Potential Therapeutic Applications of Oblimersen in CLL

Potential Therapeutic Applications of Oblimersen in CLL

ABSTRACT: Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including chronic lymphocytic leukemia (CLL). The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance. Previous studies have shown that reduction of bcl-2 expression by antisense therapy sensitizes cells to chemotherapy-induced apoptosis. In vitro, the Bcl-2 antisense drug oblimersen sodium (Genasense, previously known as G3139) enhances the apoptotic response in CLL cells to fludarabine (Fludara), corticosteroids, alemtuzumab (Campath), and rituximab (Rituxan). A phase I trial in patients with refractory/relapsed CLL showed that patients with CLL were more sensitive to oblimersen than patients with solid tumors. The maximum tolerated oblimersen dose was 3 mg/kg/d, and the most common dose-limiting reaction was hypotension, frequently in association with high spiking fever. In this study, oblimersen displayed limited singleagent activity, including tumor lysis syndrome, transient decreases in circulating CLL cells, and reduction of splenomegaly and size of lymph nodes. Major responses were observed in 9% of patients. Subsequently, a phase III trial evaluating fludarabine and cyclophosphamide with or without oblimersen (3 mg/kg/d for 7 days) was initiated in patients with relapsed or refractory CLL. This trial recently completed accrual of 241 patients.

B-cell chronic lymphocytic leukemia (B-CLL) is a disorder characterized by the unremitting accumulation of small, slowly proliferating CD5+/CD19+/CD20+ (weak)/CD23+/sIg+ (weak) monoclonal B cells.[1] CLL is very rare in people younger than age 40. However, its incidence increases sharply after the fourth decade of life, to the point of being the predominant leukemic type in the elderly in the Western world, across race and sex differences (Figure 1). It is estimated that 7,300 new cases were diagnosed in the United States in 2003.[2] Statistics from the nine population-based cancer registries of the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) Program for 2000 showed significantly better survival differences for patients younger than age 65 (average presentation age: 64 years) than for those 65 years of age and older, although CLL shortens life expectancy considerably, even in younger patients (Table 1).[3] Prognostic Indicators Neither the Rai[4] nor the Binet[5] staging systems, which discriminate CLL by the sites of disease and/or the degree of cytopenias induced by leukemic marrow replacement, enable physicians to identify patients in the good-prognosis group who will eventually progress. However, over time, these systems have proved to be extremely useful for categorizing patients, particularly those participating in clinical trials. The original Rai system[4] consisted of five stages (0 to IV) but was modified to a three-stage scheme in 1987,[6] when analysis of survival data in a large number of patients established three distinct risk categories (low, intermediate, and high), which differ significantly in terms of median survival. Patients in the low-risk group (stage 0) have lymphocytosis with no other abnormality; patients in the intermediate-risk group have enlarged lymph nodes (stage I) and/or spleen (stage II) in addition to lymphocytosis; and patients in the high-risk group have anemia (hemoglobin value < 11.0 g/dL, stage III) and/or thrombocytopenia (platelet count of < 100 * 109/L, stage IV) (Table 2). Serum levels of beta2-microglobulin,[ 7] lactate dehydrogenase, soluble CD23,[8] and the cell-surface expression of CD38[9] can help predict disease activity. However, the presence of certain cytogenetic abnormalities in the leukemic B cells [10,11] and/or somatic mutations in the immunoglobulin heavy-chain genes seem to predict rapid disease progression and survival more accurately.[12,13] Genetic Components CLL B cells with mutated immunoglobulin heavy-chain genes are associated with the more favorable genetic defect deletion 13q14. Conversely, unmutated immunoglobulin heavy-chain genes are associated with trisomy 12 and the high-risk 17p and 11q genomic aberrations.