This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Younes, A. Articles by Samaniego, F. Search for Related Content PubMed PubMed Citation Articles by Younes, A. Articles by Samaniego, F.

Phase II Clinical Trial of Interleukin-12 in Patients with Relapsed and Refractory Non-Hodgkin’s Lymphoma and Hodgkin’s Disease

¹ Departments of Lymphoma and Myeloma and ² Diagnostic Radiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; ³ Program in Immunology, The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas; ⁴ Department of Hematology/Oncology, Indiana University, Indianapolis, Indiana; and ⁵ Division of Hematologic Malignancies, Johns Hopkins University, Baltimore, Maryland

	ABSTRACT

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: The purpose of this study was to evaluate the clinical activity and toxicity of recombinant human Interleukin (IL)-12 in patients with relapsed and refractory non-Hodgkin’s lymphoma (NHL) or Hodgkin’s disease (HD).

Experimental Design: Forty-two previously treated patients (32 patients with NHL and 10 patients with HD) were enrolled on the study. Patients were treated with either intravenous (n = 11) or subcutaneous (n = 31) administration of IL-12. The patients had received a median of three prior treatment regimens, and 16 patients had undergone prior autologous stem cell transplantation.

Results: All patients were assessable for toxicity, and 39 of 42 (93%) patients were assessable for response. Six of 29 (21%) patients with NHL had a partial or complete response, whereas none of the 10 patients with HD responded. Furthermore, 15 patients had stable disease that lasted for up to 54 months. Progression-free survival in patients with indolent NHL, aggressive NHL, and HD was 6, 2, and 2.5 months, respectively. Treatment was well tolerated, and the most common toxicity was flu-like symptoms. Reversible grade 3 hepatic toxicity was observed in three patients requiring dose reduction. IL-12 therapy increased the median number of peripheral blood CD8 T lymphocytes from 423/µl to 576/µl (P = 0.0019). Furthermore, IL-12 therapy decreased serum vascular endothelial growth factor and basic fibroblast growth factor concentrations in 37% of the patients.

Conclusions: The ability of recombinant human IL-12 therapy to increase the number of circulating CD8+ cells and induce clinical remissions in patients with relapsed NHL warrants further investigation of the drug.

	INTRODUCTION

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Interleukin (IL)-12 is a heterodimeric cytokine composed of p35 and p40 subunits, linked by disulfide bonds (1) . The genes for these two subunits are expressed on chromosomes 3 and 5, respectively. IL-12 is predominantly produced by monocytes, macrophages, and dendritic cells. The IL-12 receptor (IL-12R) also consists of two subunits, ß1 and ß2, whose genes are located on chromosomes 19 and 1, respectively. Coexpression of both of these subunits in the same cell forms high-affinity IL-12R. IL-12R is predominantly expressed on T lymphocytes, natural killer (NK) cells, and dendritic cells. Recombinant IL-12 therapy has been shown to have an antitumor effect on several transplantable tumors in mice, presumably by induction of interferon-, activation of cytotoxic T and NK cells, and inhibition of angiogenesis (2) .

Based on these promising results, recombinant human IL-12 recently entered clinical trials for the treatment of human cancer. To date, nine Phase I clinical trials of IL-12 in patients with solid tumors and three Phase I studies in patients with hematological malignancies have been reported (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13) . These trials used several routes of IL-12 administration (including intravenous, subcutaneous, intralesional, and intraperitoneal administration) and different doses and schedules. Not surprisingly, the toxicity profile and maximal tolerated dose varied according to the route and schedule of treatment. Thus, the optimal clinically effective dose and schedule of IL-12 remain undetermined.

Although preclinical data and animal models have suggested that IL-12 has antitumor activity against several types of solid tumors, data from several Phase I trials and one Phase II study conducted in patients with solid tumors (mainly renal cell carcinoma and melanoma) have been disappointing (4 , 5 , 10 , 11 , 14) . In fact, clinical responses were observed in fewer than 10% of patients with renal cell carcinoma or melanoma. In patients with lymphoid malignancies, three Phase I studies have been conducted thus far (7 , 9 , 12) , but no Phase II data exist. In one of these Phase I trials, subcutaneous injection of IL-12 in patients with cutaneous T-cell lymphoma produced clinical remissions in 5 of 10 treated patients (9) ; in another Phase I study, which combined escalating doses of IL-12 with fixed doses of rituximab in patients with B-cell lymphoma, a high response rate was also observed (7) .

