Pentostatin and Cyclophosphamide with or without Rituximab Has Significant Activity in Patients with Previously Treated Chronic Lymphocytic Leukemia and Other Low Grade Lymphoid Neoplasms.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3484-3484 ◽  
Author(s):  
Nicole Lamanna ◽  
Matt Kalaycio ◽  
Peter Maslak ◽  
Joseph Jurcic ◽  
David A. Scheinberg ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Combination Therapy ◽  
B Cell ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Significant Activity ◽  
Purine Analogs ◽  
Heavily Pretreated ◽  
Pretreated Patients

Abstract Combination therapy with purine analogs, alkylators, and/or monoclonal antibodies represents a promising new approach in the treatment of patients with chronic lymphocytic leukemia (CLL) and other low grade B cell neoplasms. Most regimens have utilized fludarabine as the purine analog, but the severe myelosuppression and immunosuppression of these combinations requires careful attention to dosing and schedule to minimize these complications. Of the purine analogs in CLL, pentostatin appears to be least myelosuppressive. We have previously reported our experience with pentostatin and cyclophosphamide (PC regimen) in a cohort of heavily pretreated patients with CLL (JCO21:1278, 2003). We have since added rituximab to this active combination (PCR regimen) and have treated a second cohort of patients with CLL and other low grade B cell neoplasms. We now report on our cumulative experience of 69 patients (23 received PC and 46 received PCR) treated with pentostatin combination therapy. The PC regimen consisted of pentostatin 4mg/m2 and cyclophosphamide 600mg/m2, given every 3 weeks for a total of 6 treatments. In the 2nd cohort of CLL patients, rituximab 375mg/m2 was added to this regimen starting with cycle 2. Supportive measures in both studies included hydration with each treatment (and monitoring of renal function) and prophylactic administration of filgrastim, sulfamethoxazole/trimethoprim, acyclovir, and antiemetics. In the first cohort of patients treated with the PC regimen, the median number of prior treatments was 3 (range 1–5) with the median age being 64 (32–77). There were responses achieved in 74% of patients with 17% complete responses seen in this heavily pretreated group. Similar (or perhaps slightly better) results were obtained with patients treated with the PCR regimen. For this cohort the median age was 62 (30–80) and the median number of prior regimens was 2 (1–7). Of the 32 patients with CLL 28 are evaluable for response: 79% responded and this includes 29% who achieved a complete response. Ten of the 14 patients with other low grade B cell diseases (SLL 8 patients, Waldenstrom’s macroglobulinemia 2 patients, follicular lymphoma 4 patients) are evaluable for response. The overall response rate for these patients was 50% (all PRs). These regimens were generally well tolerated with grade 3/4 toxicity consisting primarily of myelosuppression and its complications. We conclude that PC and PCR are highly active, well tolerated regimens even in heavily pretreated patients. We plan to conduct a multicenter study of PCR as initial therapy in patients with CLL.

Pentostatin, Cyclophosphamide, and Rituximab Is an Active, Well-Tolerated Regimen for Patients With Previously Treated Chronic Lymphocytic Leukemia

2006 ◽  
Vol 24 (10) ◽  
pp. 1575-1581 ◽  
Author(s):  
Nicole Lamanna ◽  
Matt Kalaycio ◽  
Peter Maslak ◽  
Joseph G. Jurcic ◽  
Mark Heaney ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Unknown Origin ◽  
Drug Regimen ◽  
Median Number ◽  
Initial Therapy ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Purine Analogs ◽  
Previously Treated ◽  
Grade 3

Purpose Purine analogs and alkylators are important agents for treating chronic lymphocytic leukemia (CLL). Early studies combining fludarabine and chlorambucil were abandoned owing to increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin appears to be the least myelosuppressive. We previously reported that pentostatin and cyclophosphamide (PC) is active and well-tolerated in patients with relapsed or refractory CLL. Subsequently, we added rituximab, and now report on this three-drug combination. Patients and Methods We treated 46 patients with either previously treated CLL (32 patients) or other low-grade B-cell neoplasms (14 patients). Patients received pentostatin 4 mg/m2, cyclophosphamide 600 mg/m2, and rituximab 375 mg/m2 (PCR). All drugs were administered on the same day (rituximab omitted from cycle 1), and patients received six cycles at 3-week intervals. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. Results The median age was 62 years (range, 30 to 80 years). The median number of prior regimens was two (range, one to seven). For CLL patients, there were 24 responses (75%), including eight complete responses (25%). In fludarabine-refractory patients, 75% responded. Toxicity was acceptable, with grade 3/4 infections (including fever of unknown origin) in 28%. The regimen was well tolerated, with 72% of patients receiving the planned treatment at full dose. Conclusion PCR is safe and effective in previously treated patients with CLL. In comparison with our prior two-drug regimen, we find that rituximab did not seem to add significantly to the toxicity, but did appear to confer a survival advantage. Based on these results, we are currently studying PCR as initial therapy for patients with CLL.

