We investigated the antitumor activity and toxicity of cisplatin and interferon-α2B as the primary treatment of penile carcinoma. A total of 13 consecutive patients with nonmetastatic, histologically confirmed invasive squamous cell carcinoma of the penis underwent treatment consisting of 20 mg./m.2 cisplatin intravenously and 5 x 106 μ./m.2 interferon-α2B subcutaneously daily for 5 consecutive days. An equivalent dose of interferon was then administered subcutaneously every 2 days for 3 weeks and the regimen was repeated at 28-day intervals. Of 12 evaluable patients 9 responded: 4 achieved a pathologically confirmed complete remission of 38+, 21+, 10 and 7 months in duration (2 with relapse were treated with local therapy and remain with no evidence of disease), and 5 achieved a partial response, underwent surgical removal of residual disease and remained disease-free for 14+ to 24+ months. The most significant toxicities were anemia in 5 patients and reversible renal impairment in 3 but no patient had neutropenic fever or required platelet transfusion. We conclude that primary treatment with cisplatin and interferon-α2B induced responses in 75% of 12 patients with penile carcinoma and allowed for a less radical operation than originally scheduled. A larger number of patients and longer followup will be required to confirm these encouraging preliminary results.

Fludarabine is the most active single agent that has been studied in CLL. The response rate for both previously untreated and previously treated patients is higher than combinations that have been studied. Myelosuppression is dose-limiting with substantial evidence of suppression of normal T- lymphocytes, both in patients receiving fludarabine as a single agent and in patients being treated with fludarabine plus prednisone. Along with the myelosuppression noted in advanced stage disease, infections are the most common complication with many of the infections being associated with T-cell immunodeficiency rather than the more traditional characteristics of neutropenia and hypogammaglobulinemia. Comparative clinical trials are being conducted in Europe with a cyclophosphamide, doxorubicin, prednisone regimen in previously untreated and previously treated patients. In the United States, previously untreated patients are being entered in a trial comparing fludarabine with chlorambucil alone or the combination of fludarabine and chlorambucil. The eventual contribution of fludarabine to the management of chronic lymphocytic leukemia awaits the conclusion of these clinical trials.

Between 1980 and 1988, 126 patients with leukemia were treated with piperazinedione and fractionated total body irradiation (TBI) followed by allogeneic bone marrow transplantation from HLA matched siblings. Sixty‐one patients had acute myelogenous leukemia, 46 acute lymphoblastic leukemia, and 19 chronic myelogenous leukemia. Patients with acute leukemia in first complete remission were transplanted only if perceived to have a low probability of remaining in remission with conventional therapy. The toxicity from the preparative regimen was similar to that of cyclophosphamide and TBI except that none of the patients in the study had hemorrhagic cystitis or veno‐occlusive disease. After a median follow up of 114 months, 29 patients (23%) are still alive without relapse. The survival of patients with acute myelogenous or lymphoblastic leukemia transplanted in their first remission were 35% and 43%, respectively. The survival of patients transplanted in their first chronic phase of chronic myelogenous leukemia was 60%. The results of this preparative regimen are comparable to those of cyclophosphamide and TBI. © 1994 Wiley‐Liss, Inc. Copyright © 1994 Wiley‐Liss, Inc., A Wiley Company