[14] CLL B cells with unmutated immunoglobulin heavy-chain genes generally show the distinctive expression of the zetaassociated protein of 70 kD (ZAP-70), an intracellular tyrosine kinase, which has been found to be associated with enhanced immunoglobulin receptor signaling in CLL B cells. Mounting data indicate that expression of ZAP- 70 is a more reliable marker of the risk of early disease progression than the mutational status of the expressed immunoglobulin heavy-chain genes in CLL.[15,16] Disease Subtypes Based on these recent findings, it has been proposed that there are two types of CLL (Table 3). The first type arises from relatively less differentiated or "immunologically naive" pregerminal B cells with unmutated immunoglobulin heavy-chain genes, displays atypical CLL morphology, and has a poor prognosis. The other type evolves from more differentiated postgerminal "memory" B cells with somatically mutated immunoglobulin heavy-chain genes and has a good prognosis.[17,18] Treatment With Chemotherapy or Chemoimmunotherapy Approximately one-third of patients with CLL never require treatment. In another third, an initial indolent phase is followed by disease progression. The remaining third show aggressive disease at the outset and need immediate treatment. Ultimately, 50% of patients with CLL will require treatment. Deferring therapy until progression of CLL does not affect survival. Neither single-agent chlorambucil (Leukeran) nor a variety of combination chemotherapy regimens (some including anthracyclines) have been shown to increase response rates or improve survival in clinical studies.[ 19-21] A meta-analysis of 2,048 patients with early-stage disease included in seven randomized trials comparing immediate or deferred treatment with chlorambucil demonstrated no benefit in either arm.[22] A summary of clinical experience with chemotherapy and chemoimmunotherapy in CLL is provided in Table 4.[23-30] Fludarabine (Fludara), a purine analog, yields better response rates than chlorambucil but causes more myelosuppression and greater reduction in CD4+ lymphocytes.[31] The results of three phase III randomized trials in previously untreated patients with CLL demonstrated the superiority of fludarabine over other alkylating agent-based therapy in terms of response, duration of remission, and disease progression-free survival (but not overall survival).[24,25,27] A phase II trial conducted by Flinn and colleagues[26] showed a complete response rate of 47% in 17 untreated patients with CLL who received fludarabine and cyclophosphamide plus filgrastim (Neupogen) support. In a subsequent randomized phase II trial that was conducted for the Cancer and Leukemia Group B (CALGB 9712), Byrd et al[29] demonstrated that the administration of fludarabine concurrently with rituximab (Rituxan) for 6 monthly courses followed by rituximab 2 months later for 4 weekly courses also produced a complete response rate of 47% in 51 untreated patients with B-CLL. These results compared favorably with results that were observed in 53 patients who received fludarabine alone for 6 months followed sequentially 2 months later by rituximab consolidation.[ 29] Of note, two studies[32,33] testing higher doses of single-agent rituximab in patients with pretreated and untreated B-CLL demonstrated a doseresponse relationship for this agent. In addition, investigators at the University of Texas M. D. Anderson Cancer Center recently reported a complete response rate of 67% in 135 patients with CLL receiving fludarabine (25 mg/m2/d) for 3 days, cyclophosphamide (250 mg/m2/d) for 3 days, and rituximab (375 to 500 mg/m2) on day 1 of each treatment cycle.[30] These responses included a high proportion of patients with molecular remissions, indicating the possibility to consolidate the response with autologous hematopoietic cell transplantation. Another treatment option available for patients with chronic lymphocytic leukemia is conventional allogeneic bone marrow transplantation, which may be curative in some cases. However, only 10% of patients are eligible for this treatment, which is associated with significant morbidity and mortality.[34] Allogeneic bone marrow transplantation in which the patient's marrow is not completely ablated by chemotherapy with or without low-dose radiotherapy (often termed a minitransplant) is another option now being evaluated for patients with CLL.[35] Treatment With Oblimersen Sodium Preclinical Experience
