John P. Greer

Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.

PURPOSE To determine the toxicities and maximum-tolerated dose of cyclosporine (CsA) administered with daunorubicin as a modulator of multidrug resistance (MDR) in acute leukemia, and to evaluate response to treatment and its relationship to mdr1 gene expression. PATIENTS AND METHODS Patients with poor-risk acute myeloid leukemia (AML) received sequential treatment with cytarabine (3 g/m2/d intravenously [i.v.]) days 1 to 5, and daunorubicin (45 mg/m2/d) plus CsA as a 72-hour continuous infusion (CI) days 6 through 8 in a phase I/II trial. A loading dose of CsA administered over 1 to 2 hours preceded the CI. CsA dose escalations ranged from 1.4 to 6 mg/kg (load) and 1.5 to 20 mg/kg/d (CI). Whole-blood concentrations of CsA were monitored by immunoassay; plasma concentration of daunorubicin and daunorubicinol were determined by high-pressure liquid chromatography (HPLC). Specimens were analyzed for P-glycoprotein expression, and results confirmed by a quantitative RNA polymerase chain reaction (PCR) assay for the mdr1 gene transcript. RESULTS Forty-two patients are assessable for toxicity and response. P-glycoprotein was detected in 70% of cases. Dose-dependent CsA toxicities included nausea and vomiting (22%), hypomagnesemia (61%), burning dysesthesias (21%), and prolongation of myelosuppression. Transient hyperbilirubinemia developed in 62% of treatment courses and was CsA-dose-dependent. Reversible azotemia occurred in three patients receiving concurrent treatment with potentially nephrotoxic antibiotics. Steady-state blood concentrations of CsA > or = 1,500 ng/mL were achieved in all patients receiving CI doses > or = 16 mg/kg/d. Mean plasma daunorubicin, but not daunorubicinol, levels were significantly elevated in patients who developed hyperbilirubinemia (P = .017). Twenty-six (62%) patients achieved a complete remission (CR) or restored chronic phase and three patients achieved a partial remission (PR) for an overall response rate of 69% (95% confidence interval, 54% to 84%). The response rate was higher in patients who developed hyperbilirubinemia (P = .001), whereas MDR phenotype did not influence response to treatment. Among five patients with MDR-positive leukemia, cellular mdr1 mRNA decreased (n = 1) or was absent from relapsed specimens (n = 4), while mdr1 RNA remained undetectable at relapse in two patients who were MDR-negative before treatment. CONCLUSION High doses of CsA, which achieve blood concentrations capable of reversing P-glycoprotein-mediated anthracycline resistance in vitro, can be incorporated into induction regimens with acceptable nonhematologic toxicity. Transient hyperbilirubinemia occurs commonly with CsA administration and may alter daunorubicin pharmacokinetics. Recommended doses of CsA for phase II and III trials are a load of 6 mg/kg and CI of 16 mg/kg/d.

A small-cell-predominant variant of primary Ki-1 (CD30)+ T-cell lymphoma

We describe nine patients with a primary Ki-1 (CD30)+ T-cell lymphoma containing numerous, often CD30-negative, small lymphocytes with irregular nuclei and a minor population of large CD30+ tumor cells. All previously described primary Ki-1+ lymphomas have been large-cell neoplasms. In this small-cell variant, the diagnosis of lymphoma was difficult to make because there was a predominance of small lymphocytes and, in some cases, clinical features suggested an inflammatory process. Patients were young (age range 0.3–40 years, median 14 years), and frequently had B symptoms (56%); sites of involvement were predominantly skin (78%) and lymph node (67%). The actuarial 2-year disease-free survival was 14%, and the overall survival was 51%. Two patients had a rapidly fatal course. In all cases histologic sections showed a predominance of small lymphocytes with marked nuclear irregularity and often a perivascular/intravascular distribution of CD30+ large cells. All cases had a T-cell phenotype. In four cases the large and small cells could be compared and had a similar aberrant T-cell phenotype. Large cells were CD30+, but only rare small cells expressed CD30. Cytogenetic studies revealed a t(2;5)(p23;q35) in four of four cases studied. Four patients had numerous large cells on repeat biopsies; two of these developed sheets of large CD30+ cells typical of anaplastic large-cell lymphoma (ALCL). These cases provide further evidence that primary Ki-1+ lymphoma has a morphologic spectrum that includes a small-cell variant. Although very different morphologically from previously described Ki-1+ ALCL, this small-cell variant is clearly part of the disease spectrum on the basis of clinical features, the presence of the t(2;5)(p23;q35), the aberrant T-cell phenotype in the small and large cells, as well as histologic progression seen in several patients.

Clinical features of 31 patients with Ki-1 anaplastic large-cell lymphoma.