The major clinical experience with fludarabine has been obtained in patients with chronic lymphocytic leukemia (CLL). In the initial studies in previously treated patients with CLL, the complete and partial response rate (CR + PR) was over 50% and in previously untreated patients with CLL, a CR + PR rate of 75-80% was noted with or without the addition of prednisone. Subsequent clinical trials have also demonstrated major activity with fludarabine in Waldenstrom's macroglobulinemia. Fludarabine was noted to be an active agent in indolent lymphoma in phase I/II studies. Approximately 60% of patients with follicular lymphoma respond to fludarabine when it is administered as a single agent. Many of these remissions are complete remissions despite patients having received extensive prior therapy. Combination programs are being developed for application in CLL and indolent lymphoma. Because of the activity of fludarabine in inhibiting DNA repair, it has been combined with cisplatinum and cytosine arabinoside and plans are in place to explore the radiation sensitizing effect of fludarabine in clinical trials. A combination of fludarabine plus ara-C is now being used in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) and a combination of fludarabine, ara-C, and G-CSF (FLAG) has been combined with idarubicin for the management of these conditions. Many of these activities of fludarabine are associated with its interaction with many enzymes which are important in DNA and RNA metabolism and in DNA repair. It is anticipated that these actions will be explored in a wider range of studies subsequently. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Background: Fludarabine monophosphate and 2Chlorodeoxyadenosine are nucleoside analogues with activity against Waldenström macroglobulinemia. However, it is not clear whether prior exposure to one analogue precludes response to the other compound. Patients and methods: Fourteen patients with Waldenström's macroglobulinemia and prior exposure to fludarabine were treated with two courses of 2chlorodeoxyadenosine. Results: Three out of four patients that had previously responded to fludarabine and were relapsing from unmaintained remission, achieved a partial response with 2chlorodeoxyadenosine therapy. However, only one out of 10 patients with disease resistant to fludarabine responded to 2chlorodeoxyadenosine. Conclusions: 2chlorodeoxyadenosine may be effective in patients with Waldenström macroglobulinemia sensitive to fludarabine. However, this compound has limited activity for patients with disease resistant to fludarabine. © 1994 Kluwer Academic Publishers.

The utility of myeloablative therapy supported by autologous bone marrow (BM) or blood progenitor cells was assessed in 49 patients with multiple myeloma who had received at least 1 year of prior chemotherapy. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients with disease in resistant relapse despite treatment with vincristine-doxorobucin by continuous infusion with pulse dexamethasone (VAD), a 61% response rate was associated with a median remission time of 5 months. After primary resistance for more than 1 year, 6 of 15 patients responded and the overall survival was similar to that of control patients. For patients with melphalan-resistant disease that responded to VAD, the remission time was similar to that of control patients. Current myeloablative treatments supported by autologous BM or blood stem cells were useful to very few patients with multiple myeloma after the first year of chemotherapy.

Among 750 previously untreated patients with multiple myeloma, 27 (4%) presented with plasma cell leukaemia. All but one patient had high tumour mass and, when compared with comparable patients without leukaemia, more frequent extraosseous involvement, thrombocytopenia, high serum lactate dehydrogenase and hypodiploid plasma cells. Most patients also had complex cytogenetic abnormalities. Treatment with standard melphalan-prednisone was ineffective, with a median survival of 2 months, but more intensive chemotherapy induced responses in approxirnately one-half of the patients, with a median survival of 20 months. Primary plasma cell leukaemia usually results from the proliferation and extramedullary expansion of immature plasma cells and requires prompt and intensive chemotherapy.

Cis-platinum-based chemotherapy combinations have improved the outcome of patients with metastatic urothelial tumors, since two-thirds of these patients respond to treatment. Nevertheless, the majority of such patients have relapse within a median of 12 months. To define the pattern of failure and subsequent outcome, we retrospectively assessed 58 consecutive patients with relapse after prior response to cis-platinum-based combination chemotherapy. Of the patients who presented initially with local-regional metastases, 74% had relapse with involvement of a similar site, while only 26% of these patients had visceral metastases at relapse. The median survival after relapse was 9 months, and parameters associated with longer survival were local-regional relapse (10.7 months) and response to salvage chemotherapy (12.6 months). These data suggest that select patients with urothelial tumors and local-regional metastases may benefit from consolidation therapy with surgery or radiotherapy after maximum response to chemotherapy.

