Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma.

BACKGROUND: Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen which has been utilized for therapy of B-cell non-Hodgkin's lymphoma (NHL). A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m2 of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma was well tolerated and had significant clinical activity. PATIENTS AND METHODS: To assess the safety and efficacy of Rituximab treatment, an open-label, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m2 Rituximab in patients with low-grade or follicular B-cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated. RESULTS: Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with subsequent infusions. No patients developed a host antibody response (HACA) to Rituximab. The mean serum immunoglobulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were bcl-2 positive at baseline in peripheral blood became bcl-2 negative during treatment and remained negative at the time of B-cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluable patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not been reached after 19.4+ months and 13.4+ months, respectively. CONCLUSIONS: The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with those seen with four weekly doses. Further studies are warranted to investigate whether this or other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.

Long-term follow-up of patients with hairy cell leukemia after cladribine treatment.

Hairy cell leukemia is a chronic B-cell disorder that follows an indolent, but progressive course. Cladribine (2-chlorodeoxyadenosine) induces complete remissions in the majority of patients after a single course. We report the long-term outcomes, including response rates and their duration; time-to-treatment failure (TTF) rates; retreatment results; toxicities; and survival rates of patients treated at Scripps Clinic (La Jolla, CA). A total of 358 patients with hairy cell leukemia were treated with cladribine at 0.087 or 0.1 mg/kg body weight per day by continuous intravenous infusion for 7 days. The expected number of second neoplasms was based on the National Cancer Institute's Surveillance Epidemiology and End Results data. Of 349 evaluable patients, 319 (91%) achieved an initial complete response and 22 (7%) a partial response with an overall median duration of response follow-up of 52 months. Ninety patients (26%) had relapsed at a median of 29 months. The TTF rate for all 341 responders was 19% at 48 months, 16% for complete responders, and 54% for partial responders. Of 53 evaluable patients treated with second courses of cladribine at first relapse, 33 (62%) achieved complete responses and 14 (26%) partial responses. Twenty-seven patients (8%) developed second neoplasms (only 1 hematopoietic) with an observed-to-expected ratio of 1.88 (95% confidence interval, 1.24 to 2.74). The overall survival rate was 96% at 48 months. Single courses of cladribine induced long-lasting complete responses in the vast majority of patients. Relapse rates for complete responders were low. Patients who relapse can be successfully retreated with cladribine. Cladribine has high efficacy and a favorable acute and long-term toxicity profile when administered to patients with hairy cell leukemia.

Reduced charges and costs associated with outpatient autologous stem cell transplantation.

High-dose chemotherapy and stem cell rescue is increasingly being delivered in the outpatient setting. Such intensive outpatient management programs have reduced the total hospital length of stay without compromising clinical outcomes. However, a detailed financial analysis of outpatient programs has not been performed. These data are the results of a prospective study of 94 patients receiving high-dose chemotherapy and autologous peripheral blood stem cell transplant in one of three settings: traditional inpatient, partial outpatient, total outpatient. Patients were allowed to choose their own treatment setting based upon the availability of a caregiver and personal preference. Total hospital length of stay and the actual cost and charges for each patient were monitored prospectively. The patients in the three groups were well balanced with regard to age and functional status prior to high-dose chemotherapy. The average length of stay was reduced from 17.3 to 8.2 to 2.7 days in the three different treatment settings (P < 0.01). Mean procedure costs were reduced from $39.7 thousand (US dollars) to $36.2 thousand to $29.4 thousand in the three treatment settings (P < 0.029). No differences in toxicity or overall response to therapy was noted. High-dose chemotherapy and stem cell rescue can be safely administered in the outpatient setting and results in significant cost savings.

Immunolocalization of the ICE/Ced-3-family protease, CPP32 (Caspase-3), in non-Hodgkin's lymphomas, chronic lymphocytic leukemias, and reactive lymph nodes.