Pentostatin, Cyclophosphamide, Rituximab, and Mitoxantrone (PCRM): A New Highly Active Regimen for Patients with Chronic Lymphocytic Leukemia (CLL) Previously Treated with PCR or FCR.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3115-3115 ◽  
Author(s):  
Nicole Lamanna ◽  
Mark L. Heaney ◽  
Renier J. Brentjens ◽  
Joseph G. Jurcic ◽  
Mark A. Weiss
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Phase 1 ◽  
Median Number ◽  
Infectious Complications ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Prior Therapy ◽  
Treatment Regimens ◽  
Highly Active ◽  
Purine Analogs

Combination therapy with purine analogs, alkylators, and/or monoclonal antibodies has markedly improved the quality of responses in patients with chronic lymphocytic leukemia (CLL). Most regimens have utilized fludarabine as the purine analog but the severe myelosuppression and immunosuppression of these combinations require careful attention to dosing and schedule to minimize these toxic complications. Of the purine analogs active in CLL, pentostatin is the least myelosuppressive. Previously, we reported that combination pentostatin, cyclophosphamide, and rituximab was very active and acceptably safe to administer to patients with CLL and in the salvage setting this regimen appeared to have less myelosuppression and less frequent infectious complications than comparable fludarabine-based combinations. The current study combines pentostatin 4mg/m2, cyclophosphamide 600mg/m2, rituximab 375mg/m2 (omitted from cycle 1) and mitoxantrone (dose escalated in a phase 1 portion starting at 6mg/m2, 8mg/m2, and 10mg/m2) all administered on day 1 of 28-day cycles for a total of 6 treatments. Supportive measures included prophylactic administration of pegfilgrastim, sulfamethoxazole/trimethoprim, acyclovir, and antiemetics. Renal function was closely monitored and all patients received at least 1.5 liters of intravenous hydration with the administration of chemotherapy. Twenty-one patients (median age 62, range 44–74) with CLL (17 patients) or other low grade B cell neoplasms (4 patients) have been enrolled. There were 16 men and 5 women. Of the CLL patients all had either high risk disease (71%) or “active” intermediate (29%) risk disease and their median pretreatment WBC count was 74,000/μl, HGB 9.9 g/dl, and PLT 144,000/μl. The median β-2 microglobulin was 3.3 mg/l. The median number of prior treatment regimens was two (range 1–6). Most of the CLL patients (65%) had previously been treated with chemoimmunotherapy utilizing PCR or FCR. Response data is currently available for 16/17 of the CLL patients. In this group there were 15 responses (94%), including 4 CRs (25%) and 11 PRs (69%). Prior therapy with PCR or FCR did not adversely affect the frequency of response with 91% of these patients responding (CR in 19% and PRs in 73%). These preliminary results indicate that PCRM therapy is very active and well tolerated even in patients who have previously received FCR or PCR.

Pentostatin and Cyclophosphamide: An Effective New Regimen in Previously Treated Patients With Chronic Lymphocytic Leukemia

2003 ◽  
Vol 21 (7) ◽  
pp. 1278-1284 ◽  
Author(s):  
Mark A. Weiss ◽  
Peter G. Maslak ◽  
Joseph G. Jurcic ◽  
David A. Scheinberg ◽  
Timothy B. Aliff ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Response Rate ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Severe Nausea ◽  
Treatment Regimens ◽  
Purine Analogs ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Grade 3

