) were collected without prior association with chemotherapy but after the administration of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) produced in Chinese hamster ovary cells (CHO‐GM, regramostim), Escherichia coli (E. coli‐GM, molgramostim), or yeast (Yeast‐GM, sargramostim) and used in conjunction with autologous bone marrow after high‐dose chemotherapy in 69 patients with breast cancer or melanoma. The mean peripheral white blood cell (WBC) counts increased by 2.2 to 2.7‐fold after regramostim, 4.5 to 7.3‐fold after molgramostim and 4.3‐fold after sargramostim. All patients underwent three leukaphereses. The mean (& standard error) total nucleated pheresed cells per kg × 108 were 4.15 & 0.56, 15.10 & 1.77 and 7.24 & 1.00 for patients receiving regramostim, molgramostim or sargramostim respectively. The mean (& standard error) granulocyte‐macrophage colony‐forming units per kg × 104 mobilized into the PB were 8.75 & 3.63, 71.03 & 17.85, and 65.11 & 18.74 for patients receiving regramostim, molgramostim, or sargramostim respectively. The total mean (& standard error) CD34+ cells per kg × 107 collected by three leukaphereses were 3.28 & 1.62, 1.34 & 0.51 and 2.57 & 1.93, for patients receiving regramostim, molgramostim or sargramostim respectively. The use of either molgramostim‐ or sargramostim‐primed PBPCs led to complete elimination of absolute leukopenia with a WBC count under 100/mm3 in 64% and 77% of patients treated, respectively. Patients receiving molgramostim‐primed PBPCs required fewer red blood cells transfusions than patients receiving regramostim‐primed PBPCs (p = 0.0062). Our data indicate that PBPCs collected without prior association with chemotherapy but after either molgramostim or sargramostim with autologous bone marrow support and GM‐CSF shorten the hematopoietic recovery after myeloablative chemotherapy in patients with breast cancer or melanoma.