Clinical characterization of first cycle reactions in patients with chronic lymphocytic leukemia treated with oblimersen

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 16514-16514
Author(s):  
K. S. Kolibaba ◽  
A. A. Chanan-Khan ◽  
G. Bociek ◽  
T. Boyd ◽  
J. Moore ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Ex Vivo ◽  
Phase 1 ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Interferon Γ ◽  
Lymphocytic Leukemia ◽  
Bulky Disease

16514 Background: Serious adverse reactions during the first treatment cycle characterize many drugs used for chronic lymphocytic leukemia (CLL), including rituximab, alemtuzumab, flavopiridol, lenalidomide, and oblimersen. Termed cytokine release reactions (CRRs), these events have occurred more commonly in pts with bulky disease and elevated leukocyte counts, and some have been fatal. Rapid increases in serum levels of tumor necrosis factor-α, interleukin-6, interleukin-2, interferon-γ, and other cytokines may result in symptoms including fever, chills, nausea, vomiting, hypotension, and dyspnea. Ex vivo treatment of CLL cells with oblimersen induce release of vasoactive interleukin-8. First cycle reactions, including tumor lysis syndrome (TLS), proved dose-limiting in a phase 1–2 trial of oblimersen in pts with relapsed or refractory CLL. To characterize these reactions, we evaluated data from this single-agent study and from a phase 3 randomized clinical trial of oblimersen with fludarabine and cyclophosphamide (Flu/Cy). Methods: Data on investigator assessment of CRR and TLS were obtained from both studies, which included 155 pts; 40 were treated with oblimersen alone (3–7mg/kg/d by CIV for 5–7 days) and 115 with oblimersen (3 mg/kg/d × 7 days) in combination with Flu/Cy. Results: Of 145 pts treated with oblimersen 3mg/kg/d, either alone or with Flu/Cy, 2 pts (1.3%) experienced CRR and TLS, respectively. Two CRRs occurred in 10 pts treated with 4–7mg/kg/d. Reactions typically began 24–48 hours after starting treatment. CCR was usually associated with spiking fever, nausea, dehydration, rigors, and back pain. Rarely pts developed hypotension, acidosis, or reversible renal insufficiency, usually with a reduction in WBC. Symptoms lasted 1 day to several weeks (1 pt). In most cases, reactions were reversible with intensive supportive care, including IV fluids, pressors, and antibiotics; 1 death from TLS and 1 from CCR occurred during cycle 1. There was no definitive correlation with baseline measures of disease burden. Conclusion: First cycle oblimersen reactions are uncommon but represent a risk. Early symptoms (fever, nausea, and dehydration) require aggressive treatment, which may prevent progression of the reaction. [Table: see text]

scholarly journals Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia

Blood ◽  
2006 ◽  
Vol 109 (2) ◽  
pp. 399-404 ◽  
Author(s):  
John C. Byrd ◽  
Thomas S. Lin ◽  
James T. Dalton ◽  
Di Wu ◽  
Mitch A. Phelps ◽  
...  
Keyword(s):  
High Risk ◽  
Chronic Lymphocytic Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Loading Dose ◽  
Bulky Disease ◽  
Median Response

AbstractDespite promising preclinical studies with the cyclin-dependent kinase inhibitor flavopiridol in chronic lymphocytic leukemia (CLL) and other diseases, previous clinical trials with this agent have been disappointing. The discovery of differential protein binding of flavopiridol in human and bovine serum contributed to an effective pharmacokinetic-derived schedule of administration of this agent. On the basis of pharmacokinetic modeling using our in vitro results and data from a previous trial, we initiated a phase 1 study using a 30-minute loading dose followed by 4 hours of infusion administered weekly for 4 of 6 weeks in patients with refractory CLL. A group of 42 patients were enrolled on 3 cohorts (cohort 1, 30 mg/m2 loading dose followed by 30 mg/m2 4-hour infusion; cohort 2, 40 mg/m2 loading dose followed by 40 mg/m2 4-hour infusion; and cohort 3, cohort 1 dose for treatments 1 to 4, then a 30 mg/m2 loading dose followed by a 50 mg/m2 4-hour infusion). The dose-limiting toxicity using this novel schedule was hyperacute tumor lysis syndrome. Aggressive prophylaxis and exclusion of patients with leukocyte counts greater than 200 × 109/L have made this drug safe to administer at the cohort 3 dose. Of the 42 patients treated, 19 (45%) achieved a partial response with a median response duration that exceeds 12 months. Responses were noted in patients with genetically high-risk disease, including 5 (42%) of 12 patients with del(17p13.1) and 13 (72%) of 18 patients with del(11q22.3). Flavopiridol administered using this novel schedule has significant clinical activity in refractory CLL. Patients with bulky disease and high-risk genetic features have achieved durable responses, thereby justifying further study of flavopiridol in CLL and other diseases.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

scholarly journals A phase 1 study evaluating the safety and tolerability of otlertuzumab, an anti-CD37 mono-specific ADAPTIR therapeutic protein in chronic lymphocytic leukemia