Thirty-one patients were diagnosed by morphologic and immunophenotypic features as having primary Ki-1 anaplastic large-cell lymphoma (Ki-1 ALCL). the median age was 35 years (range, 4 months to 78 years); the male:female ratio was 18:13. B symptoms were observed in 13 patients. Peripheral adenopathy was present in 26 patients, while mediastinal adenopathy occurred in five. There was extranodal disease in 13 patients; the most common extranodal site was skin with seven affected. Seventeen patients had stage III/IV disease. Immunophenotypes were T cell in 24 patients and B cell in four patients; immunophenotype could not be determined in three patients. Cytogenetic abnormalities in chromosomes 2, 5, and 7 were detected in three patients. Although therapy was heterogeneous, the actuarial 2-year survival was 73%. Two-year disease-free survival was 39% for all patients; for stages I and II, it was 62% compared with 20% for stages III and IV (P = .001). Complete remission (CR) occurred in 21 of 23 patients receiving combination chemotherapy; however, nine relapses, including six of seven stage IV patients, occurred within 21 months of diagnosis. Preliminary observations suggest that Ki-1 ALCL may have a quiescent phase in the rare patient with only localized skin disease. However, the disease generally behaves as an intermediate- to high-grade lymphoma, and patients with Ki-1 ALCL should receive curative-intent combination chemotherapy.

Epipodophyllotoxin-related leukemia. Identification of a new subset of secondary leukemia

Thirty‐seven children and adults who developed acute nonlymphocytic leukemia after the administration of chemotherapy that included etoposide or teniposide for a variety of hematologic and solid malignancies were identified. The secondary leukemia that occurred in these patients could be distinguished from the secondary leukemia that occurs after treatment with alkylating agents by the following: a shorter latency period; a predominance of monocytic or myelomonocytic features; and frequent cytogenetic abnormalities involving 11q23. Patients receiving an epipodophyllotoxin are at risk for developing secondary leukemia that has features distinct from the syndrome of secondary leukemia associated with alkylating agents.

High-dose carboplatin and etoposide with autologous bone marrow transplantation in refractory germ cell cancer: an Eastern Cooperative Oncology Group protocol.

PURPOSE A phase II trial was undertaken to assess the feasibility, toxicity, and efficacy of high-dose carboplatin and etoposide with autologous bone marrow transplantation in patients with relapsed or refractory germ cell tumors. PATIENTS AND METHODS Forty patients with recurrent germ cell cancer received carboplatin 500 mg/m2 and etoposide 400 mg/m2 given at 7, 5, and 3 days before marrow infusion. Autologous marrow infusion (day 0) was accomplished using one half of the bone marrow harvested before chemotherapy. Patients who achieved a complete or partial response with the first cycle of treatment received a second identical cycle of chemotherapy followed by infusion of the remaining cryopreserved bone marrow. RESULTS Objective responses were obtained in 17 of the 38 patients (45%) assessable for response, including eight partial and nine complete remissions. Five of these patients remain in continuous complete remission with minimal follow-up of 1 year. Toxicity encountered was primarily hematologic, and five patients (13%) died of treatment-related complications. Significant toxicities often seen with high-dose cisplatin (ototoxicity, neurotoxicity, and renal toxicity) were manageable in this regimen of high-dose carboplatin. CONCLUSIONS This trial confirms the curative potential of high-dose carboplatin and etoposide in highly refractory germ cell cancer.

Peripheral T-cell lymphoma: a clinicopathologic study of 42 cases.

Clinical and histopathologic material from 42 patients with peripheral T-cell lymphoma (PTCL) was reviewed. The median age was 63.5 years (range, 11-97 years). The male:female ratio was 2.8:1. Prior immune or lymphoproliferative diseases occurred in 36% of the patients. PTCL was advanced at presentation with B symptoms (67%), generalized adenopathy (69%), and stage III/IV disease (79%). Suspected lung or pleural involvement (21%), hepatomegaly (29%), and splenomegaly (43%) were common; marrow involvement was documented in 37% of the patients at presentation and in 51% of patients during the illness. Hypercalcemia and eosinophilia occurred in 19% and 29% of patients, respectively. Among patients receiving combination chemotherapy (BCOP, CHOP, BACOP, COMLA), eight (24%) of 33 achieved a complete remission and only four (12%) of 33 had a sustained complete remission. The median survival for PTCL was 11 months. Because of the poor response to standard therapy, clinical trials should identify cases of PTCL and evaluate newer regimens in this subset of aggressive lymphoma.

Peripheral T-cell lymphoma

Peripheral T‐cell lymphoma is the most common type of T‐cell lymphoma seen in adults in the United States. Clinical data were reviewed from 134 cases of peripheral T‐cell lymphoma diagnosed in three centers. The median age of the patients was 57 years (range, 4‐97 years), 59% were male, and 36 patients (27%) had a history of a preceding disorder of the immune system. The tumors were grouped histologically into large cell (43%), mixed large and small cell (40%), and small cell (17%). The stage at diagnosis was I (7%), II (21%), III (22%), and IV (50%). B symptoms were present in 57%. The most frequent sites of extranodal involvement were bone marrow (35%), skin (13%), and lung (11%). Eighty patients were treated with a multiagent chemotherapy regimen with proven curative potential in aggressive non‐Hodgkins lymphomas and the remainder of the patients received less intensive chemotherapy (36 patients), radiotherapy (nine patients), or no treatment (nine patients). Fifty percent of the intensively treated patients achieved complete remission and the actuarial 4‐year survival was 45%. However, the 4‐year, disease‐free survival in patients with Stage IV disease was only 10%. Although peripheral T‐cell lymphomas appeared similar in many ways to their B‐cell counterparts, disease‐free survival by stage was low and patients with Stage IV disease had an especially poor outlook.