In this study, we describe our experience with single-agent IL-12 in the treatment of patients with relapsed non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD). This is the first Phase II clinical trial that provides information on the safety and single-agent activity of IL-12 in patients with lymphoid malignancies.

	PATIENTS AND METHODS

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection.
Patients eligible for this trial were at least 18 years of age and had bidimensionally measurable recurrent or refractory NHL or HD. Patients were required to have undergone no more than four prior treatment regimens, with the most recent anti-lymphoma therapy given at least 4 weeks before starting IL-12 treatment. Other entry criteria included a performance status of 0–2 on the Zubrod scale, an absolute neutrophil count of at least 1,500/µl, a platelet count of at least 100,000/µl, an absolute lymphocyte count of at least 500/µl, a bilirubin concentration of <1.5 mg/dl, serum alanine aminotransferase and aspartate aminotransferase concentrations that were <2x the upper limit of normal, and a serum creatinine concentration of <1.8 mg/dl. Patients were excluded if they had HIV infection, central nervous system lymphoma, a history of serious cardiac disease, prior allogeneic stem cell transplantation, or an active infection. The study also excluded women of child-bearing age who were pregnant or not practicing adequate contraception. The institutional review board approved the study, and all participating patients signed an informed consent form.

Within 4 weeks of therapy initiation, all participating patients had blood drawn for a complete blood count with differential, a blood chemistry profile, and HIV testing. These patients additionally had a chest radiograph; computed tomographic scans of the chest, abdomen, and pelvis; a gallium scan (if clinically indicated); and bilateral bone marrow biopsies and aspirations.

Study Design.
Recombinant human IL-12 (Genetic Institute Inc., Cambridge, MA) was supplied through the National Cancer Institute (Bethesda, MD). Initially, IL-12 was administered intravenously using a dose and schedule that were adopted from a previously published Phase I study (15) . Subsequently, the protocol was revised to allow subcutaneous administration according to recommendations from the National Cancer Institute and Genetics Institute, which were based on emerging Phase I data on the safety and efficacy of this approach (16) . Treatment schema is illustrated in Fig. 1 . Patients treated intravenously received an initial test dose of 250 ng/kg followed by a 14-day observation period. Patients who did not have substantial toxicity during the observation period were then treated with 250 ng/kg of IL-12 daily for 5 days every 3 weeks. Patients on the subcutaneous schedule received 500 ng/kg of IL-12 twice weekly. Treatment toxicity was assessed according to the National Cancer Institute Common Toxicity Criteria, Version 2.0. The dosage was reduced to 300 ng/kg twice weekly if grade 3 or grade 4 (e.g., neutropenia) toxicity occurred. If the toxicity grade remained high after 1 week despite dosage reduction, IL-12 was withheld until the toxicity resolved, and then IL-12 was restarted at 300 ng/kg. If the toxicity recurred, patients were removed from the study. Patients with grade 4 nonhematological toxicities were removed from the study without a reduction in dosage.

View larger version (20K): [in this window] [in a new window]   Fig. 1. Schedule of IL-12 therapy. A, eleven patients were treated with intravenous IL-12 injections. A test dose of 250 ng/kg was given initially, followed by 2 weeks of observation. Patients who did not develop substantial toxicity during the observation period were then treated with intravenous injections of 250 ng/kg for 5 days every 3 weeks. B, thirty-two patients were treated with twice-weekly IL-12 subcutaneous injections at 500 ng/kg. In either schedule, patients were restaged after 8 weeks. Arrows indicate times of IL-12 administration.

A complete blood count with differential and platelet count was obtained weekly in patients for the first 2 months of treatment and then obtained every 3–4 weeks while therapy continued. Serum chemistries, including electrolyte concentrations, were obtained every 3–4 weeks. Imaging studies and bone marrow biopsy and aspirations were repeated every 2–3 months during the first year and then every 3–4 months thereafter.