Blood ◽  
2014 ◽  
Vol 123 (9) ◽  
pp. 1302-1308 ◽  
Author(s):  
John C. Byrd ◽  
John M. Pagel ◽  
Farrukh T. Awan ◽  
Andres Forero ◽  
Ian W. Flinn ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Safety Profile ◽  
Phase 1 ◽  
Single Agent ◽  
Therapeutic Protein ◽  
Lymphocytic Leukemia ◽  
Phase 1 Study ◽  
Acceptable Safety Profile ◽  
Key Points

Key Points Otlertuzumab (formerly TRU-016) has modest single-agent activity in symptomatic treated and untreated CLL. Otlertuzumab demonstrates an acceptable safety profile, providing rationale for combination with other effective CLL therapies.

Serum Tumor Markers in Non-Hodgkin's Lymphomas and Chronic Lymphocytic Leukemia

1993 ◽  
Vol 8 (1) ◽  
pp. 14-20 ◽  
Author(s):  
A.N. Pavlidis ◽  
J. Kalef-Ezra ◽  
L.C. Bourantas ◽  
A. Lambrou ◽  
A. Mavridis
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Tumor Markers ◽  
Clinical Stage ◽  
Prognostic Significance ◽  
Interleukin 2 ◽  
Serum Levels ◽  
Lymphocytic Leukemia ◽  
Mean Values ◽  
Hodgkin's Lymphomas ◽  
Normal Controls

The levels of soluble interleukin-2 receptors (sIL-2R), beta-2 microglobulin (β-2M), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in the serum of 50 previously untreated patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) as well as in 25 age and sex-matched normal controls. Compared to normal controls, mean serum levels of sIL-2R and β-2M were significantly increased in both NHL and CLL (p < 0.001) while the increase in ESR and CRP was less marked (p < 0.01 and p < 0.05, respectively). Comparison of these tumor markers with histologic grading showed statistically significant differences only for CRP between low, intermediate and high-grade lymphomas (p < 0.001 and p < 0.05). More advanced stages exhibited higher mean values of all serum markers than early stages (p < 0.001 for sIL-2R, β-2M and ESR and p < 0.05 for CRP). An association with the presence of b-symptoms was observed only for sIL-2R (p < 0.05). In addition, sIL-2R as well as β-2M were able to predict time to progression in patients with diffuse large-cell lymphomas. We conclude that of the four tumor markers tested sIL-2R and β-2M more frequently showed increased serum levels and were associated with clinical stage and/or presence of b-symptoms. Both sIL-2R and β-2M were also found to have prognostic significance for survival.

scholarly journals High serum levels of soluble interleukin 2 receptor in patients with B chronic lymphocytic leukemia

Blood ◽  
1987 ◽  
Vol 70 (2) ◽  
pp. 396-400 ◽  
Author(s):  
G Semenzato ◽  
R Foa ◽  
C Agostini ◽  
R Zambello ◽  
L Trentin ◽  
...  
Keyword(s):  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Interleukin 2 ◽  
Serum Levels ◽  
High Serum ◽  
Lymphocytic Leukemia ◽  
Soluble Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 2 Receptor

Abstract By using an enzyme-linked immunosorbent assay, the presence of the soluble form of the interleukin-2 receptor (sIL-2R) was evaluated in the peripheral blood of 54 patients with B cell chronic lymphocytic leukemia (B-CLL). Serum levels of sIL-2R were correlated with clinical features, relevant hematologic and immunological data, and in some cases, with in vitro functional studies. In 51 patients (94.4%), the levels of sIL-2R were increased as compared with normal age-matched controls (1,781 U/mL +/- 231 v 276 U/mL +/- 26, respectively; P less than .001). Although this increase was observed in all stages of the disease and independently of several hematologic and immunologic parameters, a trend toward lower levels of sIL-2R was documented in patients with a less-invasive disease. When the values were correlated with the functional status of the residual T cell population, it was found that patients with the lowest levels of sIL-2R showed the best mitogenic response and helper capacity. It is suggested that in B-CLL patients the high levels of serum sIL-2R, capable of binding to its ligand, may block the T cell-produced IL-2, thus contributing toward a defective physiological action by this lymphokine. In turn, this defective availability of IL-2 may play a part in the abnormal immunoregulation that is implicated in the hypogammaglobulinemia, susceptibility to infections, and incidence of second neoplasias often observed in this disease.

