Darbepoetin alfa for treating anemia in low-risk myelodysplastic syndrome patients: Interim results after 27/28 weeks

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6564-6564 ◽  
Author(s):  
R. Paquette ◽  
J. Gabrilove ◽  
R. Lyons ◽  
C. Mushtaq ◽  
M. Sekeres ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Darbepoetin Alfa ◽  
Response Rate ◽  
Low Risk ◽  
Epoetin Alfa ◽  
Average Response Rate ◽  
Pilot Studies ◽  
Erythroid Response ◽  
Clinically Significant ◽  
Esa Therapy

6564 Background: Patients (pts) with myelodysplastic syndrome (MDS) disorders often develop anemia, resulting in increased transfusions and fatigue. Using the erythropoiesis-stimulating agent (ESA) epoetin alfa to treat anemia in low-risk MDS pts results in an average response rate of 30% (40% when used with G-CSF). Pilot studies suggest that 150 or 300 mcg/week (wk) darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in anemic MDS pts. Methods: This fully enrolled (n = 209), phase 2, single-arm, 52-wk ongoing study is examining DA 500 mcg every 3 weeks (Q3W) for treating anemic pts (Hb ≤ 11 g/dL) with low- or intermediate-risk MDS (IPSS definition). The study’s primary endpoint is the proportion of pts achieving an erythroid response by 13 wks. Other endpoints include the proportion of pts achieving an erythroid response by 27/28 wks and change in both Hb levels and FACT-F scores. Results are stratified by whether pts received ESA therapy before enrollment: ESA-naïve (ESA-N) vs ESA-treated (ESA-T). Results: Previous interim data suggested that low-risk MDS pts can achieve a major erythroid response after 13 wks of DA 500 mcg Q3W. This is the first reported summary of results from a planned interim analysis after 27/28 wks of treatment (n = 129). Of 84 ESA-N pts, 51% were men, 86% were white, and the average (SD) age was 74.1 (9.7) years; the 45 ESA-T pts had similar demographics. During 27/28 wks of treatment, a majority of pts achieved a major erythroid response. ESA-N pts had a mean (SD) 1.2 (1.4) g/dL rise in Hb levels from BL and a clinically significant increase in FACT-F score from BL ( Table ). Of the 129 pts analyzed after 27/28 wks, 83% reported an adverse event (AE) and none reported serious treatment-related AEs or thrombotic events (of 189 pts analyzed after 13 wks, 1 pt reported a serious treatment-related AE). Conclusions: These interim results suggest that DA 500 mcg Q3W is well tolerated and can raise Hb levels in anemic, low-risk MDS pts. Final 27/28-wk data from all enrolled pts (n = 209) will be shown. [Table: see text] [Table: see text]

Darbepoetin alfa for treating anemia in patients with low-risk myelodysplastic syndromes: Exploratory analysis of baseline predictors of response

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6579-6579 ◽  
Author(s):  
J. Gabrilove ◽  
R. Paquette ◽  
R. Lyons ◽  
C. Mushtaq ◽  
M. Sekeres ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Darbepoetin Alfa ◽  
Significant Rise ◽  
Low Risk ◽  
Refractory Anemia ◽  
Endogenous Erythropoietin ◽  
Erythroid Response ◽  
Predictors Of Response ◽  
Response Table ◽  
Clinically Significant

6579 Background: Patients (pts) with myelodysplastic syndromes (MDS) often develop anemia, resulting in fatigue and increased transfusions. The erythropoiesis-stimulating agents (ESAs) epoetin alfa and darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in low-risk MDS pts. Baseline (BL) endogenous erythropoietin (eEPO) levels, transfusion history, and FAB sub-type can be predictive factors of response to ESAs (Hellström-Lindberg et al., 2003). Methods: This is an ongoing, fully enrolled (n = 209), phase 2, single-arm, 52-week (wk) study of DA 500 mcg every three weeks (Q3W) for treating anemia (Hb ≤ 11 g/dL) in low- or intermediate-risk MDS pts. A planned interim analysis was done after 13 wks (n = 189). The primary endpoint is the proportion of pts with an erythroid response by 13 wks. Other endpoints include change in Hb levels and in FACT-F score from BL. Results are stratified by whether pts received an ESA before enrollment: ESA-naïve (ESA-N) pts vs ESA-treated (ESA-T) pts. Exploratory analyses of the percentage of pts with an erythroid response adjusted by BL eEPO or FAB category were done. Results: Of 130 ESA-N pts, 52% were women, 86% were white, 58% had refractory anemia (RA), 34% had RA with ringed sideroblasts (RARS), 8% had RA with excess blasts (RAEB), and the mean (SD) age was 74.8 (10.1) years. The 59 ESA-T pts had similar demographics. A majority of ESA-N pts had an erythroid response, achieved a target Hb of 11 g/dL, and had a clinically significant rise in FACT-F score; ESA-N pts with lower BL eEPO levels were more likely to have a major erythroid response ( Table ). A major erythroid response was seen in 50% of pts with RA (n = 111), in 30% of pts with RARS (n = 64), and in 23% of pts with RAEB (n = 13). Of all 189 pts, 78% had an adverse event (AE), 1 had a serious treatment-related AE (hypertension), and none had thrombotic events. Conclusions: These interim results suggest that FAB sub-type and BL eEPO may affect response. Final 13-wk data from all enrolled pts (n = 209) will be shown. [Table: see text] [Table: see text]

