Outpatient high-dose chemotherapy with autologous stem-cell rescue for hematologic and nonhematologic malignancies.

PURPOSE: A prospective study to determine the feasibility of high-dose chemotherapy (HDC) and autologous stem-cell rescue (ASCR) in the outpatient setting. METHODS: One hundred thirteen consecutive patients underwent 165 cycles of HDC/ASCR for a variety of malignancies. HDC regimens were disease-specific. Initially, patients were hospitalized for HDC, discharged on completion, and maintained as outpatients unless toxicities required rehospitalization (subtotal outpatient transplantation [STOT]). Once this was established as safe, a total outpatient transplant (TOT) program was developed in which patients received all of the HDC, as well as supportive care, as outpatients. Patients who declined the outpatient programs received the same HDC and supportive care as inpatients. RESULTS: In 140 of 165 (85%) HDC cycles, patients agreed to participate in one of the outpatient transplant programs. Five patients in the STOT program could not be discharged from the hospital because of toxicities that developed during HDC; thus, 135 patients were monitored the outpatient setting, 95 (70%) of whom were never readmitted. The mean +/- SEM total hospital length of stay (LOS), including all readmissions and excess days after chemotherapy, was 18.33 +/- 5.06 days for patients who refused the outpatient program, 8.22 +/- 5.76 days for patients in the STOT program, and 2.81 +/- 7.66 days for those in the TOT program (P < .001). One treatment-related death occurred in each treatment setting: day 120 inpatient, day 17 STOT, and day 110 TOT. CONCLUSION: Outpatient management of HDC/ASCR is safe and acceptable for the vast majority of patients. The STOT program resulted in significant reduction in hospital LOS, while the TOT program appears equally safe and further reduces LOS. Hospitalization for HDC/ASCR is unnecessary in most patients.

Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia.

PURPOSE: De novo B-cell prolymphocytic leukemia (B-PLL) is a distinct clinicopathologic entity usually characterized by marked lymphocytosis, massive splenomegaly, an aggressive course, and refractoriness to therapy. Cladribine (2-chlorodeoxyadenosine [2-CdA]; Ortho Biotech, Raritan, NJ) is a newer purine analog with potent activity against indolent lymphoproliferative disorders. PATIENTS AND METHODS: We treated eight patients with cladribine 0.1 mg/kg/d for 7 days by continuous infusion or 0.14 mg/kg/d over 2 hours for 5 days, every 28 to 35 days, for a median of three courses (range, two to five). There were five men and three women, with a median age of 62 years and a median pretreatment duration of 6 months; four patients were previously untreated. RESULTS: All eight patients were assessable: five achieved a complete response with a median response duration of 14 months (range, 1+ to 55+), and three achieved a partial response with a median duration of 3 months (range, 1 to 3). Of four patients who achieved a complete response and in whom a peripheral-blood immunophenotypic analysis was performed, two had no circulating B-PLL cells and one had no residual disease on Southern blot analysis. Myelosuppression and infection were the major toxicities: three patients developed grade 3 or 4 myelosuppression, four had bacterial infections, and two had herpes zoster infections. CONCLUSION: In this small study of patients with de novo B-PLL, cladribine was an active agent that induced a high overall and complete response rate. These results require confirmation in larger numbers of B-PLL patients.

2-Chlorodeoxyadenosine (2-CdA): A Potent Chemotherapeutic and Immunosuppressive Nucleoside.

Hereditary adenosine deaminase deficiency results in failure of the lymphocyte development. This occurs because of the accumulation of deoxyadenine nucleotides in cells with high deoxycytidine kinase and low 5'-nucleotidase activity. 2-Chlorodeoxyadenosine (2-CdA) resists the action of adenosine deaminase and accumulates in cells with high deoxycytidine kinase and low 5'-nucleotidase activity. It is equally toxic to dividing and nondividing cells and may act by preventing repair of DNA single-strand breaks. In doses of 0.1 mg/kg/day given for seven days 2-CdA manifests low toxicity. It has been found to be effective in the treatment of patients with lymphoid neoplasms, including advanced cutaneous T-cell lymphomas, chronic lymphocytic leukemia, non-Hodgkin lymphomas, and hairy cell leukemia. In the latter disorder it appears to be as or more effective than the tight-binding adenosine deaminase inhibitor, deoxycoformycin, and is probably less toxic. 2-CdA also appears to be effective in controlling autoimmune hemolytic anemia and shows promise in the treatment of other autoimmune diseases.