Measurement of Peripheral Blood Lymphocyte Subsets.
The effect of IL-12 therapy on CD4 and CD8 lymphocyte subsets in peripheral blood was determined in 23 patients by flow cytometry. When IL-12 was administered intravenously, CD4 and CD8 cell counts were determined before the initial dose of IL-12 was administered and then remeasured within 24 h before the first dose and after the fifth dose of each 5-day course. When IL-12 was administered subcutaneously, these values were obtained every 1–2 weeks during the first month of therapy and then every 3–4 weeks for a maximum of 6 months.

Measurement of Serum Angiogenesis Factors.
Because IL-12 has been reported to have an antiangiogenic effect, we determined its effect on serum concentrations of the angiogenesis factors vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in our patient population. Serum samples were obtained after proper consent was granted and stored at –70°C in a freezer until used. Serum concentrations of two angiogenesis factors, VEGF and bFGF, were determined using commercial enzyme-linked immunosorbent assay kits from Biosource International, Inc. (Camarillo, CA). All samples were measured in duplicate using a µQuant plate reader equipped with KC4 software (Bio-Tek Instruments, Inc., Winooski, VT) as described previously. The sensitivity of the VEGF assay was <5 pg/ml, and the sensitivity of the bFGF assay was 0.22 pg/ml. All experiments included a set of standard wells containing known quantities of recombinant human VEGF and bFGF. Results are reported as the mean of duplicate measurements. The measurement of VEGF was repeated in 19 patients receiving IL-12 therapy, and the measurement of bFGF was repeated in 20 patients receiving IL-12 therapy.

Statistical Analysis.
The Wilcoxon signed-rank test was used to compare changes in lymphocyte subsets and serum angiogenesis factors before and during IL-12 therapy. Progression-free survival (PFS) was calculated from the time of study entry until disease progression or death from any cause. PFS was calculated by the Kaplan-Meier method using Prism 4 GraphPad statistical software (GraphPad Software, San Diego, CA). P < 0.05 was considered statistically significant.

	RESULTS

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Characteristics.
Forty-two patients were enrolled in this clinical trial. All patients received at least one dose of IL-12 and were evaluable for treatment toxicity. One patient was lost to follow-up, and 2 patients were prematurely removed from the study (within 3 weeks of enrollment) because of rapid disease progression or treatment-related toxicity, leaving 39 patients (93%) evaluable for treatment response. The clinical characteristics of all 42 eligible patients are listed in Table 1 . The median age of these patients was 49 years (range, 22–76 years), and 38% of them were men. Thirty-two patients had NHL, and 10 patients had HD. The patients had received a median of three prior treatment regimens, and 16 patients (38%) had been treated previously with high-dose chemotherapy and stem cell transplantation. IL-12 was administered intravenously to 11 patients (26%) and subcutaneously to 31 patients (74%).

View larger version (12K): [in this window] [in a new window]   Fig. 2. Effect of IL-12 therapy on PFS for all evaluable patients (n = 39). The PFS for patients with indolent lymphoma, aggressive NHL, and HD was 6, 2, and 2.5 months, respectively. Solid line, aggressive NHL; short-dashed line, indolent NHL; long-dashed line, HD.

Toxicity.
Treatment was well tolerated. The majority of toxic effects were grade 1 or 2. The most common adverse effects (occurring in >10% of the patients) and their grades are shown in Fig. 3 . All patients complained of fatigue, which was of grade 3 in 19% of the patients. Fever occurred in 95% of the patients, was more severe in patients who received IL-12 intravenously than in those who received IL-12 subcutaneously, was more common during the early weeks of therapy, and responded well to acetaminophen treatment. Eighty-one percent of the patients reported generalized myalgia and arthralgia, but such constitutional symptoms improved with chronic administration of IL-12. Nausea was observed in 55% of the patients and was associated with vomiting in one patient. Nine (21%) of the patients had infections, which were of grade 3 in 5% of the patients. Infections included sinusitis, flu, conjunctivitis, and pharyngitis. No systemic bacterial or fungal infections were observed. Grade 3 hepatic toxicity was observed in three patients and necessitated a reduction in the dosage of IL-12. Hematological toxicities were predominantly of grade 1 and 2 (Fig. 3) .

View larger version (17K): [in this window] [in a new window]   Fig. 3. Toxicity of IL-12 therapy. Most toxic effects were of grade 1 or 2. , grade 1; , grade 2; , grade 3; , grade 4.

