Richard Ghalie

Pulmonary complications of bone marrow transplantation: A comparison of total body irradiation and cyclophosphamide to busulfan and cyclophosphamide

PURPOSE To retrospectively compare the acute and long-term pulmonary toxicities of total body irradiation and busulfan in bone marrow transplantation. METHODS AND MATERIALS From March 1984 through February 1991, 144 patients received high-dose therapy with cyclophosphamide plus either total body irradiation (TBI-CY) or busulfan (BU-CY) followed by bone marrow rescue. Treatment protocols were based on disease type. Cyclophosphamide dose was 120-200 mg/kg, given in 2-4 days. Total body irradiation was given as 12 Gy in four fractions over 4 days, or 14.4 Gy in eight fractions over 4 days. Busulfan dose was 16 mg/kg given over 4 days. RESULTS Seventy-nine patients were treated with TBI-CY and 65 patients with BU-CY. More patients in the TBI group had allogeneic transplants (40 vs. 18). Pulmonary events occurred in 48 patients, 19 in BU-CY and 29 in TBI-CY. Of the 58 patients with allogeneic transplants, 21 (36%) developed chronic graft-vs.-host disease (GVHD), and 10 of those patients developed pulmonary complications (including 2 with obliterative bronchitis and 1 with asthma). Interstitial pneumonitis (IP) occurred in 14 patients, 12 in the TBI-CY group and 2 in the BU-CY group. Cytomegalovirus and pneumocystis infections were associated with IP in 11 of those patients. Fatal idiopathic IP occurred in one patient in each of the TBI-CY and BU-CY groups. Multivariate analysis showed that only chronic GVHD and prior bleomycin use were significant predictors of interstitial pneumonitis; no difference was seen between TBI-CY and BU-CY. CONCLUSIONS Pulmonary complications were most commonly associated with GVHD and prior bleomycin use. The incidence of cytomegalovirus or pneumocystis carinii pneumonitis was greater in the patients receiving the TBI regimen; fatal pulmonary complications were not significantly different between TBI and nonTBI regimens.

Cyclosporine monitoring improves graft-versus-host disease prophylaxis after bone marrow transplantation.

OBJECTIVE: The principal objective of this study was to determine whether a relationship exists between trough cyclosporine concentrations measured by HPLC and the development of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation. DESIGN: A retrospective analysis of 59 consecutive human leukocyte antigen-matched bone marrow transplants. Patients received uniform GVHD prophylaxis with cyclosporine and methotrexate. Whole blood trough cyclosporine concentrations were measured at least twice weekly during hospitalization and weekly after discharge. SETTING: A dedicated bone marrow transplant unit in an academic center. MAIN OUTCOME MEASURES: The means of cyclosporine concentrations were assessed for each patient on a weekly basis during the first 50 days after transplant. These means were compared between patients developing grade 2–4 acute GVHD and patients without significant GVHD. RESULTS: Eighteen patients developed acute GVHD at a median of 25 days after bone marrow transplant (range 10–50). There was no correlation between the development of GVHD and patient age, diagnosis, donor age, donor gender, donor-recipient gender mismatch, and time to neutrophil engraftment (> 1000 × 106cells/L). Although mean weekly cyclosporine concentrations were consistently lower in patients developing acute GVHD, the difference in values compared with those of patients with GVHD was not statistically significant. Mean weekly cyclosporine concentrations at the time of neutrophil engrafiment were statistically associated with the development of GVHD. Patients with GVHD had mean ? SD concentrations of 174 ± 69 ng/mL, significantly lower than 254 ± 114 ng/mL in patients without GVHD. Furthermore, the rate of GVHD was 82 percent in patients with mean concentrations <200 ng/mL at the time of neutrophil engrafiment as compared with a rate of 34 percent in patients with concentrations ≥200 ng/mL (relative risk = 2.4). Also, mean cyclosporine concentrations measured during the week of onset of GVHD were significantly lower compared with mean cyclosporine concentrations of all other patients at risk of GVHD during that week. CONCLUSIONS: Cyclosporine concentrations are associated with the development of acute GVHD. Patients with HPLC whole blood concentrations <200 ngl/mL are at significantly higher risk of developing GVHD, particularly if these concentrations are observed during the week of neutrophil engrafirnent. More effective GVHD prophylaxis could be achieved by careful monitoring of cyclosporine concentrations after transplant.

