Richard S. Stein

Erythroid response to treatment with G-CSF plus erythropoietin for the anaemia of patients with myelodysplastic syndromes : proposal for a predictive model

Previous studies have shown that approximately 40% of patients with myelodysplastic syndrome (MDS) and anaemia respond to treatment with human recombinant granulocyte‐CSF (G‐CSF) plus erythropoietin (epo). The present study was designed to investigate pre‐treatment variables for their ability to predict erythroid responses to this treatment. 98 patients with MDS (30 RA, 31 RARS, 32 RAEB, five RAEB‐t) were treated with a combination of G‐CSF (0.3–3.0 μg/kg/d, s.c.) and epo (60–300 U/kg/d, s.c.) for at least 10 weeks. Minimum criteria for erythroid response was a 100% reduction of red blood cell (RBC) transfusion need or an increase in haemoglobin level of  1.5 g/dl. 35 patients (36%) showed responses to treatment. Medium duration of response was 11–24 months. In multivariate analysis, serum erythropoietin levels and initial RBC‐transfusion need retained high statistical significance (P < 0.01). Using pre‐treatment serum epo levels as a ternary variable (< 100, 100–500 or > 500 U/l) and RBC transfusion need as a binary variable (< 2 or  2 units per month), the analysis provided a predictive score for erythroid response. This score divided patients into three groups: one group with a high probability of erythroid responses (74%), one intermediate group (23%) and one group with poor responses to treatment (7%). This predictive scoring system could be used in decisions regarding use of these cytokines for treating the anaemia of MDS, both for defining patients who should not be given the treatment and for selecting patients for inclusion in prospective trials.

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.

Cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) combination sequential chemotherapy for advanced diffuse histiocytic lymphoma.

A program of combination sequential chemotherapy using cyclophosphamide, vincristine, methotrexate with leucovorin rescue, and cytarabine (COMLA) was administered to 42 previously untreated patients with advanced diffuse histiocytic lymphoma. Twenty-three patients achieved a complete remission as determined by strict clinical restaging criteria. The observed median duration of survival for the complete responders is longer than 33 months. Eight patients achieved a partial response, with a median survival longer than 21 months. Eleven patients showed no response, with a median survival of 5 months. Toxicity was acceptable. None of the responders have shown central nervous system relapse. There was no difference in response rates between patients with stage III or IV lymphoma or between asymptomatic or symptomatic patients. The COMLA program produces a high rate of complete and durable remissions and should be considered as an initial form of management of patients with advanced diffuse histiocytic lymphoma.

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.

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.

Lithium Carbonate Attenuation of Chemotherapy-Induced Neutropenia

The administration of lithium to psychotic patients is associated with leukocytosis.1 2 3 Although the mechanism of this leukocytosis is not established, preliminary studies have suggested that the...

Malignant lymphomas of follicular center cell origin in humans. V. incidence, clinical features, and prognostic implications of transformation of small cleaved cell nodular lymphoma

Seventy‐five cases of small cleaved cell nodular lymphoma (SCC‐N) were reviewed. Thirty‐four cases underwent repeat biopsy a median of 54 months after diagnosis (range, 7–116 months) because of progressive or recurrent disease. Histologic conversion to a transformed (noncleaved) cell lymphoma was found at re‐biopsy in 13 of 34 cases (38%). Neither age, gender, stage, visceral sites of disease, nor symptoms at presentation were predictive of subsequent conversion. Similarly, none of the clinical features analyzed at the time of rebiopsy were predictive of whether the rebiopsy would show stable histology or transformation. Documentation of transformation was of significant prognostic value. Although rebiopsies were performed at the time of progressive disease, survival following re‐biopsy was 37.5 months for patients found to have cleaved cell lymphoma at re‐biopsy, and only 2.5 months for those with transformed cell lymphoma at re‐biopsy. Two of the cases which had immunoglobulin surface markers studied at diagnosis and at transformation, showed retention of heavy and light chain markers. This implies that the change in appearance involves the original neoplastic clone and was not due to a second neoplasm. Development of transformed cell lymphoma is one of the most common features of the aggressive phase of indolent lymphoma. Repeat biopsy in all patients with indolent lymphoma who have relapsing or progressive disease is recommended. Cancer 53:1109‐1114, 1984.