Immunohistochemical analysis of the apoptosis-effector protease CPP32 (Caspase-3) in normal lymph nodes, tonsils, and nodes affected with reactive hyperplasia (n = 22) showed strong immunoreactivity in the apoptosis-prone germinal center B-lymphocytes of secondary follicles, but little or no reactivity in the surrounding long-lived mantle zone lymphocytes. Immunoblot analysis of fluorescence-activated cell sorted germinal center and mantle zone B cells supported the immunohistochemical results. In 22 of 27 (81%) follicular small cleaved cell non-Hodgkin's B-cell lymphomas, the CPP32-immunopositive germinal center lymphocytes were replaced by CPP32-negative tumor cells. In contrast, the large cell component of follicular mixed cells (FMs) and follicular large cell lymphomas (FLCLs) was strongly CPP32 immunopositive in 12 of 17 (71%) and in 8 of 14 (57%) cases, respectively, whereas the residual small-cleaved cells were poorly stained for CPP32 in all FLCLs and in 12 of 17 (71%) FMs, suggesting that an upregulation of CPP32 immunoreactivity occurred during progression. Similarly, cytosolic immunostaining for CPP32 was present in 10 of 12 (83%) diffuse large cell lymphomas (DLCLs) and 2 of 3 diffuse mixed B-cell lymphomas (DMs). Immunopositivity for CPP32 was also found in the majority of other types of non-Hodgkin's lymphomas studied. Plasmacytomas were CPP32 immunonegative in 4 of 12 (33%) cases, in contrast to normal plasma cells, which uniformly contained intense CPP32 immunoreactivity, implying downregulation of CPP32 in a subset of these malignancies. All 12 peripheral blood B-cell chronic lymphocyte leukemia specimens examined were CPP32 immunopositive, whereas 3 of 3 small lymphocytic lymphomas were CPP32 negative, suggesting that CPP32 expression may vary depending on the tissue compartment in which these neoplastic B cells reside. The results show dynamic regulation of CPP32 expression in normal and malignant lymphocytes.

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.

2-chlorodeoxyadenosine administration to patients with the myeloid blast phase of chronic myelogenous leukemia.

Three patients with chronic myelogenous leukemia (CML) in myeloid blast phase received 2-chlorodeoxyadenosine (2-CdA) at 0.7 mg/kg per course over 5 days every 2-4 weeks for 7, 2 and 5 courses. Each patient had a decrement in their white blood cell count, and in the absolute number and percentage of circulating immature cells following 2-CdA administration. Two patients achieved hematologic responses of 14 and 3 months and survived 19 and 6 months, respectively, while the non-responder died 2 months later. 2-CdA-induced anemia and thrombocytopenia, generally mild and reversible, were observed in all patients. Given the dismal results and considerable toxicities that follow multiagent induction chemotherapy for CML in myeloid blast phase, 2-CdA therapy may represent a reasonable therapeutic alternative, although confirmation is required in larger numbers of patients.

2-Chlorodeoxyadenosine: a potent antimetabolite with major activity in the treatment of indolent lymphoproliferative disorders.

2-Chlorodeoxyadenosine (2-CdA) is unique compared with traditional antimetabolites in that it is equally active against dividing and resting lymphocytes, which may be especially important in the treatment of indolent lymphoproliferative disorders because most cells in these disorders are in the resting phase. Significant clinical activity has been demonstrated for 2-CdA in the treatment of hairy cell leukemia, chronic lymphocytic leukemia, low-grade non-Hodgkin's lymphoma, Waldenström macroglobulinemia, and more recently prolymphocytic leukemia. More modest activity has been shown for 2-CdA in acute and chronic leukemias and in a variety of miscellaneous conditions, including Langerhans'-cell histiocytosis and multiple sclerosis.

Prolonged, complete remission after 2-chlorodeoxyadenosine therapy in a patient with refractory essential mixed cryoglobulinemia.