The effect of hepatic enzyme inducers on busulfan neurotoxicity and myelotoxicity

SummaryAnticonvulsants are commonly used empirically to prevent seizures in patients receiving high-dose busulfan in preparation for bone marrow transplantation. This study evaluates the effects of two anticonvulsants with enzyme-inductive properties, phenytoin and phenobarbital, and an enzyme inducer without anticonvulsant properties, Aroclor 1254, on the myelotoxicity and acute neurotoxicity of busulfan in a murine model. To assess the neuroprotective effects of these agents, we studied the effects of a single dose of 100 mg/kg i.p. busulfan, previously shown in this model to be uniformly lethal due to neurotoxicity. A significantly greater proportion of mice survived when pretreated with phenytoin or phenobarbital as compared with Aroclor 1254 pretreatment or an untreated control group. Busulfan myelotoxicity was studied in another group of mice treated with 135–150 mg/kg given in divided doses over 6 days. The proportion of animals surviving the otherwise myeloablative effects of this regimen were significantly improved by Aroclor 1254, high-dose phenytoin, and phenobarbital pretreatment. We conclude that anticonvulsants offer protection from the acute neurotoxicity of busulfan. However, these enzyme-inducing agents may reduce the myelosuppresive effects as well. These results suggest than an inducible enzyme system such as microsomal or glutathione S-transferases plays an important role in busulfan metabolism, warranting concern over concomitant administration of agents that either induce or inhibit these enzymes.

Radiation therapy for carcinoma of the pinna using iridium 192 wires: A series of 70 patients

From January 1970 to November 1982, 70 patients with carcinoma of the pinna were treated by interstitial irradiation. An afterloading technique with Iridium 192 wires was used. One patient recurred and had a total pinnectomy followed by 60 Gy external radiation. This patient was alive without evidence of disease at 134 months. Three patients who had tumors greater than 4 cm in size at presentation developed late necrosis which required subsequent total pinnectomy. Cosmetic results were assessed in 55 patients and were good with few late sequelae (in 78% of cases (36/46) when the tumor measured less than 4 cm, but only in 1/9 when the tumor measured more than 4 cm). We advocate interstitial Iridium 192 irradiation for treatment of pinna tumors smaller than 4 cm. None of 39 patients with squamous cell carcinoma had biopsy proven cervical lymph node metastasis at the time of diagnosis. Four patients with squamous cell carcinoma (4/39: 10%) later developed a regional nodal metastasis after treatment of the pinna. All four relapsed in the parotid region and were managed by partial parotidectomy and neck dissection followed by external irradiation. One of these four patients died from uncontrolled cervical node disease. In our opinion, when regular follow-up is dependable, it is reasonable to save treatment of the cervical nodes for those patients who relapse with involved metastatic cervical nodes.

Prevention of hypermenorrhea with leuprolide in premenopausal women undergoing bone marrow transplantation

We report on the use of leuprolide to prevent heavy menstrual bleeding that often occurs before platelet engraftment in premenopausal women undergoing bone marrow transplantation (BMT). Leuprolide, a synthetic analog of gonadotropin‐releasing hormone (Gn‐RH‐a), was given to 34 patients by intravenous bolus injection, 1 mg daily, until platelet recovery. The median duration of therapy was 50 days (range 16–170). When necessary, patients self‐administered the drug after discharge from the hospital. No adverse effects could be related directly to the use of leuprolide. Leuprolide effectively prevented menstruation in 25 patients (73%), failed in seven (21%), and two patients were not evaluable. The success of leuprolide therapy was related to the time of onset of treatment, as anticipated from the gradual effect of Gn‐RH‐a on the menstrual cycle. The failure rate was only 6% (one of 16 patients) when leuprolide was started at least 2 weeks prior to the development of thrombocytopenia, compared to a failure rate of 33% (six of 18 patients) when leuprolide was started at a later time. We conclude that leuprolide as a single agent is a safe and effective method to prevent menstrual bleeding during BMT. Additional studies are needed to determine the best timing for the onset of therapy and the relative benefit of leuprolide compared to other prophylactic approaches in patients with lengthy thrombocytopenia.