A variety of investigational agents that include an assortment of chemical compounds, monoclonal antibodies, and biologic approaches have been evaluated for the treatment of CLL and await confirmation of their clinical usefulness in comparative studies (Table 5). Notable among them is oblimersen sodium injection (Genasense, formerly known as G3139), an innovative treatment modality in the form of an antisense oligonucleotide targeted to the Bcl-2 molecule. Bcl-2 protein is upregulated in a wide variety of lymphoid malignancies, including CLL. The protein is thought to be responsible for maintaining the viability of malignant lymphoid cells and may contribute to chemotherapy and radiotherapy resistance.[36,37] Higher levels of Bcl-2 protein expression have been inversely correlated with survival in previously untreated patients with CLL.[38] In B-CLL cells, expression levels of Bcl-2 protein were significantly elevated over those of normal B cells and correlated inversely with those of the proapoptotic protein BAX.[39] In addition, quantitative expression analysis by reverse transcription polymerase chain reaction showed the relative ratio of Bcl-2 protein to BAX to be markedly increased in CLL and also in mantle cell lymphoma.[40] Previous studies have shown that reduction of Bcl-2 protein expression by antisense therapy sensitizes cells to chemotherapy- induced apoptosis.[41,42] The activity of oblimersen in CLL has been evaluated in vitro and in vivo. Auer et al[43] showed that in cells obtained by CD19 selection of peripheral blood samples from patients with CLL, Bcl-2 protein expression was significantly downregulated and markers of apoptosis upregulated by oblimersen in a sequence-specific manner, compared with sense and nonsense oligonucleotide controls. In this system, oblimersen (2 μM) was more active than either fludarabine (50 μM) or dexamethasone (1 μM) as an inducer of apoptosis, and potentiation of this activity was noted when oblimersen was combined with either fludarabine or dexamethasone.[43] Furthermore, pretreatment with oblimersen sensitized CLL cells to the apoptotic effect of rituximab in a doseresponse relationship. With similar culture systems, synergism to induce apoptosis has been shown in vitro for oblimersen combined with the novel proteasome inhibitor bortezomib (PS-341, Velcade) [44] and with the humanized anti- CD52 monoclonal antibody alemtuzumab (Campath 1H).[45] In these studies, CD19 antibody-selected CLL cells from 12 patients were put in short-term culture with or without oblimersen (at a concentration of 5 μM) to reduce Bcl-2 protein levels. Control sense and nonsense oligonucleotides were also used. Alemtuzumab was added at concentrations ranging from 1 μg/mL to 10 μg/mL. All CLL samples showed some apoptosis with alemtuzumab alone; however, those cells pretreated with oblimersen showed an enhanced level of apoptosis. The addition of oblimersen greatly enhanced the effectiveness of alemtuzumab with similar cell kill at 20% of the dose compared with alemtuzumab alone.[45] Clinical Experience
Oblimersen was evaluated in a nonrandomized phase I/II trial as monotherapy for heavily pretreated patients with relapsed or refractory CLL to determine the maximum tolerated dose and evaluate single-agent activity.[46] Fourteen patients received oblimersen as a continuous intravenous (IV) infusion at a daily dose ranging from 3 to 7 mg/kg for 5 to 7 days every 3 weeks. Several patients exhibited antitumor effects, including tumor lysis, reduction in circulating CLL cells, and decreases in lymphadenopathy and splenomegaly. One patient with Richter's syndrome developed a stable partial response that was reported to last several years. In cycle 1, patients received one of four different oblimersen doses: 3, 4, 5, or 7 mg/kg/d. Six of the patients receiving higher dosages (3 receiving 7 mg/kg/d, 1 receiving 5 mg/kg/d, and 2 receiving 4 mg/kg/d) showed doselimiting toxicity requiring treatment discontinuation (high fever, severe hypotension, hypoglycemia, and back pain requiring opiate analgesics) despite reduction of leukocytosis. In cycle 2, two patients who were escalated from a lower dose to 7 mg/kg/d also showed dose-limiting toxicity. These findings clearly demonstrated that patients with CLL are more sensitive to the side effects of oblimersen than patients with solid tumors, in whom these doses are generally well tolerated. Either tumor lysis or direct oligonucleotide immunostimulation of the malignant B cells is thought to be responsible for this distinct toxicity pattern.