HEMATOLOGY AND HEMATOLOGIC MALIGNANCIES

The goals of the program in hematology and hematologic malignancies are to develop clinical research studies that define therapy for the diverse subtypes and stages of hematologic diseases and to apply knowledge from the laboratory to new therapeutic regimens.

A novel clinical approach to early stage Hodgkin's Disease has been developed in collaboration with the Department of Radiation Oncology. After clinical staging, patients receive therapy based on the probability that they have more extensive disease; exploratory laparotomy is not performed. Those patients with a low likelihood of having more extensive disease receive hyperfractionated radiation therapy. Those more likely to have advanced stage disease or to relapse after radiotherapy alone receive combined modality therapy with a chemotherapy regimen designed to limit long-term complications with localized radiation therapy. For newly diagnosed patients with more advanced disease, we participate in Eastern Cooperative Oncology Group (ECOG) studies. For patients with relapsed disease we continue to accrue to a protocol based on continuous infusion chemotherapy.

Patients with newly diagnosed low grade or indolent Non-Hodgkin's Lymphoma (NHL) are offered the ECOG Phase III trial of two different chemotherapy regimens, followed by observation or monoclonal antibody therapy. For patients with relapsed low grade or indolent NHL, several studies are available. One study, also open to the Fox Chase Network, examines the efficacy of a treatment regimen in which the nucleoside analogue, fludarabine, which is known to be active in these patients, alternates with alpha-interferon. Preliminary analysis suggests that, while response rates may not be improved, the potential for prolonged response duration will require longer follow-up. For patients on this study whose lymphoma cells have the t(14,18) chromosome translocation, serial blood and bone marrow samples will be studied for the presence of residual cells by a sensitive PCR method. We also participated in the studies utilizing rituximab, a humanized mouse monoclonal antibody to CD20, a protein expressed on most B cells including B cell lymphomas, or a yttrium-labeled anti-CD20 to treat relapsed or refractory low grade NHL. These studies led to the recent approval of this first therapeutic monoclonal antibody treatment for malignant disease.

For patients with aggressive NHL who have not received prior therapy, current standard therapy outside of a research protocol is the cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) regimen. For such patients under the physiologic age of 65 who have pre-treatment prognostic factors that predict a poor outcome, we activated our own phase II study in which patients with relapsed aggressive NHL are offered a protocol of sequential high-dose chemotherapy followed by stem cell support. A chemotherapy protocol of estramustine plus paclitaxel, based on our pre-clinical data, is used both at Fox Chase and its Network hospitals for the treatment of patients with relapsed aggressive NHL who are not candidates for high-dose therapy.

Interleukin-6 (IL-6) is the major growth factor for myeloma cells. It had been reported that retinoids down-regulate IL-6 receptor (IL-6R) expression. Clinical trials were disappointing, however, leading to exacerbation of disease due to compensatory IL-6 up-regulation. We hypothesized that dexamethasone, a drug that suppresses IL-6 expression and is active in myeloma, might prevent the exacerbation of the disease by retinoids and might be synergistic with retinoids by blocking IL-6/IL-6R signaling at two points. In vitro data confirmed that the combination of these two agents was more active than either one alone. Based on the pre-clinical data, a trial is now open at Fox Chase and its Network hospitals in which patients are treated with dexamethasone plus 13-cis-retinoic acid (Accutane); preliminary analysis has shown responses in 8 of 12 patients (67%). Furthermore, no patients worsened, in contrast to the hypercalcemia induced by retinoic acid alone. Patients with relapsed disease are offered a trial examining whether blockade of the multidrug-resistance pump enhances chemotherapy efficacy.

The nucleoside analog, fludarabine, is active in patients with chronic lymphocytic leukemia. Relapsed patients are now treated on a protocol using gemcitabine, a related nucleoside analog, with lymphocyte samples analyzed for induction of apoptosis.

We are collaborating with the Department of Nuclear Magnetic Resonance and Medical Spectroscopy to determine: 1) whether the sensitivity and specificity of bone marrow imaging in patients with lymphoma is such that imaging can add to bone marrow histopathology for diagnostic staging of lymphoma, and 2) whether the spectroscopy characteristics of lymphomas pre- and post-treatment can be used as a potential early indicator of which patients are going to respond to therapy.

Studies incorporating prospective assessment of plasma markers of in vivo thrombin generation (prothrombin fragment F1+2 and thrombin-antithrombin complexes) in cancer patients with thrombotic complications are being set up in collaboration with investigators at Temple University Medical School. Efforts are also underway to initiate clinical trials using Low-Molecular-Weight Heparin in subsets of cancer patients with thrombosis. This is based on recent data that, in cancer patients with thrombosis, overall mortality is improved in patients who receive low molecular weight heparin as compared with conventional anticoagulation.