The Efficacy and Safety of Darbepoetin Alfa for Treating Anemia in Low-Risk Myelodysplastic Syndrome Patients: Results after 53/55 Weeks.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2671-2671
Author(s):  
Janice Gabrilove ◽  
Ronald Paquette ◽  
Roger M. Lyons ◽  
Chaudhry Mushtaq ◽  
Mikkael A. Sekeres ◽  
...  
Keyword(s):  
Darbepoetin Alfa ◽  
Low Risk ◽  
Open Label ◽  
Eligibility Criteria ◽  
Erythroid Response ◽  
Kaplan Meier ◽  
Risk Of Progression ◽  
Red Blood Cell Transfusions ◽  
Hematopoietic Disorders ◽  
A Minor

Abstract Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by peripheral cytopenias and risk of progression to leukemia. MDS patients (pts) are often anemic, resulting in increased red blood cell transfusions (tfns) and fatigue. Previous studies have shown that 150mcg/week (wk) or 300mcg/wk of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) can raise hemoglobin (Hb) levels in low-risk MDS pts (Patton et al. J Support Oncol.2005;3:419–426). We present data from a phase 2, single-arm, open-label study on the efficacy of 500mcg DA administered every three wks (Q3W) for treating anemia in low-risk MDS pts. Eligibility criteria included ≥18 years, anemia (Hb ≤11g/dL), and low- or intermediate-1-risk MDS (IPSS definition). If pts did not respond by wk 7, the dosing frequency was escalated to Q2W. After the last DA dose on wk 52, the end of study (EOS) was wk 53 (Q2W dosing) or wk 55 (Q3W dosing). The primary endpoint was the percentage of pts with an erythroid response (International Working Group criteria) by wk 13. Secondary 53/55-wk endpoints included incidence of erythroid responses, incidence of tfns, and the change in Hb levels and FACT-F score from baseline (BL). Results were stratified by whether pts had prior ESA therapy: ESA-naive (ESA-N) vs prior ESA-treated (ESA-T). A previous interim analysis showed that low-risk MDS pts could achieve an erythroid response after 13 wks of DA 500mcg Q3W (Gabrilove et al. Blood.2005;106:abstract2541). This is the first reported summary after 53/55 wks (n=148). Of 98 ESA-N pts, 47% were men, 85% were white, and the mean (SD) age was 74 (10) years; the 50 ESA-T pts had similar demographics. Both ESA-N and ESA-T pts had similar BL Hb (Table). By wk 53/55, the percentage (95% CL) of pts with a major erythroid response (≥2g/dL Hb rise from BL or tfn independence) was 56% (46, 66) in ESA-N pts and 30% (17, 43) in ESA-T pts. Both ESA-N and ESA-T pts had a clinically meaningful rise (≥3 points) in FACT-F score from BL. Of the 148 pts, 89% reported adverse events (AEs) with the most common AE being fatigue, 7% had AEs considered related to DA treatment, and 1.4% had thromboembolic events. These results suggested that DA 500mcg Q3W was well tolerated and increased Hb levels in the MDS pts in this study. ESA-N, N=98 ESA-T, N=50 KM%= Kaplan-Meier percentage Crude % (95% CL) pts with a major erythroid response 56% (46, 66) 30% (17, 43) Crude % (95% CL) pts with a minor erythroid response 15% (8, 22) 20% (9, 31) Mean (SD) BL Hb, g/dL 9.8 (1.0) [n=84] 10.0 (1.2) [n=41] Mean (SD) Hb change (BL to wk 53/55) (last value carried forward) 1.1 (1.6) [n=84] 0.2 (1.7) [n=41] Crude % (95% CL) pts achieved target Hb (11g/dL) 68% (58, 78) [n=87] 46% (31, 60) [n=46] Mean (SD) Hb after reached Hb target, g/dL 11.7 (0.8) [n=68] 11.6 (0.9) [n=25] KM% (95% CL) pts with tfns (wk 1 to EOS) 29% (19, 39) 43% (27, 59) KM% (95% CL) pts with tfns (wk 5 to EOS) 28% (19, 38) [n=96] 43% (26, 60) [n=45] Mean (SD) change in FACT-F score (BL to wk 53/55) 5.8 (8.6) [n=45] 7.2 (9.3) [n=15]