[47,48] In a subsequent phase I/II trial in 26 patients with relapsed or refractory CLL who had previously received fludarabine, oblimersen was administered as a continuous IV infusion at a dosage of 3 mg/kg/d for 5 to 7 days every 3 to 4 weeks.[49] Six patients in phase I received the phase II dose of oblimersen (3-4 mg/kg/d). Patients had received a median of 3 (range: 1- 13) prior chemotherapy regimens for CLL. Thirteen, 7, and 4 patients had Rai stages II, III, and IV, respectively, and 2 patients had Richter's transformation. The median age was 61 years (range, 44-70). The evaluable population included 23 patients who received the phase II dose for ≥ 2 cycles (6 enrolled in phase I, and 17 enrolled in phase II). Two patients (9%) achieved partial response, 11 (48%) showed stable disease, and the remaining 10 patients (43%) had progressive disease. Reductions in circulating CLL cells of ≥ 50% from baseline were seen in 9 of 23 patients (39%). In addition ≥ 50% decrease in lymphadenopathy was seen in 8 of 19 patients (42%), and a ≥ 50% reduction of hepatomegaly or splenomegaly was seen in 8 of 16 patients (50%). Oblimersen (3 to 4 mg/kg/d) was well tolerated, with only rare grade 3 or higher toxicities reported. The most common symptoms were fatigue, night sweats, increased dyspnea, and pneumonia. Results confirmed that oblimersen has antitumor activity in pa- tients with CLL, even in the absence of other cytotoxic drugs, and that a daily dose of 3 mg/kg was well tolerated. Subsequently, a phase III trial evaluating fludarabine (25 mg/m2) and cyclophosphamide (250 mg/m2; days 1-3) with or without oblimersen (3 mg/kg/d continuous IV infusion; days 1-7) was initiated in patients with relapsed or refractory CLL. Stratification at recruitment grouped patients according to three criteria: 1) "responsiveness" or "refractoriness" to fludarabine; 2) number of previous chemotherapy regimens (1-2 vs ≥ 3); and 3) duration of response to prior therapy (≥ 6 vs < 6 months). The primary end point was response rate (complete response plus nodular partial response), and secondary end points were overall response (complete response plus nodular partial response plus partial response), overall survival, and time to disease progression. This trial recently completed accrual of 241 patients. Conclusion The rationale for evaluating oblimersen in CLL is that Bcl-2 protein is highly expressed and in all likelihood is a key survival factor in this disease. Oblimersen has shown limited single-agent activity in patients with previously treated CLL. In addition, patients with CLL appear to have considerably more sensitivity to the development of significant hypotension and fever than patients with solid tumors who receive oblimersen at similar dosages, who exhibit better tolerance. Oblimersen 3 mg/kg/d was well tolerated in phase II trials, and this dosage was used in the phase III trial. A trial of oblimersen combined with fludarabine and rituximab in patients with previously untreated or relapsed CLL has recently been initiated.


The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.


1. Cheson BD, Bennett JM, Grever M, et al: National Cancer Institute-Sponsored Working Group Guidelines for Chronic Lymphocytic Leukemia: Revised Guidelines for Diagnosis and Treatment. Blood 87:4990-4997, 1996.
2. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 53:5-26, 2003.
3. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer. SEER*Stat Database: Incidence SEER 9 Regs, 11/02 Sub (1973-2000), NCI, DCCPS, Surveillance Research Program, Cancer Statistics Branch, rel. 4/03, based on 11/02 submission.
4. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of CLL. Blood 46:219-234, 1975.
5. Binet JL, Leporrier M, Dighiero G, et al: A clinical staging system for chronic lymphocytic leukaemia: Prognostic significance. Cancer 40:855-864, 1977.
6. Rai KR: A critical analysis of staging in CLL, in Gale RP, Rai KR (eds): Chronic Lymphocytic Leukemia: Recent Progress and Future Direction, pp 253-264. NY, Alan R. Liss, 1987.