During the past year, the Peripheral Blood Stem Cell Program completed a Phase I trial of high dose carboplatin, paclitaxel, and topotecan, primarily in patients with poor prognosis ovarian cancer. This trial demonstrated that, with the support of peripheral blood stem cells, doses far exceeding those normally tolerated could be given without significant hematologic toxicity. Four cycles of this combination can be safely administered. At the same time, pharmacokinetic analyses were performed to validate the use of pharmacologic-based dosing of carboplatin. Based on the data from this phase I trial, a study is now open for patients with extensive small cell lung. Based on our phase I trial, the Gynecologic Oncology Group has opened a limited institution pilot study using high-dose carboplatin, paclitaxel, and topotecan in multiple cycles as front-line therapy for optimally debulked patients with stage III ovarian cancer; Fox Chase is one of four participating institutions. We also have opened a similar trial at the Center for patients with suboptimally debulked ovarian cancer. It is expected that we will become an accredited Foundation for the Accreditation of Hematopoietic Cell Therapy and ECOG approved stem cell center.

Leukemias and lymphomas often show characteristic cytogenetic abnormalities that have a pathogenetic role in malignancy. In theory, these chromosomal rearrangements provide tumor-specific targets for therapy. Low-grade NHL patients are incurable by current chemotherapy. Most follicular low grade NHL are characterized by the chromosomal rearrangement t(14,18), which juxtaposes the B Cell Lymphoma-2 (bcl-2) gene with a portion of the immunoglobulin (Ig) heavy chain gene. Since aberrant regulation of bcl-2 expression plays a role in lymphomagenesis, we hypothesize that down-regulation of bcl-2 might be therapeutic. Laboratory data a short antisense synthetic DNA oligonucleotide (AS-ODN) to bcl-2, can inhibit growth of a cell line carrying this translocation; this is not lymphoma-specific. We have further shown that antisense oligonucleotides targeted to the immunoglobulin sequences that are fused to bcl-2 also inhibits growth of this t(14,18)-positive cell line. This AS-ODN down-regulates bcl-2 protein and induces apoptosis of these cells. This oligonucleotide may be t(14;18) lymphoma-specific. We have shown that this AS-ODN targeted to Ig sequences of the bcl-2/Ig fusion RNA prolongs survival of severe combined immunodeficient (scid) mice injected with these human lymphoma cells by reducing bcl-2 expression and inducing apoptosis. Studies combining AS-ODN with chemotherapy are in progress.

AL-KATIB, A.M., KAMANDA, W.S., HAMDAN, M., CHELLADURAI, B., MOHAMMAD, R.M. Bryostatin 1 down-regulates mdr1 and potentiates vincristine cytotoxicity in diffuse large cell lymphoma xenografts. Clin. Cancer Res. 4:1305-1314, 1998.

SCHILDER, R.J., JOHNSON, S., GALLO, J. Phase I trial of multiple cycles of high dose chemotherapy supported by autologous peripheral blood stem cells. J. Clin. Oncol. (in press).

SMITH, M.R., XIE, T., JOSHI, I., SCHILDER, R.J. Dexamethasone plus retinoids decrease IL-6/IL-6 receptor and induce apoptosis in myeloma cells. Br. J. Hematol. 102:1090-097, 1998.

YOUNG, N.A., AL-SALEEM, T.I., EHYA, H., SMITH, M.R. Utilization of fine-needle aspiration cytology and flow cytometry in the diagnosis and subclassification of primary and recurrent lymphoma. Cancer (Cancer Cytopathol.) 84:252-61, 1998.

BOENTE, M., SCHILDER, R.J., OZOLS, R.F. Gynecologic malignancies. In Cancer Chemotherapy and Biological Response Modifiers, edited by H.M. Pinedo, D.O. Longo, B.S. Chabner. Elsevier, Amsterdam, Netherlands, Volume 17 (in press).

SCHILDER, J.R., SHEA, T.C. Multiple cycles of high dose chemotherapy for ovarian cancer. Semin. Oncol. 25(3):349-355, 1998.

^§   Fox Chase researcher

^a   S. Kindsfather: Present address--408 Bellevue Avenue, Trenton, NJ 08618

Illustrations or unpublished data in these reports should not be used without permission of the author.

Fox Chase Cancer Center

Scientific Report 1998