Biological Effects of Interleukin-12 Therapy.
The effect of IL-12 therapy on peripheral blood CD4 and CD8 cell counts varied according to the schedule and route (i.e., intravenous versus subcutaneous) of IL-12 administration and the timing of measurement (Fig. 4) . Transient lymphocytopenia was initially observed after IL-12 administration, causing a fluctuation in the lymphocyte counts (12 , 15 , 18) . This fluctuation in lymphocyte counts was more prominent after intravenous administration of IL-12 (Fig. 4 ; Ref. 18 ). The median pretreatment CD4 cell count was 339/µl (range, 59–1022/µl), but after IL-12 treatment the median peak CD4 cell count only increased slightly to 342/µl (P = 0.138; Table 4 ). In contrast, the median CD8 cell count increased from 423/µl (range, 60–789/µl) to 576/µl (P = 0.002; Fig. 4, C and D ). The median time to peak CD8+ value was 36 days (range, 12–84 days).

View larger version (24K): [in this window] [in a new window]   Fig. 4. Effect of IL-12 therapy on peripheral blood CD4 and CD8 counts. A, changes in CD4 and CD8 cell counts in a patient with NHL treated with intravenous IL-12 therapy. Arrows indicate the start of IL-12 therapy. B, changes in CD4 and CD8 cell counts in a patient with NHL and a patient with HD who were treated with subcutaneous IL-12. C, IL-12 therapy did not significantly change peripheral blood CD4 cell counts. D, IL-12 therapy significantly increased CD8 cell counts. CD4 and CD8 count after IL-12 therapy represents the highest number during treatment course.

View larger version (26K): [in this window] [in a new window]   Fig. 5. Effect of IL-12 therapy on serum angiogenesis factors. Patient sera were collected before initiating IL-12 therapy and 2–3 weeks after starting IL-12 therapy. A, effect of IL-12 therapy on serum VEGF concentration. B, effect of IL-12 therapy on serum bFGF concentration.

	DISCUSSION

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

Three Phase I studies of IL-12 have reported data on patients with lymphoid malignancies (Table 5) . The first, by Rook et al. (9) , used a subcutaneous twice-weekly schedule in 10 patients with cutaneous T-cell lymphoma; other patients received intralesional injections of IL-12. Fifty percent of the patients achieved PR or CR. A second study, by Ansell et al. (7) , used escalating dosages of IL-12 administered twice weekly by subcutaneous injection, with overlapping weekly doses of rituximab (375 mg/m²) for 4 weeks. A total of 43 patients with CD20+ B-cell lymphoma were treated with this novel combination, 25 of whom had indolent lymphoma. Nine patients were previously untreated, and six had prior stem cell transplantation. Patients were treated at four dosage levels ranging from 30 to 500 ng/kg. Sixty-nine percent of the patients achieved a PR or CR, with a median duration of response of 8 or more months (range, 5–12+ months). In a third Phase I study, Robertson et al. (12) used intravenously administered IL-12 as an adjuvant therapy after autologous stem cell transplantation. Twelve patients with lymphoid malignancies were treated with escalating doses of IL-12. Although these patients were considered at high risk for disease relapse, a long time to progression (range, 10.5–50.8 months) followed IL-12 therapy, suggesting that IL-12 may have a role in prolonging the remission duration in this patient population.

In this study, IL-12 therapy induced transient lymphocytopenia. In some patients, a mild rebound increase in the number of circulating CD4 and CD8 T lymphocytes was observed. In some cases, the increase was not persistent and perhaps reflected desensitization to IL-12 therapy. Because only 10 patients in our study received intravenous therapy with IL-12, we could not determine whether intermittent intravenous treatment could bypass this desensitization phenomenon more effectively than long-term twice-weekly subcutaneous injections.

All major responses were observed in patients with NHL. Interestingly, although none of the 10 patients with relapsed classic HD achieved a meaningful clinical response, 5 of 10 patients (50%) had stable disease lasting up to 12 months. The inability of IL-12 to induce clinical remissions in patients with HD is disappointing, especially given the fact that many of these patients had low-volume disease. However, all patients with HD were treated subcutaneously with IL-12, so it is not clear whether some of them might have responded had they been treated intravenously. Although HD patients are known to have cellular immune suppression, it is not known whether this immunosuppression status can be reversed by activating cytokine therapy. Our trial was not designed to address this biological question. Furthermore, repeated lymph node biopsies before and after IL-12 therapy were not required to evaluate whether IL-12 therapy may have increased the number of activated cytotoxic lymphocytes in the tumor microenvironment. However, even if IL-12 did activate cytotoxic lymphocytes, it is possible that the malignant Reed-Sternberg cells associated with HD are resistant to activated cytotoxic T lymphocytes.