This study assessed the feasibility and effect of blood progenitors as the only source of haemopoietic support for myeloablative therapy for patients with primary resistant multiple myeloma and markedly infiltrated bone marrow. 17 patients with advanced, primary resistant myeloma received a priming regimen of cyclophosphamide (3 g/m2) and etoposide (900 mg/m2) with GM-CSF. During haematological recovery, at least 2 x 106 CD34+ mononuclear cells/ kg were collected from each patient with 4-12 leukaphereses. High-dose chemotherapy was then given which consisted of thiotepa (750 mg/m2), busulfan (10 mg/kg) and cyclophosphamide (120 mg/kg) followed by reinfusion of the blood progenitors. Haemopoietic reconstitution was rapid with recovery of granulocytes to >1.0 x 109/l after a median of 10 d and of platelets to 50 x 109/l after a median of 29 d. The myeloma responded in 10/17 patients for a projected median duration of at least 12 months. Survival was prolonged significantly in comparison with the outcome of control patients who did not receive intensive treatment. Blood progenitors, assessed from the number of CD34+ cells, produced early haemopoietic recovery after myeloablative therapy that induced sustained control of advanced and resistant multiple myeloma.

Regression of low-grade B cell gastric lymphoma of mucosa-associated lymphoid tissue after eradication of Helicobacter pylori with antibiotic therapy was recently shown in a small number of patients with low-volume tumors. A patient with a > 10 cm nodular gastric mucosa-associated lymphoid tissue lymphoma that caused hematemesis and weight loss is described. Antibiotic therapy of H. pylori resulted in full clinical recovery and resolution of the mass lesion and morphological features of lymphoma on routine histological examination. However, monotypic immunostaining of plasma cells persisted in a separate and grossly normal-appearing region of the stomach. Antibiotic therapy may be of benefit in patients with mucosa-associated lymphoid tissue lymphoma with mass lesions and significant signs and symptoms, but periodic search for residual lymphoma is needed. © 1994.

Few effective regimens are available for patients with advanced multiple myeloma resistant to alkylating agents and VAD. We treated 65 patients with advanced and refractory multiple myeloma with the combination of cyclophosphamide (3.0 gm/m2) and etoposide (900 mg/m2) followed by GM-CSF at a daily dose of 0.125 mg/m. Thirty-five percent of patients responded with a 6% mortality rate. After a median of 2 months, 16 patients received myeloablative treatment supported by autologous bone marrow or blood stem cells. Four of ten previously resistant patients responded so that the overall response rate was 42% The median survival for all patients was 10 months and the median remission was 8 months. The median survival for patients with both low serum lactate dehydrogenase and B2 microglobulin, or for those who received myeloablative treatment, was projected at 18 months. Our combination of cyclophosphamide and etoposide provided an effective rescue treatment for many patients with advanced multiple myeloma resistant to conventional therapies. This program allowed early blood stem cell collection in support of subsequent myeloablative therapy for selected patients. © 1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

One hundred twenty-seven adults with advanced hematologic malignancies received thiotepa 450-750 mg/m2, busulfan 10 or 12 mg/kg, and cyclophosphamide 120 or 150 mg/kg as a preparative regimen for autologous (86 patients) or allogeneic (41 patients) marrow transplantation. Early regimen-related toxicity (RRT) was scored according to the Seattle toxicity grading system. Grade 1-4 RRT occurred in 94% of the patients. Grade 3-4 RRT was noted in 19 patients (9% of the autologous and 27% of the allogeneic marrow recipients) and included 6% hepatic, 5% pulmonary, 3% renal, 2% mucosal, 2% bladder, 2% cardiac, and 1% CNS toxicity at the grade 3 or 4 level. No patient experienced life-threatening or fatal gastrointestinal or cutaneous toxicity. A stepwise logistic regression analysis suggested that the higher busulfan dose, Zubrod performance status of 2 or 3, and ten or more previous cycles of chemotherapy were factors predictive of grade 3-4 RRT. The regimen-related mortality for all patients was 8% (95% Cl 4-14%). The incidence and spectrum of RRT for this novel drug combination are similar to those reported for the standard preparative regimens. Heavily pretreated patients with poor performance status receiving the higher busulfan dose have a higher incidence of severe or fatal RRT. © 1994 Springer-Verlag.

