High-dose hydroxyurea in autologous bone marrow transplantation: a promising "new" agent.

Hydroxyurea is an antineoplastic drug with a broad spectrum of clinical activity and minimal nonhematopoietic toxicity. It potentiates the cytotoxicity of alkylating agents and topoisomerase II active drugs in vitro and in vivo. It is not susceptible to alkylating agent-specific or multidrug-type resistance. We have therefore added high-dose oral hydroxyurea to widely used autologous bone marrow transplantation combination chemotherapy regimens for large cell lymphoma and metastatic breast cancer. Seventeen patients with primary-refractory or refractory-relapse large cell lymphoma received oral hydroxyurea (1.5 g/m2 every 6 hours for 12 doses) added to carmustine/cyclophosphamide/etoposide (BCV). Twelve patients with metastatic breast cancer received the same dose oral hydroxyurea added to cyclophosphamide and thiotepa. Mucositis severe enough to require parenteral narcotics was seen in over half of the patients, but none required intubation for airway maintenance. A thrombotic thrombocytopenic purpura-like hemorrhagic syndrome occurred in six patients and was fatal for three. With the BCV/hydroxyurea regimen, this syndrome was seen with the same frequency as with BCV alone. Death from rapidly progressive disease or toxicity occurred in seven of 29 patients (24%). For patients with 6 months' minimum follow-up, four of 12 (33%) of the metastatic breast cancer patients remain in complete response (median follow-up, 15 months), and four of 17 (24%) refractory large cell lymphoma patients remain in complete response (median follow-up, 10 months). High-dose hydroxyurea may increase the effectiveness of standard autologous bone marrow transplantation regimens without substantially increasing toxicity.

Preferential in-vitro growth and expansion of leukemic T lymphoblasts.

An in-vitro culture system was used to selectively grow malignant cells from the bone marrow of a patient with acute T-lymphoblastic leukemia. Molecular analysis of DNA extracted from the bone marrow cells before culture showed the presence of both rearranged and germ line patterns for the T-cell beta receptor (CTB) gene, and chromosomal analysis revealed the presence of a major and a minor abnormal clone. The cells were cultured in RPMI medium supplemented with 20% fetal calf serum, 2% lymphocyte conditioned medium, L-glutamine and antibiotics. The presence of malignant cells in the cultured population was confirmed by morphologic, molecular probing and cytogenetic analysis. After four weeks in culture, DNA extracted from the cultured cells showed only the rearranged pattern for the CTB gene. Chromosomal analysis of the same cultured sample revealed only the presence of the initially predominant abnormal clone. Shortly thereafter, analysis of fresh uncultured bone marrow cells from the patient in relapse revealed that the same chromosomally abnormal clone also predominated in vivo. Thus, our results demonstrate the selective nature of this culture system and its ability to amplify leukemic T-lymphoblasts. This culture system is also useful for detecting occult malignant cells in histologically normal bone marrow.

Pneumocystis carinii pneumonia complicating multiple myeloma.

Pneumocystis carinii pneumonia complicated the course of two patients with multiple myeloma. The diagnosis was established in both cases by bronchoalveolar lavage, which demonstrated the typical pneumocysts. Clinical and roentgenographic improvement in both patients was observed following a course of trimethoprim-sulfamethoxazole. One patient had lymphocyte subsets performed with a CD4/CD8 ratio of 0.8; both patients were HIV antibody-negative by ELISA. Both patients tolerated prophylactic TMP-SMX given concurrently with the subsequent chemotherapy for myeloma. We suggest that the immune defect seen in multiple myeloma may have placed these patients at risk for opportunistic infections such as P carinii pneumonia; however, as opposed to patients with AIDS, our patients tolerated therapy with TMP-SMZ quite well.

Pulmonary emboli in patients receiving chemotherapy for non-Hodgkin's lymphoma.

Combination chemotherapy has dramatically improved the prognosis of patients with intermediate and high grade histologic subtypes of non-Hodgkin's lymphomas. Treatment-related complications, however, are considerable, and a common problem encountered is respiratory distress or respiratory insufficiency. Usually these difficulties have been attributed to infectious etiologies or to chemotherapy-induced interstitial fibrosis, most often involving bleomycin. We describe five patients presenting with respiratory problems several weeks after the initiation of chemotherapy. These patients, who represent 3 percent of all patients treated with a single bleomycin-containing regimen for intermediate or high grade non-Hodgkin's lymphoma, were all initially thought to have chemotherapy-induced interstitial fibrosis but were found on subsequent evaluation to have pulmonary emboli. Of the three patients in whom pulmonary emboli were diagnosed antemortem, two had symptoms suggestive of pulmonary emboli and all were successfully treated and remained well and free of lymphoma for over 24 months. Two additional patients were diagnosed at autopsy. We suggest that pulmonary emboli may contribute significantly to the morbidity and mortality of patients undergoing chemotherapy for non-Hodgkin's lymphoma and recommend that patients presenting with respiratory difficulties be evaluated for pulmonary emboli.

Phase II pilot study of high-dose busulfan and CY followed by autologous BM or peripheral blood stem cell transplantation in patients with advanced chemosensitive breast cancer.

The combination of busulfan and CY ('BU-CY') has been widely employed as a conditioning regimen for patients undergoing BMT for hematologic malignancies. However, little information is available regarding the utility of BU-CY in treating patients with advanced breast cancer. Fifteen patients with heavily pretreated Stage IIIB or Stage IV chemosensitive breast cancer were treated with busulfan (16 mg/kg) and CY (6000 mg/m2) followed by rescue with autologous BM or autologous peripheral blood stem cells. Toxicity and engraftment parameters were similar to those observed in patients receiving BU-CY for other indications. The overall response rate was 87%, with 53% of patients achieving CR. The median progression-free survival was 164 days, and the median overall survival was 292 days. We conclude that BU-CY is able to induce remissions in a high percentage of patients with heavily pretreated advanced breast cancer. However, remissions are brief, and alternative strategies for patient selection and/or management will be necessary to improve on these results.

