David Topolsky

High-dose cyclophosphamide without stem-cell rescue for refractory CIDP

Four patients with chronic inflammatory demyelinating polyneuropathy (CIDP) who were refractory to conventional treatment were treated with high-dose cyclophosphamide (200 mg/kg over 4 days). All improved in functional status and muscle strength. Nerve conduction studies improved in three of four. Other immunomodulatory medications have been discontinued. High-dose cyclophosphamide can be given safely to patients with CIDP and patients with disease persistence after standard therapy may have a response that lasts for over 3 years and results in long-term disease remission.

Autologous stem cell transplantation for acute myeloid leukemia in first remission

We studied the feasibility, toxicity, and efficacy of a 2-step approach to autologous stem cell transplantation for patients with acute myeloid leukemia in first remission. Step 1 consisted of consolidation chemotherapy including cytarabine 2000 mg/m2 twice daily for 4 days concurrent with etoposide 40 mg/kg by continuous infusion over 4 days. During the recovery from this chemotherapy, peripheral blood stem cells were collected under granulocyte colony-stimulating factor stimulation. Step 2, autologous stem cell transplantation, involved the preparative regimen of busulfan 16 mg/kg followed by etoposide 60 mg/kg and reinfusion of unpurged peripheral blood stem cells. A total of 128 patients were treated. During step 1, there was 1 treatment-related death. A median CD34+ cell dose of 14 (x10(6)/kg) was collected in 3 aphereses. Ten patients suffered relapse before transplantation, and 117 patients (91%) proceeded to transplantation. During step 2, there were 2 treatment-related deaths, and 35 patients subsequently suffered relapse. With median follow-up of 30 months, 5-year disease-free survival for all patients entered in the study is projected to be 55%. By cytogenetic risk group, 5-year disease-free survival is 73% for favorable-risk patients, 51% for intermediate-risk patients, and 0% for poor-risk patients. We conclude that this 2-step approach to autologous transplantation produces excellent stem cell yields and allows a high percentage of patients to receive the intended therapy. Preliminary efficacy analysis is very encouraging, with outcomes that appear superior to those of conventional chemotherapy.

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.

High‐Dose Cyclophosphamide in the Treatment of Multiple Sclerosis

High dose cyclophosphamide (HDC) has been successfully used for the treatment of a variety of autoimmune diseases. In this study, we sought to determine whether the use of high dose cyclophosphamide provided stabilization of relapsing remitting MS (RRMS), secondary progressive MS (SPMS), or primary progressive MS (PPMS). The parameters evaluated were EDSS scores, lesion load and brain volumes by MRI and frequency of relapses. Twenty‐three patients underwent immunoablative therapy with HDC and were followed for 3.5 years. Nine were relapsing remitting (RRMS), 11 secondary progressive (SPMS), and 3 primary progressive (PPMS). Four of 9 RRMS have had no clinical progression up to 3.5 years following treatment. Three of 9 patients maintained a normal neurologic examination with improved EDSS scores. Seven of the nine RRMS patients had reduction in flare frequency which was maintained for 3.5 years following treatment or no immunomodulating agents. Subgroup analysis in the RRMS patients of lesion load and brain parenchymal volume revealed a favorable trend in these parameters which did not reach statistical significance. The treatment was generally ineffective for SPMS and failed in the 2 PPMS patients. HDC was well tolerated, demonstrated a good safety profile and had minimal adverse effects. These results along with previous reports suggest that early use of HDC therapy in RRMS is promising.

Bronchiolitis obliterans after bone marrow transplantation : the effect of preconditioning

While half of all patients receiving bone marrow transplantation (BMT) for malignancies and related diseases may achieve prolonged disease-free survival, 2-10% of patients undergoing allogeneic transplantation develop bronchiolitis obliterans (BrOb). We have hypothesized that total body irradiation (TBI) which has been used for pretreatment may influence the subsequent development of BrOb in patients undergoing allogeneic BMT. Since 1976, we have treated 104 patients undergoing allogeneic BMT with non-TBI preconditioning. Of 60 patients that survived and were evaluable for chronic graft versus host disease (GVHD) 26 developed chronic GVHD (43%). Four of 104 patients (3.9%) developed BrOb by clinical and/or pathologic findings. Four of 4 patients (100%) with BrOb had chronic GVHD. Two of these 4 patients (50%) were alive at the end of 2 years. These data demonstrate that chronic GVHD is a risk factor for BrOb in patients receiving non-TBI preconditioning regimens. The similar incidence of BrOb in this population compared to other studies using TBI suggest that the preconditioning regimen is not a factor in the development of BrOb. Further study is needed to confirm these findings. Allogeneic bone marrow transplantation (BMT) has revolutionized the therapeutic approach toward acute and chronic leukemias, aplastic anemia and rare immunodeficiency disorders. Half of all patients that undergo BMT achieve long-term disease-free survival but a similar number develop significant complications [1].(ABSTRACT TRUNCATED AT 250 WORDS)