Purpose: Purine analogs and alkylators are important agents in the treatment of chronic lymphocytic leukemia (CLL). Previously, combinations of fludarabine and chlorambucil were abandoned because of increased toxicity from overlapping myelosuppression and immunosuppression. Of the purine analogs active in CLL, pentostatin may be least myelosuppressive. We hypothesized that combining pentostatin with cyclophosphamide would have less myelotoxicity than combinations using other purine analogs. Patients and Methods: We studied 23 patients with previously treated CLL. All patients received pentostatin 4 mg/m2. Seventeen patients received cyclophosphamide 600 mg/m2, and six patients received cyclophosphamide 900 mg/m2. Both drugs were administered on day 1 of each cycle, and cycles were repeated every 3 weeks for six treatments. Filgrastim, sulfamethoxazole/trimethoprim, and acyclovir were administered prophylactically. The median number of prior treatment regimens was three (range, one to five) with 13 patients (57%) refractory to prior fludarabine therapy. Results: The cyclophosphamide 900 mg/m2 dose level was associated with moderate to severe nausea, and we chose cyclophosphamide 600 mg/m2 as the dose for further study. There were 17 responses (74%; 95% confidence interval, 63% to 85%), including four complete responses. The response rate was 77% in fludarabine-refractory patients. Myelosuppression was acceptable with grade 3/4 neutropenia and thrombocytopenia, seen in 35% and 30% of patients, respectively. The relative sparing of thrombopoiesis can be seen in that only one patient (5%) with an initial platelet count of more than 20,000 required platelet transfusions while receiving therapy. Conclusion: Pentostatin 4 mg/m2 with cyclophosphamide 600 mg/m2 is safe and effective in previously treated patients with CLL. On the basis of these results, we are currently studying pentostatin, cyclophosphamide, and rituximab (PCR) therapy in patients with CLL.

Cytokine-Release Syndrome in Patients With B-Cell Chronic Lymphocytic Leukemia and High Lymphocyte Counts After Treatment With an Anti-CD20 Monoclonal Antibody (Rituximab, IDEC-C2B8)

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2217-2224 ◽  
Author(s):  
U. Winkler ◽  
M. Jensen ◽  
O. Manzke ◽  
H. Schulz ◽  
V. Diehl ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
B Cell ◽  
Tumor Cells ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Anti Cd20 ◽  
Cell Chronic Lymphocytic Leukemia

Eleven patients with relapsed fludarabine-resistant B-cell chronic lymphocytic leukemia (CLL) or leukemic variants of low-grade B-cell non-Hodgkin’s lymphoma (NHL) were treated with the chimeric monoclonal anti-CD20 antibody rituximab (IDEC-C2B8). Peripheral lymphocyte counts at baseline varied from 0.2 to 294.3 × 109/L. During the first rituximab infusion, patients with lymphocyte counts exceeding 50.0 × 109/L experienced a severe cytokine-release syndrome. Ninety minutes after onset of the infusion, serum levels of tumor necrosis factor- (TNF-) and interleukin-6 (IL-6) peaked in all patients. Elevated cytokine levels during treatment were associated with clinical symptoms, including fever, chills, nausea, vomiting, hypotension, and dyspnea. Lymphocyte and platelet counts dropped to 50% to 75% of baseline values within 12 hours after the onset of the infusion. Simultaneously, there was a 5-fold to 10-fold increase of liver enzymes, d-dimers, and lactate dehydrogenase (LDH), as well as a prolongation of the prothrombin time. Frequency and severity of first-dose adverse events were dependent on the number of circulating tumor cells at baseline: patients with lymphocyte counts greater than 50.0 × 109/L experienced significantly more adverse events of National Cancer Institute (NCI) grade III/IV toxicity than patients with less than 50.0 × 109/L peripheral tumor cells (P= .0017). Due to massive side effects in the first patient treated with 375 mg/m2 in 1 day, a fractionated dosing schedule was used in all subsequent patients with application of 50 mg rituximab on day 1, 150 mg on day 2, and the rest of the 375 mg/m2 dose on day 3. While the patient with the leukemic variant of the mantle-cell NHL achieved a complete remission (9 months+) after treatment with 4 × 375 mg/m2 rituximab, efficacy in patients with relapsed fludarabine-resistant B-CLL was poor: 1 partial remission, 7 cases of stable disease, and 1 progressive disease were observed in 9 evaluable patients with CLL. On the basis of these data, different infusion schedules and/or combination regimens with chemotherapeutic drugs to reduce tumor burden before treatment with rituximab will have to be evaluated.