The Combination of Lenalidomide and Rituximab Induces Complete and Partial Responses In Patients with Relapsed and Refractory Chronic Lymphocytic Leukemia.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1395-1395 ◽  
Author(s):  
Alessandra Ferrajoli ◽  
Xavier Badoux ◽  
Susan O'Brien ◽  
William G. Wierda ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Research Funding ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Cell Activity ◽  
Lymphocytic Leukemia ◽  
Cytotoxic T Cell ◽  
Tumor Lysis ◽  
Significant Difference ◽  
Grade 3

Abstract Abstract 1395 Lenalidomide is an immunomodulatory drug with single-agent activity in untreated and relapsed patients (pts) with chronic lymphocytic leukemia (CLL). Lenalidomide may potentiate the activity of rituximab through enhancement of NK and cytotoxic T-cell activity and antibody-dependent cytotoxicity. As lenalidomide is active as single-agent in relapsed/refractory CLL, we designed a trial to evaluate the combination of lenalidomide and rituximab in pts with previously treated CLL. Between 09/2008 and 10/2009, 59 pts with relapsed or treatment-refractory CLL were enrolled in this Phase II trial. Pts were eligible if they had relapsed disease requiring treatment and had received prior fludarabine-based therapy. Pts were required to have adequate performance status (WHO <3) and adequate renal and liver function (serum Cr or bilirubin <2mg/dl). Pts with an unrelated malignancy or with HIV, hepatitis B or C infection were excluded. Rituximab 375 mg/m2 was given intravenously weekly × 4 from Day 1 in Cycle 1 then every 4 weeks during cycles 3 – 12. Oral lenalidomide 10 mg/day was started on Day 9 of cycle 1 on a continuous dosing schedule. Cycles were 28 days with intention to continue therapy for 12 cycles or longer if the patient experienced a clinical response. Dose reductions were made following grade 3 or 4 lenalidomide-related toxicity. Allopurinol 300mg daily was prescribed during the first 2 weeks as tumor lysis prophylaxis. Response evaluation was performed with after cycles 3, 6 and every 6 cycles thereafter using 2008 IWCLL response assessment guidelines. Toxicity was graded according to CTC-v3.0 criteria. All 59 pts are evaluable for response and clinical outcome. Patient pre-treatment characteristics are shown in Table 1. All pts had prior rituximab therapy and 52 (88%) pts had prior chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR). The overall response rate was 64% with 5 complete responses (CR, 8%), 3 CR with incomplete hematological recovery (CRi, 5%), 7 nodular partial remissions (nPR, 12%) and 23 PR (39%). Most response (32/38, 84%) occurred by 3 cycles of therapy, but the majority of CR/CRi (7 of 8, 88%) occurred after 6 cycles of therapy. At a median follow-up of 14 months, the estimated treatment failure rate was 42% and estimated overall survival (OS) was 90%. There was no significant difference in responses or TTF for pts with deletion 17p when compared to other FISH subgroups. Two deaths occurred while on study therapy, one due to ischemic stroke and one to infectious exacerbation of chronic obstructive pulmonary disease. Six deaths occurred after progression of disease during subsequent therapies. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 40 (68%), 13 (22%) and 6 (10%) pts, respectively. Grade 3/4 infections occurred in 18 pts (31%), mostly lower respiratory tract. Seventy-three % of pts required a dose reduction of lenalidomide with a median tolerated daily dose of 5mg (2.5mg – 10mg). One patient experienced a grade 3 tumor lysis syndrome and 22 pts had grade 1–2 tumor flare reactions. In conclusion, combination therapy with lenalidomide and rituximab induces both complete and partial responses as salvage therapy in CLL. The addition of rituximab to lenalidomide appears to improve responses relative to single agent lenalidomide (Ferrajoli 2008, Chanan-Khan 2006) despite all pts having received prior rituximab-based therapies. This treatment was well tolerated with the most common toxicity being myelosuppression. Disclosures: Ferrajoli: Celgene: Research Funding; Genentech: Research Funding. Off Label Use: The use of lenalidomide in the treatment of chronic lymphocytic leukemia. O'Brien:Celgene: Consultancy; Genentech BioOncology: Consultancy. Wierda:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech BioOncology: Advisory Board, Consultancy, Speakers Bureau. Estrov:Celgene: Consultancy. Keating:Celgene: Consultancy; Genentech: Consultancy.