The value of early myeloablative therapy supported by autologous bone marrow or blood progenitor cells was assessed in 72 patients with multiple myeloma who were treated within 1 year of initial therapy. Forty-five patients were consolidated during remission, and 27 patients were treated for primary refractory disease. Outcomes were compared with those of similar patients who did not receive intensive treatment primarily for socioeconomic reasons. Among patients who had responded previously, myeloablative therapy increased the rate of complete remission from 5% to 45% (P < .01) but did not prolong progression-free intervals or survival times. The same treatment controlled the myeloma in 70% of patients with primary resistant disease and prolonged the median survival from 37 to 83 months (P = .03). Intensive treatment for primary resistant myeloma administered later in the disease course resulted in significantly lower response rates and shorter progression-free intervals. Current myeloablative regimens supported by autologous stem cells appeared useful primarily in patients with primary resistant disease during the first year of therapy.

Objective: To determine the following: a reference range for serum calcitriol during hypercalcemia in a control group of patients with myeloma in whom calcitriol production is known to be appropriately suppressed; the incidence of elevated serum calcitriol levels in hypercalcemic patients with non-Hodgkin lymphoma according to this derived reference range; and the incidence of abnormal calcium metabolism in normocalcemia patients with non-Hodgkin lymphoma. Design: Prospective clinical study. Setting: Referral cancer center. Patients: 2 groups of hypercalcemic patients: 16 control patients with myeloma and 22 patients with non-Hodgkin lymphoma divided into those with elevated or normal serum calcitriol levels; 1 group of 22 normocalcemia patients with non-Hodgkin lymphoma. Measurements: Serum chemistries and intact parathyroid hormone, calcitriol, parathyroid hormone-related protein, and urinary electrolyte levels. Results: On the basis of the mean serum calcitriol level of the control group plus 3 standard deviations, the reference range for serum calcitriol during hypercalcemia was defined as less than 42 pg/mL. Although serum calcium and parathyroid hormone levels in the study patients were similar to those in controls, 12 of the 22 hypercalcemic patients with non-Hodgkin lymphoma (55%) had serum calcitriol levels greater than 42 pg/mL (range, 51 to 170 pg/mL). No features distinguished the patients with elevated serum calcitriol levels from those with normal levels. Seventy-one percent of normocalcemia patients with non-Hodgkin lymphoma were hypercalciuric, and 18% had serum calcitriol levels greater than the normocalcemic reference range (20 to 76 pg/mL). Conclusions: Serum calcitriol levels are elevated in most hypercalcemic patients with non-Hodgkin lymphoma in the absence of elevated serum levels of parathyroid hormone, which implicates extrarenal calcitriol production in the pathogenesis of this syndrome. Abnormal calcium metabolism, hypercalciuria, and dysregulated calcitriol production are also common in normocalcemic patients with non-Hodgkin lymphoma.

Purpose: To assess the activity of 2-chlorodeoxyadenosine (2CdA) as primary therapy for patients with Waldenström's macroglobulinemia. Patients and Methods: 2CdA was given to 26 consecutive, previously untreated and symptomatic patients with Waldenström's macroglobulinemia. Two courses were administered to outpatients at a dose of 0.1 mg/ kg body weight per day for a 7-day continuous infusion using a portable pump through a central venous catheter. Responding patients were followed up without further therapy and were scheduled to receive two additional treatments with 2CdA on disease relapse. Results: Twenty-two of 26 patients responded to the 2CdA therapy (85%; 95% confidence interval [Cl], 65% to 96%), including three patients who achieved a complete response and 19 patients who had a partial response. Treatment was well tolerated, with no acute hematologic toxicity. A marked and sustained reduction of CD4+ lymphocytes occurred in all patients and may have contributed to a fatal infection with disseminated herpes simplex in one patient. With a median follow-up of 13 months, five patients have relapsed and all re-treated patients have responded again to 2CdA. Conclusion: 2CdA is highly active in previously untreated patients with Waldenström's macroglobulinemia. A limited program of treatment induced responses of good quality and long duration in more than 80% of patients. © 1994 by American Society of Clinical Oncology.