Pharmacokinetic Study of Single Doses of Oral Fludarabine Phosphate in Patients With “Low-Grade” Non-Hodgkin's Lymphoma and B-Cell Chronic Lymphocytic Leukemia

1999 ◽  
Vol 17 (5) ◽  
pp. 1574-1574 ◽  
Author(s):  
James M. Foran ◽  
David Oscier ◽  
Jennifer Orchard ◽  
Stephen A. Johnson ◽  
Mary Tighe ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Intravenous Administration ◽  
Pharmacokinetic Study ◽  
Lymphocytic Leukemia ◽  
Hodgkin's Lymphoma ◽  
Low Grade ◽  
Fludarabine Phosphate ◽  
Non Hodgkin's Lymphoma ◽  
Cell Chronic Lymphocytic Leukemia

PURPOSE: Fludarabine phosphate (F-AMP), a purine analog, requires daily intravenous administration. A pharmacokinetic study of an oral formulation (10 mg immediate-release tablet) was undertaken in patients with “low-grade” non-Hodgkin's lymphoma and B-cell chronic lymphocytic leukemia. PATIENTS AND METHODS: Oral F-AMP was incorporated into the “conventional” treatment schedule. Single oral trial doses of 50, 70, and 90 mg of F-AMP were given on the first day of three cycles of treatment; a comparative 50-mg intravenous trial dose was given on the first day of the fourth cycle. Intravenous F-AMP (25 mg/m2) was given on days 2 to 5 at 4-week intervals. Pharmacokinetic samples taken after each trial dose were analyzed for plasma 2-fluoro-arabinofuranosyl-adenine (2F-ara-A) concentration (its main metabolite); area under the curve 0 to 24 hours (AUC(0-24h)) and maximum concentration (Cmax) were calculated. Eighteen patients received all three oral trial doses, and bioavailability was determined in 15 patients who completed four courses of therapy. RESULTS: Oral administration of F-AMP resulted in a dose-dependent increase in Cmax and AUC(0-24h) of 2F-ara-A and achieved an AUC(0-24h) similar to intravenous administration, although at a lower Cmax. The linear increase in mean AUC(0-24h) by factors of 1.36 ± 0.22 (mean ± SD) and 1.72 ± 0.31 corresponded well with the increase in oral dose from 50 to 70 mg (factor of 1.4) and 90 mg (factor of 1.8), respectively. Bioavailability (approximately 55%, with low intraindividual variation) and time to Cmax were dose independent. CONCLUSION: Oral doses of F-AMP can achieve an AUC(0-24h) of 2F-ara-A similar to intravenous administration, with dose-independent bioavailability. The tablet will greatly enhance the use of F-AMP in a palliative setting.

B Cell Activating Factor and c-Myc Regulate the Progression of Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 359-359
Author(s):  
Weizhou Zhang ◽  
Arnon P. Kater ◽  
Han-Yu Chuang ◽  
Thomas Enzler ◽  
George F. Widhopf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Disease Progression ◽  
Cell Population ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Low Grade ◽  
B Cell Activating Factor