A Dose Escalation Study of Ibrutinib with Lenalidomide for Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1987-1987 ◽  
Author(s):  
Daniel A. Pollyea ◽  
Steven Coutre ◽  
Lia Gore ◽  
Nichole Adler ◽  
Pamela Harris ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Median Number ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
Bcr Signaling ◽  
Expansion Cohort

Abstract Introduction: Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is dependent upon dysregulated signaling through the B-cell receptor (BCR) pathway. Bruton’s tyrosine kinase (BTK) mediates BCR signaling, and inhibition of BTK with ibrutinib, a selective, irreversible BTK inhibitor, is effective and well tolerated for patients (pts) with relapsed/refractory CLL/SLL. However, complete remissions (CRs) are infrequent, mechanisms of resistance to single-agent ibrutinib have been identified, and the duration of response beyond 3 years is unknown. Lenalidomide, a multi-functional immunomodulatory agent, is active in CLL/SLL, but limited by tumor flare reactions, which occur secondary to B-cell activation. Ibrutinib and lenalidomide modulate several key overlapping factors involving the CLL tumor microenvironment, and therefore a phase 1 combination study with lenalidomide dose escalation was undertaken. Methods: The primary objective was to determine the maximum tolerated dose (MTD) of lenalidomide in combination with ibrutinib. Secondary objectives included assessments of efficacy, PK/PD, and other mechanistic correlative studies. A 1-month (cycle 0) period of 420 mg of daily oral ibrutinib was administered as a single agent to decrease BCR signaling and mitigate lenalidomide-associated tumor flare. Beginning with the second month (cycle 1), ibrutinib was given concomitantly with lenalidomide. Four dose escalation cohorts of lenalidomide were planned using a 3+3 design; 2.5, 5, 7.5 and 10 mg. After the 2.5 mg cohort, intra-patient dose escalation was employed: in cohort 2, pts received 2.5 mg in week 1 followed by 5 mg subsequently; pts in cohort 3 received 2.5 mg in week 1, 5 mg in week 2 and 7.5 mg subsequently; pts in cohort 4 will receive 2.5 mg in week 1, 5 mg in week 2, 7.5 mg in week 3 and 10 mg subsequently. Ibrutinib was not dose escalated (420 mg). Pts receive 12 cycles of the combination, after which lenalidomide is discontinued and ibrutinib continues until unacceptable toxicity or disease progression. Eligible pts had relapsed/refractory CLL/SLL with adequate organ and bone marrow function. Pts who relapsed after stem cell transplantation were excluded. Results: To date, 11 pts were enrolled; 9 are evaluable (1 voluntarily withdrew consent prior to completing 3 cycles, the protocol-defined minimum to be evaluable, and 1 was a screen fail). The median age was 65 (49-81). Eight were male and 8 had CLL. Median Rai stage was 1 (1-4). The median number of prior therapies was 2 (range 1-8); 3 were purine analog resistant. Six had bulky (>5 cm) disease. Two had del(17p13.1) and 4 had del(11q22.3). The median number of cycles completed was 8 (range 1-13). Adverse events (AEs) were reported according to the NCI CTCAE v4.0. Possibly related grade 1/2 AEs that occurred in >1 patient included: rash (n=4), muscle cramps (n=3) and abdominal discomfort (n=2). Possibly related grade 3 AEs included neutropenia (n=4), lymphocytosis (n=2), neutropenic fever (n=1), anemia (n=1) and thrombocytopenia (n=1). There was 1 possibly related grade 4 AE, neutropenia, which was pre-defined as DLT, in the 7.5 mg lenalidomide cohort. One patient experienced grade 2 tumor pain, thought to be due to a lenalidomide-associated tumor flare reaction. Four pts required a lenalidomide dose reduction, for neutropenia (n=2) and fatigue (n=2). Six required a treatment hold, of either lenalidomide or both agents, for a median 7 days (2-28), for neutropenia (n=2), anemia (n=1), fatigue/diarrhea (n=1), atrial fibrillation (n=1) and to obtain a lymph node biopsy (n=1). Lymphocytosis was noted in 5 pts, peaking at a median of 22.5 days. The ORR is 100% (9/9), with all responders experiencing PRs. One progressed with Richter’s transformation during cycle 7, 4 months after achieving a PR. All 9 remain alive with a median follow up of 263 days (range 97-391). The 7.5 mg dose cohort is currently being expanded to 6 pts; after the MTD is determined, a 10 patient dose expansion cohort will commence. Conclusions: Ibrutinib with lenalidomide appears to be well tolerated, although lenalidomide dose reductions were common. Tumor flare reactions were rare. Response assessments at higher dose cohorts of lenalidomide are ongoing. Completed phase 1 data, preliminary data from the expansion cohort and correlative findings will be presented. Disclosures Pollyea: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Lenalidomide for CLL/SLL. Byrd:Genentech: Research Funding; Pharmacyclics: Research Funding.