PURPOSE: To assess changes in the magnetic resonance (MR) appearance of the spine in patients with multiple myeloma who responded to chemotherapy. MATERIALS AND METHODS: Twenty patients with multiple myeloma underwent MR imaging of the spine before and after chemotherapy. Sagittal T1-weighted images were obtained before and after administration of contrast material. MR patterns of marrow involvement before treatment were classified as focal, diffuse, or variegated. The changes seen on MR images after treatment were analyzed and correlated with the clinical response as defined with standard criteria. RESULTS: Patterns of complete response included resolution of marrow abnormality or persistent abnormality without enhancement or with peripheral rim enhancement. Conversion of a diffuse to a variegated or focal pattern and a decrease in the amount of marrow abnormality with persistent enhancement were observed in patients who showed a partial response. Ten patients sustained new or progressive compression fractures after successful therapy. CONCLUSION: Recognition of spinal MR patterns of response to treatment supported the occurrence of remission in patients with multiple myeloma. MR findings may help clarify response to therapy in patients with equivocal clinical changes or nonsecretory myeloma.

Background: The treatment of multiple myeloma remains unsatisfactory and new active agents are needed. Paclitaxel is effective against a variety of solid tumors and we assessed the utility against multiple myeloma. Patients and methods: From March 1993 to May 1994, we treated 33 patients with newly diagnosed multiple myeloma with paclitaxel given intravenously at a dose of 125 mg/m2 over 24 hours (13 patients) or at a dose of 135 mg/m2 over 3 hours (20 patients). Results: Five of 33 patients responded (15%; 95% CI: 5 to 32%) with an unmaintained remission of 3-11+ months. Severe but reversible neutropenia was the major dose limiting toxicity, but myalgias and alopecia were also common. Conclusions: Paclitaxel was slightly active against multiple myeloma. Whether higher doses or new analogues of this agent can produce superior results requires further study. © 1994 Kluwer Academic Publishers.

Purpose: To determine the efficacy and toxicity of etoposide, cyclophosphamide, and fractionated total-body irradiation (TBI) as the conditioning regimen for allogeneic bone marrow transplantation (BMT) in patients with hematologic malignancies. Patients and Methods: Seventy-nine patients underwent BMT from a human leukocyte antigen (HLA)-identical sibling using cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis. Thirty-four patients had early leukemia (acute leukemia or lymphoblastic lymphoma in first remission, chronic myelogenous leukemia [CML], or refractory anemia [RA]), and 45 patients had more advanced disease. Patients received etoposide 1,500 mg/m2 on day -8, followed by cyclophosphamide 60 mg/kg/d on days -7 and -6, and 10.2 Gy of TBI administered in six fractions of 1.7 Gy given twice daily for 3 days from day -3 to -1. Donor bone marrow was harvested and infused on day 0. Results: Patients with early leukemia had a disease-free survival rate of 53% ± 9% and an overall survival rate of 57% ± 10% at 3 years. Patients with advanced disease had a disease-free survival rate of 15% ± 5% and overall survival rate of 17% ± 5%. The actuarial relapse rate for the early-leukemia group is 33% ± 9% versus 69% ± 9% for patients with more advanced disease. Severe toxicity was most frequently manifested as pulmonary hemorrhage followed by multiorgan failure and death. The 100-day mortality rate for the early- leukemia group was 10% versus 50% for patients with more advanced disease. Conclusion: The combination of cyclophosphamide, etoposide, and TBI is a relatively safe and effective preparative regimen for patients with early hematologic malignancies. Controlled trials are needed to evaluate critically this combination versus other standard preparative regimens. Greater toxicity was observed in patients with advanced disease, and this program does not appear to offer any advantage over other regimens.