A dose-escalation phase IIa study of 2,2-dimethylbutyrate (HQK-1001), an oral fetal globin inducer, in sickle cell disease

2,2‐dimethylbutyrate (HQK‐1001), an orally‐bioavailable promoter‐targeted fetal globin gene‐inducing agent, was evaluated in an open‐label, randomized dose‐escalation study in 52 subjects with hemoglobin SS or S/β0 thalassemia. HQK‐1001 was administered daily for 26 weeks at 30 mg/kg (n = 15), 40 mg/kg (n = 18) and 50 mg/kg (n = 19), either alone (n = 21) or with hydroxyurea (n = 31). The most common drug‐related adverse events were usually mild or moderate and reversible. Gastritis was graded as severe in three subjects at 40 mg/kg and was considered the dose‐limiting toxicity. Subsequently all subjects were switched to the maximum tolerated dose of 30 mg/kg. Due to early discontinuations for blood transfusions, adverse events or non‐compliance, only 25 subjects (48%) completed the study. Drug plasma concentrations were sustained above targeted levels at 30 mg/kg. Increases in fetal hemoglobin (Hb F) were observed in 42 subjects (80%), and 12 (23%) had increases ≥4%. The mean increase in Hb F was 2% [95% confidence interval (CI), 0.8–3.2%] in 21 subjects receiving HQK‐1001 alone and 2.7% (95% CI, 1.7–3.8%) in 31 subjects receiving HQK‐1001 plus hydroxyurea. Total hemoglobin increased by a mean of 0.65 g/dL (95% CI, 0.5–1.0 g/dL), and 13 subjects (25%) had increases ≥1 g/dL. Future studies are warranted to evaluate the therapeutic potential of HQK‐1001 in sickle cell disease. Am. J. Heamtol. 88:E255–E260, 2013.

Successful pregnancy in a bone marrow transplant recipient following oocyte donation

SummaryWe describe the successful establishment of pregnancy in a woman status post-bone marrow transplantation using assisted reproduction. Oocyte donation offers women with gonadal failure secondary to cytotoxic agents a reasonable chance at childbearing.

Anticonvulsants and Busulfan

Excerpt To the Editor:Two recent letters (1, 2) described the use of anticonvulsants to prevent seizures secondary to high-dose busulfan therapy as a preparative regimen for bone marrow transplanta...

Patterns of failure following bone marrow transplantation for metastatic breast cancer: The role of consolidative local therapy

PURPOSE The purpose of this analysis is to evaluate the patterns of failure and the role of local therapy in conjunction with bone marrow transplantation (BMT) for metastatic or recurrent breast cancer. METHODS AND MATERIALS Between June 1986 and November 1991, 46 patients with hormone unresponsive metastatic or recurrent breast cancer underwent high dose chemotherapy (HDC) with hematopoietic stem cell support. The most commonly used preparative regimen consisted of thiotepa (750 mg/m2), cisplatin (150 mg/m2), and cyclophosphamide (120 mg/kg) followed by autologous BMT. Consolidative surgery or irradiation was considered in patients whose cancer responded to BMT and had localized sites of disease. RESULTS Six patients (13%) died of BMT-related complications. Of the remaining 40 patients, 22 were candidates for consolidative therapy, and 18 of those patients received consolidative irradiation (17 patients) or surgery (1 patient) to one or more sites. At median follow-up of 27 months (range, 20-78), 12 of 18 (67%) patients have continuous local control at the 22 consolidated sites (1 of 4 controlled at chest wall sites, 7 of 8 at regional nodal sites, 7 of 7 at localized bone sites, and 1 of 3 at lung/mediastinal sites). Toxicity of consolidative irradiation was mainly limited to myelosuppression in 6 of 17 patients. Two patients did not complete the consolidative local therapy, one because of hematologic toxicity and one because of rapid systemic tumor progression during treatment. CONCLUSION In patients with localized areas of extravisceral metastases, consolidative irradiation is feasible with acceptable hematologic toxicity. Consolidative irradiation can result in continuous local control, especially in isolated bone metastases and in regional nodal sites; however, the advantage is less clear in patients undergoing consolidative irradiation for chest wall failures. Because distant visceral metastases still remain a major site of failure after this HDC regimen, a more effective systemic therapy is needed. Consolidative local treatment should be considered in future HDC/BMT protocols for metastatic breast cancer, especially in localized nodal and osseous sites.