Essential mixed cryoglobulinemia is a systemic disorder in which cutaneous vasculitis and frequently glomerulonephritis are associated with cryoprecipitable serum immune complexes. Typically, the treatment regimen consists of plasmapheresis, high-dose corticosteroids, and cytotoxic chemotherapy, as well as interferon alfa for hepatitis C virus-related cryoglobulinemia. Herein we describe a man with progressive, symptomatic cryoglobulinemia and multisystem organ dysfunction in whom corticosteroid and alkylating therapy failed; however, he had a complete and long-lasting remission after administration of 2-chlorodeoxyadenosine (cladribine).

New perspectives on the approach to chronic lymphocytic leukemia.

Investigation of the biological actions of loxoribine in chronic lymphocytic leukemia (CLL) was undertaken because of the pervasive immunostimulatory effects of the nucleoside on normal B cells. In vitro studies with cells from a spectrum of CLL patients demonstrate that loxoribine induces B-CLL cells to enter and traverse the cell cycle. This is reflected by marked increases in DNA synthesis, by standard morphological criteria, and by flow cytometric evaluation of cell cycle status and of cell surface activation markers. Cells from about 75% of patients studied evince this response. Analysis of a variety of biological parameters indicate that only the ratio of T cells (CD4+ or CD8+) to B-CLL cells correlates with induction and degree of proliferative response. Co-stimulation with loxoribine and IL-2 results in modest proliferative synergy, presumably due to upregulation of IL-2R alpha expression on B-CLL cells by loxoribine. Prolonged exposure of B-CLL cells to stimulatory concentrations of loxoribine frequently culminates in progression of the responsive cells to apoptosis. The capacity of loxoribine to transiently approximate the reversible transformation of a low grade B cell malignancy to one of a higher grade presents the opportunity for evaluation of cycle-active drugs under these conditions. Recent studies indicate that pre-treatment of B-CLL cells with loxoribine results in synergistic killing of leukemic cells with cycle-active drugs. The ability to induce B-CLL cells into cell cycle entry and/or into either activation-induced apoptosis or into phases of the cell cycle sensitive to cytotoxic therapy opens up new perspectives for the development of potentially curative strategies for this chronic leukemia.

Pharmacokinetic study of oral and bolus intravenous 2-chlorodeoxyadenosine in patients with malignancy.

PURPOSE: This study was designed to evaluate the absolute bioavailability (F value) of 2-chlorodeoxyadenosine (cladribine; 2-CdA) after multiple oral administrations, and the intersubject variability after oral and 2-hour intravenous (IV) administration schedules in patients with malignancy. PATIENTS AND METHODS: Patients with advanced malignancies were eligible. There were two treatment cycles; during cycle 1, patients received 2-CdA solution at 0.28 mg/kg/d orally under fasting conditions for 5 consecutive days concomitantly with omeprazole, and 4 weeks later during cycle 2 patients received 2-CdA as a 2-hour IV infusion of 0.14 mg/kg/d for 5 consecutive days. Serial blood samples for 2-CdA plasma levels were obtained after drug administrations on days 1 and 5 during each treatment cycle. RESULTS: Ten patients completed cycles 1 and 2. The F value of oral 2-CdA measured on days 1 and 5 was 37.2% and 36.7%, respectively. For both oral and IV multiple administrations, there was no significant accumulation in maximum concentration (Cmax), and the intersubject variabilities (coefficient of variation [CV], approximately 40%) in Cmax and area under the concentration-time curve from 0 to 24 hours [AUC(0-24)] values were comparable for both routes on days 1 and 5. A three-compartment open model was applied to the plasma concentration data after oral and IV administrations and resulted in good agreement between observed and simulated concentration-time profiles. Neutropenia was the principal adverse event observed when 2-CdA was administered orally and IV. CONCLUSION: The F value of 2-CdA after oral administration was approximately 37% and there were no cumulative differences in bioavailability observed on multiple dosing of the drug. The absorption and disposition characteristics of oral 2-CdA were linear and predictable with this dosing regimen.