7. Kantarjian HM, Smith T, Estey E, et al: Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia. Am J Med 93:599-604, 1992.
8. Molica S, Levato D, Dell’Olio M, et al: Cellular expression and serum circulating levels of CD23 in B-cell chronic lymphocytic leukaemia: Implications for prognosis. Haematologica 81:428-433, 1996.
9. Ibrahim S, Keating M, Do KA, et al: CD38 expression as an important prognostic factor in B-cell chronic lymphocytic leukemia. Blood 98:181-186, 2001.
10. Han T, Ozer H, Sadamori N, et al: Prognostic importance of cytogenetic abnormalities in patients with chronic lymphocytic leukemia. N Engl J Med 310:288-292, 1984.
11. Juliusson G, Oscier DG, Fitchett M, et al: Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities. N Engl J Med 323:720-724, 1990.
12. Hamblin TJ, Davis Z, Gardiner A, et al: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94:1848-1854, 1999.
13. Damle RN, Wasil T, Fais F, et al: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94:1840-1847, 1999.
14. Oscier DG, Gardiner AC, Mould SJ, et al: Multivariate analysis of prognostic factors in CLL: Clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors. Blood 100:1177-1184, 2002.
15. Rassenti LZ, Huynh L, Toy TL, et al: ZAP-70 is a more reliable marker of disease progression risk than immunoglobulin mutation status in chronic lymphocytic leukemia (abstract 106). Blood 102(11 pt 1):34, 2003.
16. Grever MR, Dewald GW, Lucas DM, et al: ZAP-70 protein expression varies by interphase cytogenetic group and may predict disease progression to requirement of treatment among select genetic groups in patients with chronic lymphocytic leukaemia (CLL) (abstract 244). Blood 102(11 pt 1):73, 2003.
17. Kröber A, Seiler T, Benner A, et al: IgV(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100:1410-1416, 2002.
18. Hamblin TJ, Orchard JA, Ibbotson RE, et al: CD38 expression and immunoglobulin variable region mutation are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 99:1023-1029, 2002.
19. French Cooperative Group on Chronic Lymphocytic Leukemia: Effects of chlorambucil and therapeutic decision in initial forms of CLL (stage A): Results of a randomized clinical trial on 612 patients. Blood 75:1414-1421, 1990.
20. French Cooperative Group on Chronic Lymphocytic Leukaemia: Long-term results of the CHOP regimen in stage C chronic lymphocytic leukemia. Br J Haematol 73:334- 340, 1989.
21. French Cooperative Group on Chronic Lymphocytic Leukemia: A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. Blood 75:1422-1425, 1990.
22. CLL Trialists’ Collaborative Group: Chemotherapeutic options in chronic lymphocytic leukemia: A meta-analysis of the randomized trials. J Natl Cancer Inst 91:861-868, 1999.
23. Johnson S, Smith AG, Loffler H, et al: Multicentre prospective randomised trial of fludarabine vs cyclophosphamide, doxorubicin, and prednisone for treatment of advancedstage chronic lymphocytic leukaemia. French Cooperative Group on CLL. Lancet 347:1432- 1438, 1996.
24. Rai KR, Peterson BL, Appelbaum FR, et al: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343:1750-1757, 2000.
25. Leporrier M, Chevret S, Cazin B, et al: Randomized comparison of fludarabine, CAP and CHOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98:2319-2325, 2001.
26. Flinn IW, Byrd JC, Morrison C, et al: Fludarabine and cyclophosphamide with filgrastim support in patients with previously untreated indolent lymphoid malignancies. Blood 96:71-75, 2000.
27. O'Brien SM, Kantarjian HM, Cortes J, et al: Results of the fludarabine and cyclophosphamide combination regimen in CLL. J Clin Oncol 19:1414-1420, 2001.
28. Cazin B, Maloum K, Divine M, et al: Oral fludarabine and cyclophosphamide in previously untreated CLL: Preliminary data on 59 pts (abstract 3214). Blood 98(11 pt 1):772, 2001.