Non-Hodgkin's lymphoma of the gastrointestinal tract: an analysis of clinical and pathologic features affecting outcome

Clinical and histopathologic data from 87 patients with primary non-Hodgkins lymphoma of the gastrointestinal (GI) tract diagnosed between 1974 and 1984 were reviewed. B-cell lymphomas of intermediate- or high-grade histology constituted 78% of lesions. Stage of disease varied with histologic grade, with a preponderance of advanced disease (stages IIIE and IV) in patients with low-grade lymphoma (15 of 21) (71%), compared with higher grade lesions (38%, P = .01). Among patients with nonlocalized (stages IIE through IV) lymphoma of intermediate- or high-grade histology, surgical resection of the primary focus afforded a higher rate of complete remission (CR) (70% v 50%) and sustained CR (61% v 21%, P = .04) after cytotoxic therapy compared with the nonresected cohort. The median survival in the resected group was 51 months + compared with 13 months in the nonresected patients (P = .012). Differences in outcome were attributable to a high risk of treatment-related complications (perforation and/or hemorrhage) (43% v 0%, P = .001) and local relapse (29% v 4%, P = .05) in nonresected individuals. Life-threatening local complications were not observed in patients with low-grade lymphoma managed solely with medical therapy. Histologic findings from surgically staged patients identified presence of extravisceral disease and intermediate- or high-grade tumor histology as features predictive of transmural invasion, enabling potential identification of patients who might be optimally managed by resection of the primary GI focus before initiation of cytotoxic therapy.

Clinical value of empirical amphotericin B in patients with acute myelogenous leukemia

From August 1977 to October 1978, 23 patients with acute myelogenous leukemia (AML) received induction therapy at Vanderbilt University Hospital. Six patients died of documented fungal infection, predominantly aspergillus pneumonia; the complete remission rate was only 40%. Based on this experience we began using amphotericin B empirically in any AML patient remaining febrile or having recurrent fever after a week of broad spectrum antibiotics. Of 22 patients treated from October 1978 to August 1980, none died of fungal infection during induction therapy; the remission rate increased significantly to 77%. Chemotherapy and supportive care were otherwise unchanged during this period. While the first group was older, the improvement in remission rate was also seen in patients younger than 60 years of age. Since fungal infection may be difficult to document, this study suggests that empirical amphotericin B is reasonable therapy in leukemic patients remaining febrile or having a recurrent fever following a week of broad spectrum antibiotics, if the institution has a high incidence of fungal infections.

Effects of high-dose cytarabine

Plasma, urine, cerebrospinal fluid, and tear concentrations of cytarabine (ara‐C) were measured in 15 patients receiving 3 gm/m2 IV ara‐C given as a 1 hr infusion every 12 hr for 6 days. The two assay methods used for measuring ara‐C concentrations (high‐pressure liquid chromatography and radioimmunoassay) gave much the same results. Peak plasma ara‐C concentrations (2.0 mM) after high‐dose therapy were 50 times those achieved with more conventional (100 to 300 mg/m2) doses. High doses of ara‐C were not sufficient to saturate cytidine deaminase; plasma ara‐C half‐lifes (t½s) after high‐dose therapy (distribution t½ = 6.2 min; elimination t½ = 154 min) were much the same as those after conventional ara‐C doses. Kinetics of ara‐C were not altered by repeated dosing over a 6‐day period. Cerebrospinal fluid ara‐C concentrations after high‐doses (x̄ = 7.8 μM) were 10 times those after conventional intravenous dosing, but were 0.5% to 1.0% those achieved by intrathecal ara‐C doses. Tear concentrations of 22 and 38 μM were measured in two patients who developed conjunctivitis after high‐dose therapy so that the presence of ara‐C in tears may be a cause of the conjunctivitis seen in some patients.