Purine nucleoside therapy of low-grade follicular lymphoma.

Low-grade follicular lymphomas, follicular small cleaved and follicular mixed, generally follow an indolent but progressive course. Although available therapies induce responses, continuous relapse occurs. In investigating potential therapeutic regimens, researchers have sought regimens that will result in a postchemotherapy survival plateau rather than a pattern of continuous relapse. The newer, purine analogs, 2'-deoxycoformycin, fludarabine, and 2-chlorodeoxyadenosine have shown activity in the low-grade B-cell lymphomas, especially with the follicular histologic subtype. Response rates in studies of previously untreated patients approach 100%. The newer purine analogs are emerging as an important treatment approach for indolent B-cell lymphomas, but the impact on survival remains to be assessed.

The optimal management of hairy cell leukaemia.

Hairy cell leukaemia is an uncommon B cell chronic lymphoproliferative disorder characterised by circulating lymphocytes displaying prominent cytoplasmic projections. Therapy is initiated for severe cytopenias or recurrent infections. Splenectomy, the first standard treatment, is now less commonly used as primary treatment. Interferon-alpha (IFN alpha) induces partial responses in most patients but complete responses in only a few. Adverse effects from IFN alpha are common but not life-threatening. The ability of two newer purine analogues, pentostatin (2'-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine), to induce long-lasting complete remissions in the majority of patients has revolutionised the treatment of this disease. Cladribine is emerging as the treatment of choice because of its favourable toxicity profile, brief duration of treatment, high percentage of unmaintained complete remissions and low incidence of relapse.

2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia.

PURPOSE: 2-chlorodeoxyadenosine (2-CdA; cladribine) is a purine analog with activity in patients with chronic lymphocytic leukemia (CLL) who fail to respond to alkylator therapy. We conducted a phase II trial of 2-CdA in previously untreated CLL patients. PATIENTS AND METHODS: 2-CdA was administered to 20 patients with previously untreated CLL as a 0.1-mg/kg/d 7-day continuous intravenous infusion every 28 to 35 days until maximum response or prohibitive toxicity. RESULTS: A median of four courses (range, one to nine) was administered to each patient. Five patients (25%) achieved a complete response and 12 (60%) achieved a partial response, for an overall response rate of 85%. The median response follow-up duration was 8+ months (range, 3 to 27). Myelosuppression was the principal toxicity. Four of 20 patients (20%) experienced grade III or IV thrombocytopenia. Three patients, all of whom received corticosteroid therapy, developed opportunistic infections at a median of 19 months following discontinuation of 2-CdA therapy. CONCLUSION: 2-CdA has major activity in patients with previously untreated CLL, and the lower response rates seen in previously treated patients may be due in part to poor marrow reserve from prior therapy. Determination of the relative effectiveness of 2-CdA, fludarabine, and chlorambucil in the treatment of CLL patients will require a randomized trial.

Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia.

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA) induces complete remissions in 85% of patients. Complete remission has been defined as the absence of hairy cells in the bone marrow after routine morphologic examination. To determine if hairy cells could be detected in complete remission bone marrows using immunohistochemical techniques with antibodies L26 (CD20) and DBA.44, 154 bone marrow biopsies performed between 3 months and 25 months after therapy were studied. Of the biopsies, 50% exhibited staining with L26 and/or DBA.44 in five or more cells with morphologic features of hairy cells. Minimal residual disease was usually less than 1% of the total cellular population. DBA.44-positive cells were demonstrated in 91% of the biopsies, although in 48% of these the morphologic features of the positive cells were not sufficiently distinctive for hairy cells. The proportion of biopsies with residual hairy cells was similar over the 25 months of follow up, indicating a relatively stable amount of residual disease. Immunomorphologic analysis is a more sensitive method for detecting residual hairy cells than morphology alone. Although further follow up is necessary to determine the clinical significance of the L26/DBA.44-positive staining in cells with and without distinctive morphologic features of hairy cells, we conclude that many patients in a stable clinical remission may have residual hairy cells.