Darbepoetin Alfa for the Treatment of Anemia in Patients with Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2542-2542 ◽  
Author(s):  
Pilar Giraldo ◽  
Benet Nomdedeu ◽  
Javier Loscertales ◽  
Carmen Requena ◽  
Raquel de Paz ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Darbepoetin Alfa ◽  
Recombinant Human Erythropoietin ◽  
Treatment Compliance ◽  
Previous Treatment ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Efficacy Analysis ◽  
Erythroid Response ◽  
Human Erythropoietin

Abstract Background: Anemia is one of the main problems associated with myelodysplastic syndrome (MDS) leading to fatigue, increased red blood cell transfusions, and reduced quality of life. Erythropoiesis-stimulating proteins (ESPs) have been used to treat MDS-induced anemia. Darbepoetin alfa (Aranesp®) is a unique ESP that can be administered less frequently than recombinant human erythropoietin (rHuEPO) due to its longer serum half-life, increasing patient convenience and possibly enhancing treatment compliance. Methods: We performed a retrospective analysis of medical records from anemic patients with confirmed MDS that had been treated with darbepoetin alfa in 2004 in 9 Spanish centers. Data were collected 16 weeks before and 16 weeks after the starting date of darbepoetin alfa treatment. Response to darbepoetin alfa was evaluated using the International Working Group criteria. Results: This study included data from 81 patients. Median age was 70 years (range, 38.0 – 87.0) at diagnosis and 75 years (range, 39.0 – 91.0) at the beginning of treatment with darbepoetin alfa. The proportion of female patients was 56.8%. French-American-British (FAB) classification: 39.5% refractory anemia (RA), 46.9% RA with ringed sideroblasts (RARS), 9.9% RA with excess blasts (RAEB), 1.2% RAEB in transformation (RAEB-T), and 2.5% chronic myelomonocytic leukemia (CMML). International Prognostic Scoring System (IPSS) classification: 55.3% low; 36.2% intermediate-1 and 8.5% intermediate-2. ECOG status: 0–1 in 79% of patients. Median baseline hemoglobin level was 8.9 g/dL (range, 8.4 – 9.1). Previous treatment with recombinant human erythropoietin (rHuEPO) occurred in 44.4% of patients and time from last rHuEPO dose to initiation of darbepoetin alfa treatment was lower than 1 week in 53.1% of patients (average of 16.7 weeks; range, 0.0–159.0). Starting darbepoetin alfa dose was 150 mcg/week in 69.1% and 300 mcg/week in 29.6% of patients. Darbepoetin alfa dose was increased in 18.5% and reduced in 9.9% of patients. Median time until dose adjustment was 8 weeks. Granulocyte colony-stimulating factor (G-CSF, Filgrastim) support was required in 6.5% of patients and this percentage was maintained during the 16-week followup. A total of 69 patients (34 rHuEPO-naïve and 35 rHuEPO-treated) were evaluable for efficacy analysis (Hb and transfusion data available). Erythroid response was achieved in 55% of patients (29% major and 26% minor) with 65% of rHuEPO-naïve responders and 46% of rHuEPO-treated responders. A total of 66% responses were achieved before or at week 8. Conclusion: These results indicate that darbepoetin alfa treatment appears to be effective in patients with MDS regardless of whether or not they had received previous treatment with rHuEPO.