29. Byrd JC, Peterson BL, Morrison VA, et al: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: Results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101:6-14, 2003.
30. Keating MJ, Manshouri T, O’Brien S, et al: A high proportion of molecular remissions can be obtained with a fludarabine, cyclophosphamide, rituximab combination (FCR) in chronic lymphocytic leukaemia (CLL) (abstract 771). Blood 100(11 pt 1):205, 2002.
31. Grever MR, Kopecky KJ, Coltman CA, et al: Fludarabine monophosphate: A potentially useful agent in chronic lymphocytic leukemia. Nouv Rev Fr Hematol 30:457-459, 1988.
32. O’Brien SM, Kantarjian H, Thomas DA, et al: Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19:2165- 2170, 2001.
33. Byrd JC, Murphy T, Howard RS, et al: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 19:2153-2164, 2001.
34. Dreger P, Montserrat E: Autologous and allogeneic stem cell transplantation for chronic lymphocytic leukemia. Leukemia 16:985-992, 2002.
35. Khouri IF, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-vs-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 16:2817-2824, 1998.
36. Aguilar-Santelises M, Rottenberg ME, Lewin N, et al: Bcl-2, Bax and p53 expression in B-CLL in relation to in vitro survival and clinical progression. Int J Cancer 69:114-119, 1996.
37. Aviram A, Rabizadeh E, Zimra Y, et al: Expression of bcl-2 and bax in cells isolated from B-chronic lymphocytic leukemia patients at different stages of the disease. Eur J Haematol 64:80-84, 2000.
38. Faderl S, Keating MJ, Do KA, et al: Expression profile of 11 proteins and their prognostic significance in patients with CLL. Leukemia 16:1045-1052, 2002.
39. Klein U, Tu Y, Stolovitzky GA, et al: Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194:1625-1638, 2001.
40. Korz C, Pscherer A, Benner A, et al: Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosisassociated genes. Blood 99:4554-4561, 2002.
41. Kitada S, Takayama S, De Riel K, et al: Reversal of chemoresistance of lymphoma cells by antisense-mediated reduction of bcl-2 gene expression. Antisense Res Dev 4:71-79, 1994.
42. Pepper C, Thomas A, Hoy T, et al: Antisense-mediated suppression of Bcl-2 highlights its pivotal role in failed apoptosis in B-cell chronic lymphocytic leukemia. Br J Haematol 107:611-615, 1999.
43. Auer RL, Corbo M, Fegan CD, et al: Bcl- 2 antisense (Genasense) induces apoptosis and potentiates activity of both cytotoxic chemotherapy and rituximab in primary CLL cells (abstract 3358). Blood 98(11 pt 1):808, 2001.
44. Pahler JC, Ruiz S, Niemer I, et al: Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia. Clin Cancer Res 9:4570-4577, 2003.
45. Cotter FE, Auer R, Corbo M, et al: Oblimersen sodium (G3139) sensitizes malignant B-cells to alemtuzumab (Ab) induced apoptosis (abstract 910). Proc Am Soc Clin Oncol 22:227, 2003.
46. O’Brien S, Giles F, Rai K, et al: Bcl-2 antisense (Genasense) as monotherapy for refractory chronic lymphocytic leukemia (abstract 3213). Blood 98(11 pt 1):772, 2001.
47. Decker T, Hipp S, Kreitman RJ, et al: Sensitization of B-cell chronic lymphocytic leukemia cells to recombinant immunotoxin by immunostimulatory phosphorothioate oligodeoxynucleotides. Blood 99:1320-1326, 2002.
48. Decker T, Schneller F, Sparwasser T, et al: Immunostimulatory CpG-oligonucleotides cause proliferation, cytokine production, and an immunogenic phenotype in chronic lymphocytic leukemia B cells. Blood 95:999-1006, 2000.
49. Rai KR, O’Brien S, Cunningham C, et al: Genasense (Bcl-2 antisense) monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia: Phase I and II results (abstract 1490). Blood 100(11 pt 1):384, 2002.
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