Abstract Abstract 359 Chromosomal translocations involving c-Myc are frequently found in high grade lymphoma and multiple myeloma. In contrast, c-Myc translocations rarely occur in low-grade lymphomas/leukemias like chronic lymphocytic leukemia (CLL), but when present they are associated with rapid disease progression and bad prognosis. Overexpression of c-myc may also be the result of increased transcription by several proto-oncogene transcription factors, including NF-kB. Mice with c-Myc de-regulation at different stages of B cell development develop either aggressive B cells lymphomas or plasma cell neoplasm. So far, no c-Myc mouse model developed low-grade lymphoma/leukemia. iMycCa mice develop an expansion of CD5+ peritoneal B1 cells, as compared with WT littermates mice. These mice have a normal life-span and very rarely develop B cell lymphoma at older age. Interestingly, in iMycCa mice mature B cells, but not plasma cells,could be rescued from apoptosis by administration of B cell-activating factor belonging to the TNF family (BAFF). To our surprise, double transgenic iMycCa/Baff-Tg (Myc/Baff) mice developed a disease resembling human CLL, with dramatically shorter mean survival than parental strains, due to early onset and rapid clonal expansion of a mature CD5+B220low B cell population. Those cells transferred the disease into Baff-Tg (Baff) mice with marked infiltration in lymphoid organs and bone marrow. Gene-expression analyses revealed that among the genes altered in Myc/Baff CD5+B220lowleukemia cells were those with known relevance to human CLL disease, including elevated anti-apoptotic Bcl2 family members. Apart from studies on individual genes, sub-network analysis was performed which showed enrichment of apoptosis-related and stress-induced gene sets in Myc/Baff CD5+CD3- leukemia cells. The NF-kB gene set, a major target downstream of BAFF signaling, was also enriched in Myc/Baff CD5+CD3- leukemia cells. We observed a continuum in levels of c-MYC mRNA in 166 samples using Affymetrix array analyses. Changes in c-Myc protein expression were confirmed by immunoblot analyses and correlated with disease progression. In accordance with the functions of c-Myc as a promoter of cell cycle progression, as well as apoptosis, we found enhanced spontaneous cell death in vitro in CLL cells expressing high levels of c-Myc, which could be abrogated by co culture with BAFF expressing nurse-like cells (NLC) or recombinant BAFF. In addition to its anti-apoptotic role, BAFF treatment of primary human CLL cells led to dramatically enhanced expression of c-Myc through the IKK/NF-kB pathway. Inhibition of the NF-kB pathway significantly reduced viability of both Myc/Baff CD5+CD3- leukemia cells and human CLL cells co-cultured with NLC. Also it significantly lowered CD5+B220low leukemia cell population in blood and spleen, and prevented the infiltration of leukemia cells into lymph nodes and bone marrow of transplanted mice. This study demonstrates a potential pathologic role for c-Myc, in the pathogenesis and progression of CLL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals bcl-2 gene hypomethylation and high-level expression in B-cell chronic lymphocytic leukemia

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1820-1828 ◽  
Author(s):  
M Hanada ◽  
D Delia ◽  
A Aiello ◽  
E Stadtmauer ◽  
JC Reed
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Lines ◽  
Methylation Status ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Low Grade ◽  
Gene Rearrangements ◽  
Normal Peripheral Blood ◽  
Cell Chronic Lymphocytic Leukemia

Abstract The bcl-2 gene becomes transcriptionally deregulated in the majority of low-grade non-Hodgkin lymphomas as a result of t(14;18) translocations that place the bcl-2 gene at 18q21 into juxtaposition with the Ig heavy- chain locus at 14q32. This chromosomal translocation or similar bcl-2 gene rearrangements involving the Ig light-chain genes have been reported to occur in some cases of B-cell chronic lymphocytic leukemia (B-CLL). We analyzed the structure, methylation, and expression of the bcl-2 gene in 20 cases of B-CLL or closely related variants of this lymphoproliferative disorder, including at least 16 typical examples of CD5+ B-CLL. None of the 20 specimens had evidence of bcl-2 gene rearrangements, based on Southern blot analysis using three different bcl-2 probes. However, immunoblot analysis using antibodies specific for the Bcl-2 protein showed that 14 of 20 cases (70%) contained levels of p26-Bcl-2 that were equal to or greater than those found in a t(14;18)-bearing lymphoma cell line. Furthermore, in 19 of 20 cases (95%), the Bcl-2 protein was present at levels that were 1.7- to 25- fold higher than in normal peripheral blood lymphocytes. These differences in the relative levels of Bcl-2 protein among cases of B- CLL appeared to be functionally significant, in that a preliminary analysis of 3 representative cases showed that CLL cells with higher levels of Bcl-2 protein survived longer in culture and were delayed in their onset of DNA degradation relative to CLL cells with lower Bcl-2 protein levels. Evaluation of the methylation status of the bcl-2 gene using the isoschizomers Msp I and Hpa II, and a probe corresponding to the first major exon of the gene showed complete demethylation of both copies of the bcl-2 gene in a region corresponding to a 2.4-kb Msp I fragment in all 20 cases of B-CLL. In contrast, analysis of 6 of 6 B- cell lines that harbor a t(14;18) was consistent with hypomethylation of only one of the two bcl-2 alleles. Neither copy of the bcl-2 gene was demethylated in this region in 5 of 5 lymphoid cell lines that lack this translocation. However, hypomethylation of the bcl-2 gene did not necessarily correlate with the relative levels of Bcl-2 protein present in the B-CLL cells, suggesting that additional mechanisms for regulating bcl-2 expression are involved.(ABSTRACT TRUNCATED AT 400 WORDS)

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