A Phase 2, Single-Arm, Open-Label Trial To Evaluate the Effectiveness of Darbepoetin alfa for the Treatment of Anemia in Patients with Low-Risk Myelodysplastic Syndrome.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2541-2541
Author(s):  
Janice Gabrilove ◽  
Ron Paquette ◽  
Roger Lyons ◽  
Chaudhry Mushtaq ◽  
Mikkael Sekeres ◽  
...  
Keyword(s):  
Adverse Event ◽  
Primary Endpoint ◽  
Darbepoetin Alfa ◽  
Test Period ◽  
Low Risk ◽  
Refractory Anemia ◽  
Phase 2 ◽  
Open Label ◽  
Erythroid Response ◽  
Open Label Trial

Abstract Patients (pts) with myelodysplastic syndromes (MDS) often develop clinically significant anemia due to ineffective hematopoiesis. Using the erythropoiesis-stimulating protein (ESP) epoetin alfa to treat anemia results in an average response rate of approximately 30% (40% when used with G-CSF) in low-risk MDS pts. Darbepoetin alfa (DA) (150 to 300 mcg/week) also effectively increases hemoglobin (Hb) concentrations and reduces red blood cell transfusion requirements in these pts. This study is a phase 2, single-arm, open-label trial (with a planned sample size of 200 pts), evaluating the efficacy of DA 500 mcg given SC every 3 weeks (Q3W) for treating anemia in low-risk MDS pts during the 13-week (wk) test period. Eligible pts had low or intermediate-1 risk MDS (IPSS/FAB criteria), anemia (Hb ≤11 g/dL), and no previous or ongoing chemotherapy or biologic response modifiers (except for ESPs [stopped ≥7 days and ≤1 month before enrollment] and G-CSF [allowed for infection before enrollment]). The primary endpoint is the proportion of pts achieving an erythroid response during the test period. Secondary endpoints include the change in Hb from baseline at wk 13, transfusion incidence, and impact on pt-reported fatigue. This study has completed enrollment and data are available from a planned interim analysis of the first 100 pts; 63 pts were not treated with an ESP before enrollment (ESP-naive ([EN]). Of the EN pts, 51% were female, 81% were white, 73% had low-risk MDS, 22% had intermediate-1 risk MDS, 60% had refractory anemia (RA), 30% had RA with ringed sideroblasts (RARS), and 10% had RA with excess blasts (RAEB). Results for EN pts are shown in the table. Of the 37 pts treated with an ESP before enrollment, the crude percentage (95% CL) with an overall (major plus minor) erythroid response was 36% (20, 53), the crude percentage (95% CL) with a major erythroid response was 21% (7, 35), and the crude percentage (95% CL) that required transfusions during wks 1 to 13 was 32% (17, 48 ). During the test period, 16% of all pts reported a serious adverse event (none were considered treatment-related). Injection site pain (reported by 4% of pts) was the most common treatment-related adverse event. No thromboembolic events have been reported. Interim results from this fully-enrolled study indicate that DA 500 mcg Q3W appears to be well tolerated and capable of increasing Hb levels in low-risk MDS pts. Final results for the primary endpoint will be presented. ESP-Naive Pts, N = 63 No. of Patients Evaluated (n) Crude % (95% CL) pts with overall erythroid response 77% (66, 88) 57 Crude % (95% CL) pts with major erythroid response 47% (34, 60) 57 Mean (95% CL) baseline Hb 9.9 (9.6, 10.1) g/dL 56 Mean (95% CL) change in Hb at wk 13 (last value carried forward approach) 1.1 (0.8, 1.4) g/dL 56 Crude % (95% CL) pts with transfusions (wks 1 to 13) 17% (8, 27) 63 Mean (95% CL) baseline FACT-F score 29.8 (25.9, 33.8) 46 Mean (95% CL) change in FACT-F score at wk 13 (available data) 5.7 (2.3, 9.0) 41

scholarly journals Lenalidomide for the Treatment of Myelodysplastic Syndrome

2020 ◽  
Vol 95 (2) ◽  
pp. 74-77
Author(s):  
Sung-Yong Kim
Keyword(s):  
Myelodysplastic Syndrome ◽  
Response Rate ◽  
Malignant Cell ◽  
Low Risk ◽  
Genetic Response ◽  
National Health Insurance System ◽  
Risk Patients ◽  
The Individual ◽  
Diverse Groups ◽  
Line Drug

Myelodysplastic syndrome (MDS) is a disease affecting clinically and cytogenetically diverse groups of patients. Consequently, MDS patients differ in their response to the individual agents used to treat their disease. Lenalidomide, which has been covered by the national health insurance system of Korea since 2019, is used to relieve transfusion-dependent anemia and has been shown to achieve a genetic response in MDS patients, especially those carrying the del(5q) mutation. Although the mechanism of action of lenalidomide is not yet clear, it may block malignant cell proliferation directly by inhibiting haplodeficient phosphatase, but also act indirectly by killing malignant cells through an immunomodulatory effect. In clinical studies, low-risk patients with the del(5q) mutation who were treated with lenalidomide had a hematologic response rate of 55–60% and a median survival of 2–2.5 years. The genetic response rate was 50–73%, and the complete genetic response rate 30–45%. However, in high-risk patients, the response rate was low (20–30%). These results demonstrate the potential utility of lenalidomide as a first-line drug for transfusion-dependent, del(5q), low-risk patients in Korea.