scholarly journals Clinical response and pharmacokinetics from a phase 1 study of an active dosing schedule of flavopiridol in relapsed chronic lymphocytic leukemia

Blood ◽  
2009 ◽  
Vol 113 (12) ◽  
pp. 2637-2645 ◽  
Author(s):  
Mitch A. Phelps ◽  
Thomas S. Lin ◽  
Amy J. Johnson ◽  
Eunju Hurh ◽  
Darlene M. Rozewski ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Clinical Response ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Parameter Estimates ◽  
Population Parameter ◽  
Time Curve ◽  
Mixed Effects Modeling

Abstract We previously reported interim results of a phase 1 trial in patients with chronic lymphocytic leukemia (CLL) whereby flavopiridol was administered intravenously as a 30-minute bolus followed by 4-hour infusion. We now report full pharmacokinetic (PK) data, correlations of PK with clinical outcomes, and final response and progression-free survival (PFS). Twenty-one (40%) of 52 patients with relapsed CLL achieved a partial response (PR) with a median PFS of 12 months. Responders included 17 (40%) of 43 fludarabine refractory patients, 7 (39%) of 18 patients with del(17p13), and 14 (74%) of 19 patients with del(11q22). Six responders received repeat therapy at relapse, and 5 responded again with a second median PFS of 10 months. Noncompartmental analysis and nonlinear mixed effects modeling was used to estimate PK parameters and evaluate covariates. Two-compartment population parameter estimates were 31.4 L/h, 65.8 L, 8.49 L/h, and 157 L for CL, V1, Q, and V2, respectively. Flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome, and glucuronide metabolite AUC correlated with tumor lysis syndrome. These composite results confirm high activity of this pharmacokinetically derived schedule in relapsed, genetically high-risk CLL. Furthermore, PK describes some, but not all, variability in response and toxicity.

scholarly journals The malignant B cells from B-chronic lymphocytic leukemia patients release TAC-soluble interleukin-2 receptors

Blood ◽  
1988 ◽  
Vol 72 (2) ◽  
pp. 447-450 ◽  
Author(s):  
NE Kay ◽  
J Burton ◽  
D Wagner ◽  
DL Nelson
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Interleukin 2 ◽  
Elevated Serum ◽  
Serum Levels ◽  
Mean Value ◽  
Lymphocytic Leukemia ◽  
Membrane Expression

Abstract Both membrane (p55) and soluble (p45) forms of TAC-reactive interleukin- 2 receptor (IL-2R) are expressed and/or released by activated lymphocytes or monocytes. Previous work has detected increased levels of circulating, TAC-soluble IL-2R (soluble TAC antigen) in the serum of most B-cell chronic lymphocytic leukemia (B-CLL) patients. We detected soluble TAC antigen in B-CLL patients (mean of 3,332 U/mL v 410 for controls). Serum soluble TAC antigen levels increased with stage (mean value of 1,187 U/mL for stage 0 v 2,527 for stage 2 and 5,410 for stages 3 and 4). We next attempted to determine whether the elevated serum levels of soluble TAC antigen in B-CLL patients might result from shedding or secretion of the receptor from the circulating, malignant B cells. Purified, malignant B cells from B-CLL patients were capable of producing easily detectable soluble TAC antigen after 48 hours of in vitro culture (range of 60 to 1,563 U/mL). IL-2R production by CLL B cells was dose dependent in most patients over a concentration of 10 x 10(6) to 60 x 10(6)/mL. In contrast, there was little or no detectable soluble TAC antigen when highly purified T cells from the same patients were cultured. Finally, despite elaboration of soluble IL-2R by CLL B cells, membrane expression of B-cell IL-2R was detected in only six of 11 patients. Thus, the cellular source of the elevated serum IL-2R levels is the malignant CLL B cell. Taken together these data suggest that (a) the malignant CLL B cell is “activated” in terms of release of soluble IL-2R and may serve as a tumor marker in this disease and (b) the elevated levels of circulating IL-2R may be an associated factor in the cellular immunodeficiency noted in B-CLL patients.

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