To test the in vivo antiangiogenic effect of IL-12, we measured VEGF and bFGF levels before and after IL-12 therapy. Both factors were elevated in patients with relapsed NHL and HD. Patients with aggressive NHL had higher baseline concentrations than did patients with indolent NHL or HD (19, 20, 21, 22) . In most patients, IL-12 therapy either reduced or had no major effect on VEGF or bFGF serum concentrations. In a few patients who did not respond to IL-12 therapy, the concentrations of these factors increased. This increase is likely due to disease activity and not to IL-12 therapy.

Collectively, our data suggest that IL-12 therapy has a modest single-agent activity in patients with relapsed NHL. This clinical activity is likely related to the ability of IL-12 to activate T cells and NK cells and to inhibit angiogenesis factors. Further investigation of IL-12, either as a monotherapy in an adjuvant setting or in combination with other immune therapeutic agents such as monoclonal antibodies or vaccine therapy, is warranted.

	FOOTNOTES

 
Grant support: National Cancer Institute Grant N01-CM-17003 (A. Younes), M. D. Anderson Cancer Center Core Grant CA-16672, a grant from the Genetics Institute, NIH Grant MO1 RR00075-310649, and Clarian Values Fund Grant VFR-81 (M. Robertson).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Requests for reprints: Anas Younes, Department of Lymphoma and Myeloma, Unit 0429, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-2860; Fax: (713) 794-5656; E-mail: ayounes{at}mdanderson.org

Received 3/17/04; revised 5/ 4/04; accepted 5/ 5/04.