Impact of a new dosing regimen of epoetin alfa on quality of life and anemia in patients with low-risk myelodysplastic syndrome

2004 ◽  
Vol 84 (3) ◽  
pp. 167-176 ◽  
Author(s):  
M. A. Aloe Spiriti ◽  
R. Latagliata ◽  
P. Niscola ◽  
A. Cortelezzi ◽  
M. Francesconi ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Myelodysplastic Syndrome ◽  
Low Risk ◽  
Epoetin Alfa ◽  
Dosing Regimen

A Phase II Study of Low Dose Intravenous Clofarabine for Elderly Myelodysplastic Syndrome Patients Who Have Failed 5-Azacytidine

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4955-4955
Author(s):  
Seah H Lim ◽  
John McMahan ◽  
Jian Zhang ◽  
Yana Zhang
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndrome ◽  
Disease Progression ◽  
Phase Ii ◽  
Low Dose ◽  
Response Rate ◽  
Phase Ii Study ◽  
Low Risk ◽  
The Other ◽  
Low Doses

Abstract Abstract 4955 Based on the observations of changes in DNA methylation status of various tumor suppressor genes, epigenetic targeting of myelodysplastic syndrome (MDS) with DNA hypomethylating agents are currently used for these patients. However, only up to 40% of the patients respond to these treatments. Therapeutic options for non-responders or responders whose disease progresses while on therapy are very limited. Based on our recent findings that low concentration clofarabine induced DNA hypomethylation, we carried out a Phase II study of elderly MDS patients who had failed 5-azacytidine (5-aza) therapy to determine the efficacy and toxicities of low dose intravenous clofarabine (ClinicalTrials.gov Identifier NCT00700011). Patients in Cohort 1 received intravenous clofarabine at 10 mg/m2/day and patients in Cohort 2 5 mg/m2/day for 5 days, each infusion given over 2 hours and each cycle repeated every 4 to 8 weeks, depending on the rate of bone marrow recovery. Eight patients were planned for each of the treatment dose. The patients were treated until disease progression or intolerable toxicities. The International Working Group response criteria were used. The study was closed after 10 patients were treated. Of the 10 patients (6 males and 4 females) treated, ei8 received 10 mg/m2/day (Cohort 1) of clofarabine and 2 patients 5 mg/m2/day (Cohort 2). The median age was 73 years (range 65–78). Five patients had only received 5-aza prior to being treated with clofarabine while the other 5 patients had also received other therapy (lenolidomide and decitabine). Three patients received 1 cycle, 4 patients received 2 cycles, 1 patient received 3 cycles and 2 patients received 4 cycles of clofarabine. The following responses were observed in the 9 evaluable patients: 1 CR (11%), 1 PR (11%), 2 HI (22%), 3 SD and 2 PD. The overall response rate was 44% in this group of elderly patients. All responses were observed in patients who received clofarabine 10 mg/m2/day. Response rate of 67% (4/6) was observed in patients with low risk MDS (IPSS < 1). In contrast, all 3 evaluable patients with high risk/Int.-2 MDS showed disease progression. The median time to response was 6 weeks (range 4–6 weeks) and 1 cycle of clofarabine. The patient who achieved a CR remained in CR for 14 months. The 2 patients who achieved HI both restored the erythroid-responsiveness to recombinant erythropoietin and became transfusion-independent, both for 10 months (1 patient received only 1 cycle and the other patient 2 cycles of clofarabine). As of July 31, 2010, diseases in all four responders have relapsed/progressed. The median duration of response was 10 months (range 5–14). Despite using low doses of clofarabine, severe and prolonged pancytopenia was observed in all 10 patients. All 10 patients needed considerable blood and platelet transfusions. Eight of these ten patients also needed hospitalization for neutropenic fever. Of the 22 cycles of clofarabine administered, there were a total of 13 hospital admissions with 100 hospital days. A total of 169 units of irradiated packed red blood cells (median 10 units/cycle; range 1.5–14 units/cycle) and 211 units of irradiated single donor platelets (median 10 units/cycle; range 2–30.5 units/cycle) were used. One patient died, within 2 weeks of completing cycle 1 of clofarabine, from intracranial bleed despite intensive support of severe thrombocytopenia with aggressive platelet transfusion. This patient was already thrombocytopenic prior to starting clofarabine and had a history of severe thrombocytopenic gastrointestinal bleed prior to starting on clofarabine. Nonhematologic toxicities occurred very infrequently and were mainly Grade 2 or lower. In all cases, clofarabine was discontinued due to either disease progression (2 patients) or toxicities (8 patients). With a median follow-up of 7.5 months (range 0.5–22), the overall survival for the whole group was 50%. In conclusion, elderly MDS patients, especially those with low risk disease, who have failed 5-aza may respond to low dose clofarabine. However, even at the low doses used in this study, bone marrow toxicity was significant. It remains to be determined whether the dose of clofarabine can be reduced further to minimize toxicities without compromising efficacy in this group of patients. Future studies should investigate the role of low dose clofarabine in low risk MDS patients. Study supported by Genzyme Corporation, Cambridge, MA, USA Disclosures: No relevant conflicts of interest to declare.