Long-term follow-up of patients with cutaneous T-cell lymphoma treated with extracorporeal photochemotherapy

BACKGROUND Few studies have assessed the long-term outcome of patients with cutaneous T-cell lymphoma (CTCL) treated with extracorporeal photochemotherapy (ECP). OBJECTIVE Our objective was to assess the efficacy, safety, and survival of a cohort of patients with refractory T-cell lymphoma in various stages of cutaneous involvement who were treated with ECP. METHODS Twenty patients who had received at least 6 months of ECP between September 1988 and April 1991 were reevaluated and the data analyzed statistically to obtain outcome data through December 1995. RESULTS A complete response (disappearance of all lesions) was obtained in five patients (25%) and a partial response (disappearance of at least 50% of lesions) in five patients (25%). Of the 10 responders, seven (70%) were weaned from ECP. Two of seven patients had a relapse. Ten patients (50%) showed no response to ECP. No statistically significant differences between responders and nonresponders were found with respect to demographic, clinical, or laboratory variables. Seven patients died of causes directly related to CTCL and two patients died of unrelated causes. Median survival time for the entire cohort was 96 months (range, 16 to 152 months). An assessment of early response after 6 to 8 months of ECP had a sensitivity of 100% and a specificity of 90% for predicting long-term (> 4 years) outcome. Adverse effects were minimal. CONCLUSION ECP is a safe effective alternative therapy for CTCL that is refractory to other therapies; it can induce a long-term, disease-free remission in a minority of patients. Response in the first 6 to 8 months of treatment predicts long-term outcome.

T-cell-rich B-cell lymphomas: A clinicopathologic study of 19 cases

T-cell-rich B-cell lymphomas (TCRBCLs) are recently described, unusual non-Hodgkins lymphomas that have a diffuse morphology, a predominance of reactive T-cells, and a minority of neoplastic B-cells. The clinical and pathological features of 19 TCRBCLs, all of which demonstrated B-cell clonality, are presented. These lymphomas generally affected older patients by widespread disease and usually were nodal in origin. Treatment varied, but continuous complete remissions (eight patients) were achieved only in those receiving chemotherapy directed at intermediate-grade lymphomas. Although morphologically heterogeneous, all cases resembled peripheral T-cell lymphomas (PTCLs); several TCRBCLs also contained Reed-Sternberg-like cells. Flow cytometry or frozensection immunoperoxidase failed to detect monotypic immunoglobulin (Ig) in eight of eight cases tested. In contrast, paraffin immunoperoxidase was very useful diagnostically, showing large L26 (CD20-associated) positive cells scattered singly or in small clusters among numerous small T-cells (UCHL1[CD45RO] positive) in all cases. Monotypic cytoplasmic Ig was present in 16 of 19 cases, one of which exhibited plasmacytic differentiation. Southern blot analysis demonstrated relatively faint Ig JH and/or JK bands, indicating a small monoclonal B-cell population in nine of 11 cases, one of which also showed a bcl-2 rearrangement. No T-cell receptor gene rearrangements were observed. These results showed that TCRBCLs may be easily confused with PTCLs or occasionally confused with Hodgkins disease. TCRBCLs are probably heterogeneous biologically; some cases are of follicular center cell origin. These lymphomas respond to chemotherapy directed at intermediate-grade lymphomas, apparently have a better prognosis than PTCLs, and seem to represent morphological variants of different types of large B-cell lymphomas.

Effective treatment of small-noncleaved-cell lymphoma with high-intensity, brief-duration chemotherapy.

Small-noncleaved-cell (SNC) lymphoma is a high-grade, biologically aggressive neoplasm notable for poor response to therapy, high relapse rate, and less than a 20% long-term survival. We treated 20 patients with SNC lymphoma with a novel chemotherapeutic regimen using intensive doses of chemotherapy at frequent intervals in the inpatient setting. All patients were previously untreated. Sixteen patients (80%) had stage IV disease. Most patients (95%) had at least one other characteristic associated with poor prognosis (bulky [greater than 10 cm] disease, multiple extranodal sites, poor performance status), and 85% had two or more characteristics associated with poor prognosis. Seventeen patients (85%) achieved a complete response (CR) to therapy, including all three patients with human immunodeficiency virus (HIV)-associated disease. There have been three relapses, all occurring less than 18 months after treatment, and two of three relapses occurred in patients who were unable to complete therapy. At a median follow-up of 29 months, 13 patients (65%) remain disease-free; the calculated 5-year actuarial disease-free survival is 60%. Toxicity, chiefly myelosuppression, was severe but manageable. There were two treatment-related deaths, both in elderly patients with poor performance status and advanced-stage disease. These data suggest that such a dose-intensive approach improves the response and survival of patients with SNC lymphoma.