A correlation of serum C3DP levels with chemotherapeutic management of cancer patients.

Serial serum C3DP levels of 33 patients at our institution have been followed for up to 10 months. Individuals experiencing periods free of symptoms and signs of proliferating or expanding malignant disease, had C3DP levels which remained below 150 microgram/ml. Patients with active or recurrent disease, while on chemotherapy, had elevated C3DP values (greater than 150 microgram/ml). Serum C3DP values declined abruptly following treatment which resulted in major reduction of tumor mass. Decreases in C3DP levels from values above 150 microgram/ml to values within the normal range (50-150 microgram/ml) were observed during 89% (25/28) of the favorable clinical responses which have been followed with C3DP assays. Increases in C3DP levels from values within the normal range to values above 150 microgram/ml were observed either prior to or coordinate with clinical symptoms of disease recurrence 83% of the time (10/12 cases). These studies suggest that serial C3DP determinations offer an excellent prognostic aid for evaluating the response of malignant tumors during chemotherapeutic management.

Antibody against megakaryocytes in idiopathic thrombocytopenic purpura.

Purified human IgG from both serum and the culture of human splenic cells was radiolabeled with 125I. Incubation of radiolabeled IgG from patients with idiopathic thrombocytopenic purpura (ITP) with normal homologous platelets or bone marrow cells resulted in significant (P less than .001) binding when compared with control IgG. Radioautographs showed that the radioactivity was associated with the platelets or megakaryocytes. The antiplatelet antibody in ITP has specificity for antigens associated with both platelets and megakaryocytes and suggests that thrombopolesis may also be affected in this disease.

Antibody-dependent lymphocytotoxicity induced by immunoglobulin G from Hodgkin's disease splenic lymphocytes.

Immunoglobulin G, produced in cultures of splenic lymphocytes obtained from patients with Hodgkin's disease, bound to a population of homologous peripheral blood lymphocytes and initiated antibody-dependent cell cytotoxicity in cultures from five out of eight patients. Two patients whose cultures produced negative results had minimal disease; the other was in remission. The target cells appear to be T lymphocytes; the effector cells bear Fc receptors that are inhibited by antigen-antibody complexes. Antibody-dependent cell cytotoxicity events may produce the anergy and lymphopenia often seen in Hodgkin's disease.

Platelet-associated IgG in immune thrombocytopenic purpura.

A method for the measurement of immunoglobulin G associated with gel-filtered platelets is described and finding in 70 control subjects and 37 patients with immune thrombocytopenic purpura (ITP) are reported. Control platelet-associated IgG (PAIgG) levels (nanograms IgG per 10(9) platelets) averaged (+/-SD) 1231+/-424; samples studied after 24 and 48 hr remained within the control range. PAIgG values of 19 adult and 12 childhood patients with chronic ITP averaged 4711+/-3025 and 4923+/-3955, respectively, and differed significantly from controls (p less than 0.001). There was an inverse correlation between PAIgG values and the chronic ITP patient's platelet count. Six patients with childhood acute ITP had PAIgG levels ranging from 5588 to 56,250 and appeared to represent a different statistical population from those with chronic ITP. In chronic ITP patients responding to splenectomy, there was an immediate normalization of PAIgG levels; however, a certain percentage of patients studied several months after splenectomy evidenced elevated PAIgG levels in association with normal platelet counts. These data showed that the direct measurement of platelet associated antibody is a useful technique in the diagnosis and follow-up of patients with chronic ITP. Preliminary studies in patients with acute ITP have suggested that this method may be useful in differentiating acute and chronic childhood ITP.

A clinical evaluation of serum C3DP levels in individuals with malignant diseases.