	REFERENCES

Top ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 

1. Watford WT, Moriguchi M, Morinobu A, et al The biology of IL-12: coordinating innate and adaptive immune responses. Cytokine Growth Factor Rev, 14: 361-8, 2003.[CrossRef][Medline]
2. Colombo MP, Trinchieri G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev, 13: 155-68, 2002.[CrossRef][Medline]
3. Weiss GR, O’Donnell MA, Loughlin K, et al Phase 1 study of the intravesical administration of recombinant human interleukin-12 in patients with recurrent superficial transitional cell carcinoma of the bladder. J Immunother, 26: 343-8, 2003.
4. Van Herpen CM, Huijbens R, Looman M, et al Pharmacokinetics and immunological aspects of a phase Ib study with intratumoral administration of recombinant human interleukin-12 in patients with head and neck squamous cell carcinoma: a decrease of T-bet in peripheral blood mononuclear cells. Clin Cancer Res, 9: 2950-6, 2003.[Abstract/Free Full Text]
5. Gollob JA, Veenstra KG, Parker RA, et al Phase I trial of concurrent twice-weekly recombinant human interleukin-12 plus low-dose IL-2 in patients with melanoma or renal cell carcinoma. J Clin Oncol, 21: 2564-73, 2003.[Abstract/Free Full Text]
6. Lenzi R, Rosenblum M, Verschraegen C, et al Phase I study of intraperitoneal recombinant human interleukin 12 in patients with Mullerian carcinoma, gastrointestinal primary malignancies, and mesothelioma. Clin Cancer Res, 8: 3686-95, 2002.[Abstract/Free Full Text]
7. Ansell SM, Witzig TE, Kurtin PJ, et al Phase 1 study of interleukin-12 in combination with rituximab in patients with B-cell non-Hodgkin lymphoma. Blood, 99: 67-74, 2002.[Abstract/Free Full Text]
8. Gollob JA, Mier JW, Veenstra K, et al Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res, 6: 1678-92, 2000.[Abstract/Free Full Text]
9. Rook AH, Wood GS, Yoo EK, et al Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses. Blood, 94: 902-8, 1999.[Abstract/Free Full Text]
10. Portielje JE, Kruit WH, Schuler M, et al Phase I study of subcutaneously administered recombinant human interleukin 12 in patients with advanced renal cell cancer. Clin Cancer Res, 5: 3983-9, 1999.[Abstract/Free Full Text]
11. Motzer RJ, Rakhit A, Schwartz LH, et al Phase I trial of subcutaneous recombinant human interleukin-12 in patients with advanced renal cell carcinoma. Clin Cancer Res, 4: 1183-91, 1998.[Abstract]
12. Robertson MJ, Pelloso D, Abonour R, et al Interleukin 12 immunotherapy after autologous stem cell transplantation for hematological malignancies. Clin Cancer Res, 8: 3383-93, 2002.[Abstract/Free Full Text]
13. Lee P, Wang F, Kuniyoshi J, et al Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma. J Clin Oncol, 19: 3836-47, 2001.[Abstract/Free Full Text]
14. Atkins MB, Robertson MJ, Gordon M, et al Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res, 3: 409-17, 1997.[Abstract]
15. Robertson MJ, Cameron C, Atkins MB, et al Immunological effects of interleukin 12 administered by bolus intravenous injection to patients with cancer. Clin Cancer Res, 5: 9-16, 1999.[Abstract/Free Full Text]
16. Bajetta E, Del Vecchio M, Mortarini M, et al Pilot study of subcutaneous recombinant human interleukin 12 in metastatic melanoma. Clin Cancer Res, 4: 75-85, 1998.[Abstract]
17. Cheson BD, Horning SJ, Coiffier B, et al Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol, 17: 1244 1999.[Abstract/Free Full Text]
18. Portielje JE, Lamers CH, Kruit WH, et al Repeated administrations of interleukin (IL)-12 are associated with persistently elevated plasma levels of IL-10 and declining IFN-gamma, tumor necrosis factor-alpha, IL-6, and IL-8 responses. Clin Cancer Res, 9: 76-83, 2003.[Abstract/Free Full Text]
19. Bellamy WT, Richter L, Frutiger Y, et al Expression of vascular endothelial growth factor and its receptors in hematopoietic malignancies. Cancer Res, 59: 728-33, 1999.[Abstract/Free Full Text]
20. Salven P, Teerenhovi L, Joensuu H. A high pretreatment serum vascular endothelial growth factor concentration is associated with poor outcome in non-Hodgkin’s lymphoma. Blood, 90: 3167-72, 1997.[Abstract/Free Full Text]
21. Moehler TM, Ho AD, Goldschmidt H, Barlogie B. Angiogenesis in hematologic malignancies. Crit Rev Oncol Hematol, 45: 227-44, 2003.[Medline]
22. Salven P, Orpana A, Teerenhovi L, Joensuu H. Simultaneous elevation in the serum concentrations of the angiogenic growth factors VEGF and bFGF is an independent predictor of poor prognosis in non-Hodgkin lymphoma: a single-institution study of 200 patients. Blood, 96: 3712-8, 2000.[Abstract/Free Full Text]

This article has been cited by other articles:

				M. Del Vecchio, E. Bajetta, S. Canova, M. T. Lotze, A. Wesa, G. Parmiani, and A. Anichini Interleukin-12: Biological Properties and Clinical Application Clin. Cancer Res., August 15, 2007; 13(16): 4677 - 4685. [Abstract] [Full Text] [PDF]

				S. M. Ansell, S. M. Geyer, M. J. Maurer, P. J. Kurtin, I. N.M. Micallef, P. Stella, P. Etzell, A. J. Novak, C. Erlichman, and T. E. Witzig Randomized Phase II Study of Interleukin-12 in Combination with Rituximab in Previously Treated Non-Hodgkin's Lymphoma Patients. Clin. Cancer Res., October 15, 2006; 12(20): 6056 - 6063. [Abstract] [Full Text] [PDF]

				R. F. Little, J. M. Pluda, K. M. Wyvill, I. R. Rodriguez-Chavez, G. Tosato, A. T. Catanzaro, S. M. Steinberg, and R. Yarchoan Activity of subcutaneous interleukin-12 in AIDS-related Kaposi sarcoma Blood, June 15, 2006; 107(12): 4650 - 4657. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Younes, A. Articles by Samaniego, F. Search for Related Content PubMed PubMed Citation Articles by Younes, A. Articles by Samaniego, F.