Phase I/II study of high-dose cyclophosphamide, etoposide and cisplatin followed by autologous bone marrow or peripheral blood stem cell transplantation in patients with poor prognosis Hodgkin's disease or non-Hodgkin's lymphoma.

We conducted a phase I/II study to determine the efficacy, toxicity and maximum tolerable doses of CY, etoposide and cisplatin (CEP) in the management of patients with relapsed or refractory malignant lymphoma. Thirty patients with relapsed or refractory Hodgkin's disease (n = 10) or non-Hodgkin's lymphoma (n = 20) received CY 6000 mg/m2, etoposide 900-2700 mg/m2 and cisplatin 150 mg/m2 followed by autologous BM or autologous peripheral blood stem cell rescue. The dose of etoposide was escalated after each 3 to 4 patients. The maximum tolerated dose of etoposide, when administered with the indicated doses of CY and cisplatin, was 2400 mg/m2. Three of the 30 patients (10%) died of treatment-related toxicity. Although 14 of the 30 patients had residual bulky and/or chemotherapy-resistant disease at the time of the transplant, 26 patients (87%) responded to this regimen, including 18 patients (60%) who achieved CR and 8 patients (27%) who achieved partial remission. Seven patients (23%) remain alive and free of progression at a median of 21 months post-transplant. Three additional patients relapsed after transplant but are enjoying prolonged disease-free survival at a median of 31 months post-transplant following additional post-transplant therapy. We conclude that high-dose CY, etoposide and cisplatin followed by autologous BM or peripheral blood stem cell rescue is an active and acceptably tolerated regimen in the treatment of relapsed or refractory malignant lymphoma.

The residual mediastinal mass following radiation therapy for Hodgkin's disease.

Thirty-two patients with mediastinal involvement by Hodgkin's disease (HD), treated with an isocentric technique of extended-field radiation therapy (RT) with or without chemotherapy, are described. Twenty-nine patients (91%) had a complete response to therapy and four patients subsequently relapsed, with a median follow-up of 54 months. Five of seven patients not in continuous complete remission were salvaged, with one additional salvage therapy. Ten patients had persistent mediastinal masses at 1 year, following completion of planned therapy; only one of these has had recurrent disease. Of those who achieved complete response, only one patient has had disease recurrence in the mediastinum. We conclude that extended-field RT, using an isocentric technique, provides excellent local disease control in HD; however, persistent mediastinal widening after therapy is frequent, and additional therapy should not be given in the absence of conclusive evidence of disease progression.

Radiation therapy alone versus radiation therapy and chemotherapy in the management of Hodgkin's disease.

Forty-four patients with histologically proven Hodgkin's disease underwent initial treatment with extended-field radiation therapy. Nineteen of these patients also received combination chemotherapy. For analysis, patients were assigned to three treatment groups: group 1 received radiation therapy only (25 patients); group 2 received combination chemotherapy followed by consolidative (low-dose extended-field) radiation therapy; and group 3 was treated with alternate chemotherapy and radiation therapy using the sandwich technique. The actuarial 5-year disease-free survival rates were 83% (group 1), 83% (group 2), and 100% (group 3). The overall actuarial survival rates were 96% (group 1), 92% (group 2), and 100% (group 3). No factor was identified as being of prognostic value in predicting relapse. We conclude that extended-field radiation therapy delivered in this manner is a safe and effective approach to the initial management of Hodgkin's disease.

Effect of low-dose granulocyte-macrophage colony-stimulating factor (LD-GM-CSF) on platelet transfusion-dependent thrombocytopenia.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor known to promote the proliferation and differentiation of precursors of granulocytes and monocytes. GM-CSF at standard doses (125-500 micrograms/m2) alleviates neutropenia secondary to cytotoxic chemotherapy, myelodysplastic syndromes, and aplastic anemia, but has minimal effect on anemia or thrombocytopenia. GM-CSF at doses < 30 micrograms/m2 has been reported to improve platelet counts in some patients exhibiting cytopenia related to hematologic disorders such as aplastic anemia and myelodysplastic syndrome. Low-dose GM-CSF (10-20 micrograms/m2) was evaluated in 20 patients with transfusion-dependent thrombocytopenia persisting after myeloablative cytotoxic chemotherapy or with disease-related cytopenia. Seven patients (35%) responded as defined by a reduction in the platelet transfusion requirements by at least 75%. Low-dose GM-CSF did not significantly increase neutrophil counts or decrease red blood cell transfusion requirements. These results indicate that low-dose GM-CSF has a thrombopoietic effect in about one-third of patients with platelet transfusion-dependent thrombocytopenia which has not been observed at higher doses.

Failure of karyotypic instability to predict clinical progression in patients with dysmyelopoietic syndromes.

Twenty-five patients with leukemia and dysmyelopoietic syndrome underwent serial cytogenetic analysis during the course of their disease. All 21 patients with leukemia had improvement or disappearance of karyotypic abnormalities with effective treatment of their leukemia, and karyotypic progression was observed only in instances of recurrent or progressive leukemia. All four patients with dysmyelopoietic syndrome exhibited karyotypic instability, which was independent of therapeutic interventions or disease progression. The data presented suggest that karyotypic instability in the dysmyelopoietic syndromes may be more common than currently accepted.