A human serum DNA-binding protein (C3DP) derived from complement component C3 has been found in elevated concentrations in the sera of individuals with malignant diseases. An assay system has been devised which reveals quantitative values of serum C3DP levels. Results obtained using this system indicate that normal human sera have an average C3DP level of 242 mug/ml (range, 40 to 146), whereas sera from individuals with active carcinomas have an average C3DP level of 242 mug/ml (range, 146 to 400). Sera from individuals with active leukemias, lymphomas, and melanomas all had elevated levels of C3DP, whereas sera from individuals with polycythemia vera or other nonmalignant diseases had normal or only slightly elevated C3DP concentrations. No tissue specificity seems to be required for malignant growths to result in elevated C3DP serum concentrations. The levels of C3DP in 79% of the individuals who experienced disease remission were found to decline to normal values, concurrent with the disease regression. Patients who did not respond to therapy regimens retained high C3DP levels.

Immune neutropenia.

A patient with hyperthyroidism and severe neutropenia had a clinical course and family history that suggested an immune cause. Neutrophil-binding IgG was demonstrated in serum using the Fab-anti Fab assay. The antineutrophil factor bound specifically to either homologous or autologous neutrophils and could be adsorbed by the target neutrophils. The quantity of IgG required to saturate the neutrophil-binding sites (175 000 molecules per neutrophil) and the serum concentration (1.3 mug/ml) were determined. It was estimated that at the time that blood and marrow neutrophils were markedly reduced, serum contained sufficient neutrophil-binding IgG to saturate the binding sites of 1.2 times the total blood neutrophil pool.

Different antiplatelet antibody specificities in immune thrombocytopenic purpura.

It is generally accepted that patients with immune thrombocytopenic purpura (ITP) produce antibody against platelet-associated antigens; however, it is not known if these antiplatelet antibodies are directed towards the same or different antigenic sites. In the present studies, quantities of antiplatelet antibody from different ITP patients, sufficient to saturate platelet antigenic sites, were simultaneously incubated with normal platelets and the quantity of platelet-binding IgG (PBIgG) was determined. In each of the five comparisons made, the amount of PBIgG bound after incubation of normal platelets with saturating quantities of two ITP antibodies approximated to the sum of the PBIgG bound after incubation with the antibodies separately. These data suggest that the antiplatelet antibody from these ITP patients differed in antigenic specificity.

The effect of corticosteroids on human IgG synthesis.

The effect of prolonged, high-dose corticosteroid therapy on total IgG synthesis rates by human bone marrow and splenic leukocytes was studied in patients with immune thrombocytopenia. Marrow IgG production rates begin to decrease 3 weeks after beginning therapy and reach levels approximately one-fourth of pre-treatment rates after 6 weeks. No effect of corticosteroids on splenic IgG production rates could be shown. Marrow IgG synthesis rates in these patients were on the average from 3 to 10 times greater than corresponding splenic production rates and, in addition, appeared to correlate with serum IgG levels. These data suggest that the marrow is an important contributor to the total body IgG pool; and since corticosteroids appear to suppress marrow IgG production, this may be one reason for their therapeutic usefulness in antibody-mediated diseases.

Thrombocytopenia associated with gold therapy. Observations on the mechanism of platelet destruction.

Severe thrombocytopenia developed in a patient with rheumatoid arthritis during gold therapy. Increased numbers of marrow megakaryocytes, shortened 51Cr-labeled platelet survival and platelet phagocytosis by splenic macrophages indicated that thrombocytopenia was due to excessive platelet destruction. Aurothiomalate disodium antigenicity was demonstrated by increased lymphocyte blastogenesis, and accentuation of blood and splenic leukocyte migration in the presence of the gold salt. In vitro splenic immunoglobulin G (IgG) production was markedly increased, and a significant portion of the culture-produced IgG attached specifically to homologous platelets and platelet membranes. Serum antiplatelet antibodies could not be demonstrated, nor could it be shown that gold enhanced the binding of splenic-synthesized IgG to platelets. The data indicate an immunologic mechanism for gold-associated thrombocytopenia and permit speculation as to possible ways in which unidentified antigens may be involved in the pathogenesis in idiopathic thrombocytopenic purpura.