Late Mortality and Relapse following BuCy2 and HLA-Identical Sibling Marrow Transplantation for Chronic Myelogenous Leukemia

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only known curative therapy for chronic myelogenous leukemia (CML). Failure, because of relapse or nonrelapse mortality (NRM), generally occurs within 3 years of transplantation, but large studies with long-term follow-up are limited. We present mature results in 335 patients with CML who underwent allogeneic bone marrow transplantation (BMT) from HLA-identical siblings following busulfan and cyclophosphamide (BU/Cy2). Two hundred twenty-nine were in chronic phase (CP) and 106 in accelerated or blastic phase at transplantation. Median follow-up exceeded 14 years. The estimated probability of 18-year leukemia-free survival (LFS) for CP patients was 55.6% and for those beyond CP, 10.5%. Of 182 patients who survived leukemia-free at 3 years, the estimated probability of LFS at 18 years was 61.9%. Late relapse (P = .039) and late NRM (P = .008) occurred at higher rates in patients beyond CP at transplantation. There was no plateau in LFS.

Arterial occlusions as a presenting feature of acute promyelocytic leukemia.

Arterial thrombosis as a presentation of acute promyelocytic leukemia is uncommon. The authors report a patient who presented with a clot in the left external iliac artery and pulmonary emboli. The literature is reviewed.

Ulcerative balanoposthitis of the foreskin as a manifestation of chronic lymphocytic leukemia: case report and review of the literature

Ulcerative lesions of the penis have many possible etiologies, including infectious, neoplastic, traumatic, drug-induced, and autoimmune. Although the most frequent neoplasm presenting as an ulcerative penile lesion is squamous cell carcinoma, it may rarely be a manifestation of other malignancies, including those of hematolymphoid origin. We report a case of ulcerative balanoposthitis as a manifestation of chronic lymphocytic leukemia. Chronic lymphocytic leukemia and other hematolymphoid malignancies should be considered in the large differential diagnosis of nonhealing penile ulcers.

Extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-α therapy

We report the previously undescribed occurrence of extramedullary blast crisis in a patient with chronic myelogenous leukemia in complete cytogenetic and molecular remission on interferon-alpha. Development of bilateral testicular swelling prompted a biopsy showing stromal infiltration with CD20 and TdT positive immature cells. On repeated examinations, the bone marrow remained BCR/ABL negative by RT-PCR analysis. However, the cerebrospinal fluid (CSF) contained atypical lymphocytes positive for the P210 BCR-ABL product. Following treatment with testicular irradiation, intrathecal methotrexate, systemic chemotherapy and an unrelated donor transplant, the patient showed no evidence of disease until 9 months post-transplant, when he relapsed in lymphoid blast crisis in both bone marrow and CSF.

Use of granulocyte colony-stimulating factor after high-dose chemotherapy and autologous peripheral blood stem cell transplantation : What is the optimal timing?

Administration of granulocyte colony-stimulating factor to patients undergoing high-dose chemotherapy and autologous peripheral blood stem cell transplantation accelerates neutrophil recovery and decreases hospitalization time. The optimal timing for granulocyte colony-stimulating factor infusion remains unknown. In this retrospective, case-controlled, two-armed study, we reviewed our experience at Hahnemann University Hospital to determine whether initiating granulocyte colony-stimulating factor infusions on posttransplant day 0 versus day 8 affects neutrophil recovery time, posttransplant discharge date, total hospital days after high-dose chemotherapy, and autologous peripheral blood stem cell transplantation. All patients hospitalized between 1994 and 1998 at Hahnemann University Hospital, Bone Marrow Transplantation Unit with breast cancer or non-Hodgkin’s lymphoma, who underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation and received granulocyte colony-stimulating factor either on posttransplant day 0 (16 patients) or day 8 (16 patients). The day 0 and day 8 groups had no statistically significant differences in age, sex, weight, height, body surface area, disease characteristics, pretransplant harvesting or conditioning regimens, or transplant CD34+ cell counts. Our main outcome measure was the mean time to reach absolute neutrophil count greater than or equal to 0.5 × 109/l, the number of hospital days after transplant, and the total hospital days. The mean days to neutrophil recovery (10.56 versus 9.68, p = 0.48), posttransplant hospital days (13.62 versus 12.81, p = 0.39), and total hospital days (20.25 versus 20.25, p = 1.00) were not significantly different between day 8 and day 0 groups, respectively. No significant effects on neutrophil recovery time, posttransplant hospital days, or total hospital days were observed with the initial granulocyte colony-stimulating factor infusion on day 0 versus day 8 after transplant. Delayed administration may allow substantial cost savings (US