Identification of monoclonal immunoglobulins and quantitative immunoglobulin abnormalities in hairy cell leukemia and chronic lymphocytic leukemia.

Serum and urine samples from 161 cases of hairy cell leukemia (HCL) and 50 cases of chronic lymphocytic leukemia (CLL) were analyzed for monoclonal immunoglobulin (MIg) by using a combination of high-resolution protein electrophoresis, immunoelectrophoresis, and immunofixation. Quantitative immunoglobulin analysis also was performed on all serum samples. Monoclonal immunoglobulin, usually of low intensity, was identified in serum or urine in 26 (16.1%) cases of HCL compared with 27 (54%) cases of CLL. Forty-eight (29.8%) cases of HCL had an increase in one or more immunoglobulins; increases in IgG were the most frequent. In CLL, 48 (96.0%) cases had a decrease in one or more immunoglobulins, with decreases in IgG, IgA, and IgM in 76%, 68%, and 56% of the cases, respectively. The correlation between serum or urine monoclonal immunoglobulin light chain and the surface membrane light chain was 88% in CLL compared with 47.4% in HCL. These findings confirm previous observations of frequent polyclonal hyper-gamma-globulinemia in HCL, hypo-gamma-globulinemia in CLL, and weak monoclonal immunoglobulins in both disorders. The contrasting immunoglobulin abnormalities in HCL and CLL indicate distinctive biologic differences in these chronic B-cell leukemias.

Loxoribine induces chronic lymphocytic leukemia B cells to traverse the cell cycle.

Leukemic B cells from a majority of patients with chronic lymphocytic leukemia (CLL) enter the cell cycle upon stimulation in vitro with loxoribine, a potent 7,8-disubstituted guanine ribonucleoside immunostimulant. In the absence of added costimulants, a proportion of these cells become activated and undergo DNA synthesis and mitosis accompanied by a marked increase in expression of an array of cell surface activation antigens. The resultant activated B-CLL cells exhibit greatly enhanced sensitivity to cycle-active cytotoxic drugs. This approach may be of potential value in the therapy of CLL.

Complete hematologic remissions in chronic-phase, Philadelphia-chromosome-positive, chronic myelogenous leukemia after 2-chlorodeoxyadenosine.

BACKGROUND: 2-Chlorodeoxyadenosine (Cladribine, Leustatin, Ortho Biotech, Raritan, NJ) (2-CdA) is a purine analog with activity in the treatment of lymphoid neoplasms. Interferon induces cytogenetic remissions in chronic myeloid leukemia (CML) and partial remissions in hairy cell leukemia, a disorder in which single courses of 2-CdA induce complete remissions. In vitro clonal growth of immature myeloid progenitors from normal marrow is markedly inhibited by 2-CdA. METHODS: 2-CdA was administered to 12 patients with Philadelphia-chromosome-positive CML, 11 chronic phase, and 1 accelerated phase, at 0.1 mg/kg/day by continuous intravenous infusion for 7 days every 28-35 days, until maximum peripheral hematologic response. RESULTS: Of 12 patients, 10 (83%) achieved complete hematologic responses and 2 (17%) partial hematologic responses after a median of two courses of 2-CdA. The median first hematologic response duration was 3 months. Of the seven patients who relapsed and were retreated with a median of two further courses of 2-CdA, five obtained responses (four complete and one partial) and two did not respond. The median second hematologic response duration was 4 months. No patient had significant Philadelphia-chromosome suppression. Reversible myelosuppression and severe cumulative T-cell immunosuppression associated with opportunistic infections in four patients were the principal toxicities. CONCLUSIONS: 2-CdA is active in CML, inducing complete hematologic responses, but the absence of cytogenetic responses and severe immunosuppression may limit its clinical use.