CD8+ CD28null T Cell Expansion Impairs Lenalidomide Immunomodulatory Function in Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1117-1117
Author(s):  
Jessica M. McDaniel ◽  
JianXiang Zou ◽  
Alan F. List ◽  
P.K. Epling-Burnette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Myelodysplastic Syndrome ◽  
Interleukin 2 ◽  
Low Risk ◽  
Effector Memory ◽  
Cell Parameters ◽  
Variable Expression ◽  
Erythroid Response

Abstract Abstract 1117 Lenalidomide, a thalidomide analog, is known to induce high rates of transfusion independence in Myelodysplastic Syndrome (MDS) patients harboring a commonly deleted region on chromosome 5q (del(5q)). Erythroid response is also seen in 20–30% of low-risk, non-del(5q) patients, although the mechanism of response is incompletely understood. Lenalidomide is a potent immunomodulating agent and hematopoietic response has been linked to increased lymphocyte infiltration in the bone marrow and improved T cell and NK cell proliferation/function. Lenalidomide's effect on the erythroid compartment is well documented, but the effect of lenalidomide on the immune compartment, and the relationship between the T cell compartment and erythroid response in vivo in MDS is not known. We therefore examined 23 T cell parameters before lenalidomide treatment and correlated them to hematologic response. We found that patients who fail lenalidomide therapy had higher CD8+ Terminal Effector Memory (TEM) T cells than did responders (p=0.02). TEM cells express CD45RA, have variable expression of the CD45RO memory marker and loss of L-selectin (CD62L) lymph node homing receptor. Interestingly, T cells within the TEM compartment are uniformly CD28 deficient (CD28null). Lenalidomide has been shown by us and others to increase the proliferation and function of T cells by providing co-stimulation (LeBlanc et al. 2004, Blood) through CD28, so CD28 expression may be important for immunomodulatory response. We found that MDS patients non-responsive to lenalidomide had an overall increase in CD4 (p=0.0195) and CD8 (p=0.0317) CD28null T cells, as well as an increase in CD28null cells (p=0.0159) within the TEM compartment compared to hematologic responders. To determine if CD28 expression is necessary for lenalidomide action in T cells, we sorted healthy donor T cells into CD8+CD28+ and CD8+CD28− populations, and found that lenalidomide-induced proliferation and interleukin-2 (IL-2) production were completely ablated within the CD28null subset. Because CD28null T cells displayed less proliferation (p<0.001) and produced less IL-2 (p<0.001) after stimulation, possibly related to excessive proliferative history in vivo, we therefore used shRNA to knockdown CD28 in healthy (CD28+) T cells and determined the functional response of these cells to lenalidomide. With CD28 knockdown, lenalidomide produced significantly less IL-2 compared to CD28+ controls (p<0.001), indicating the necessity of the immunotyrosine-based activation motifs (ITAMs) on the intracellular domain of the CD28 receptor for lenalidomide action. These results indicate that lenalidomide-mediated immune modulation requires CD28 expression on T cells and expansion of CD8+ CD28 deficient T cells may represent a predictor of erythroid non-response in non-del(5q) low-risk MDS patients. Disclosures: List: Celgene: Consultancy. Epling-Burnette:Celgene: Research Funding.

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