- Email: [email protected]
Lenalidomide—A Transforming Therapeutic Agent in Myelodysplastic Syndromes
AML/MDS Leukemia 2008 Proceedings
Lenalidomide—A Transforming Therapeutic Agent in Myelodysplastic Syndromes Alan List Abstract Lenalidomide is an immunomodulatory drug (IMiD™) with erythropoietic activity in myelodysplastic syndromes (MDS) that is karyotype dependent. The MDS-003 multicenter registration trial in deletion of chromosome 5q (del[5q]) showed that lenalidomide suppresses the del(5q) clone in patients who achieve transfusion independence and is a prerequisite for sustained restoration of effective erythropoiesis. Long-term outcome data indicate that cytogenetic response to lenalidomide might confer a survival advantage compared with cytogenetic nonresponders, with a corresponding reduced risk for acute myeloid leukemia (AML) progression. In lower-risk, transfusion-dependent patients with MDS without del(5q), lenalidomide has significant, albeit less erythropoietic, activity that could relate to dual effects on both the MDS clone and the bone marrow environment. The most common adverse effects are neutropenia and thrombocytopenia, which occur early and with greater frequency in patients with del(5q), consistent with the drug’s action to suppress the MDS clone. Combination strategies are now in both MDS and AML that could further broaden the therapeutic potential of lenalidomide. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S302-S304, 2009; DOI: 10.3816/CLM.2009.s.028 Keywords: Acute myeloid leukemia, del(5q), Erythroid response, Immunomodulatory drugs
Introduction Lenalidomide (Revlimid®, Celgene Corporation) is a member of a proprietary class of thalidomide analogues termed immunomodulatory drugs (IMiDs™) that modulate immunologic and inflammatory responses.1 Lenalidomide is a more potent inhibitor (approximately 2000-fold) of ligand-induced tumor necrosis factor (TNF)-A production than is thalidomide.2 Its immunomodulatory activities range from inhibition of cyclooxygenase-2, interleukin (IL)-1B, transforming growth factor-B, and IL-6 induction to potentiation of IL-2 generation.3,4 The complementary action of lenalidomide on both the malignant clone and the surrounding microenvironment distinguishes it from more selective therapeutic agents such as the hematopoietic cytokines. Lenalidomide has direct antitumor effects that are complimented by its inhibitory effects on supportive stroma and its inherent ability to augment tumor selective T-cell and natural killer cell immune responses.5,6 In myelodysplastic syndromes (MDS), these effects are complemented by the agent’s capacity to potentiate erythropoietin-induced hematopoietic response and restore erythroid H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Submitted: May 8, 2009; Revised: Jul 17, 2009; Accepted: Jul 17, 2009 Address for correspondence: Alan List, MD, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, MCC-VP, Tampa, FL 33612-9497 Fax: 813-745-3727; e-mail: [email protected]
differentiation potential.7 In CD34+ selected cells from normal marrow donors, treatment with lenalidomide or its analogue, pomalidomide, induces the expansion of immature progenitors and, in particular, erythroid bursts.5,8 A recent microarray analysis of bone marrow gene expression profiles from patients treated with lenalidomide showed that responding patients display a profound decrease in expression of genes involved in erythroid differentiation.9 Moreover, following in vitro drug exposure, lenalidomide restored erythroid differentiation with corresponding upregulation of the natively suppressed erythroid gene expression signature.
Clinical Trials in Myelodysplastic Syndromes The safety and hematologic activity of lenalidomide in MDS was first investigated in a study involving 43 patients with transfusion-dependent or symptomatic anemia (Table 1).10-12 All patients in the trial either did not respond to treatment with a recombinant erythropoietic stimulating agent (ESA) or had a poor cytokine response profile characterized by heavy transfusion burden and high serum erythropoietin concentration (> 500 mU/mL). At doses of either 25 mg/day, 10 mg/day, or 10 mg/day for 21 of every 28 days, 56% of the patients experienced durable erythroid responses according to International Working Group (IWG) 2000 criteria, with 20 of 32 transfusion-dependent patients achieving transfusion independence. Significant differences in erythroid response rate were observed in select karyotypes. Of 12 patients with deletion of
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
S302
| Clinical Lymphoma, Myeloma & Leukemia Supplement
September 2009
Table 1 Phase I/II Studies of Lenalidomide in Patients With Myelodysplastic Syndromes N
Dose, mg/Day
Erythroid HI, n (%)a
Erythroid HI-Major, n (%)a
Cytogenetic Response, n (%)
I/II10
43
10-25
24 (56)
21 (49)
11/20 (55)b
Phase II Del(5q)11
148
10
112 (76)
99 (67)
62/85 (73)
214
10
92 (43)
56 (26)
9/47 (19)
Study Phase
Phase II
Non-Del(5q)12
aHI
denotes hematologic improvement according to International Working Group 2000 criteria. cytogenetic responses in 10 of 12 patients with del(5q). Abbreviation: del(5q) = deletion of chromosome 5q
bIncludes
chromosome 5q (del[5q]), 10 had an erythroid response compared with 57% of patients with a normal karyotype and 12% of patients with other chromosomal abnormalities. Responses were durable, with the median duration of major response exceeding 2 years. Myelosuppression was dose limiting, with grade ≥ 3 neutropenia occurring in 58% of the patients with del(5q) and thrombocytopenia in 50%. Two multicenter, confirmatory trials validated the karyotypedependent erythroid response rate in low/intermediate-1 risk, transfusion-dependent patients with MDS (Table 1).11,12 In both studies, patients received treatment with lenalidomide 10 mg daily or for 21 days every 4 weeks. This non-del(5q) MDS trial was limited to patients without del(5q) and included 214 patients.12 The overall transfusion response rate was 43%, with 26% of the patients achieving transfusion independence with a > 1 g/dL rise in hemoglobin that was sustained for a median of 43 weeks, and a minority of patients (19%) experienced a cytogenetic response. Myelosuppression remained the principal adverse effect responsible for dose adjustment; however, grade ≥ 3 neutropenia or thrombocytopenia developed in < 25% of the patients. As demonstrated in the initial safety and efficacy trial, the transfusion response rate was much higher in patients with del(5q) treated in the del(5q) registration study that included 148 patients with del(5q) with varied cytogenetic complexity.11 Overall, 76% of the patients experienced a transfusion response according to IWG 2000 criteria, and 67% achieved transfusion independence with a ≥ 1 g/dL rise in hemoglobin. Unlike the non-del(5q) study, cytogenetic responses were common (73% overall; 45% complete) and intimately linked to achievement of transfusion independence and resolution of cytologic dysplasia. Moreover, additional chromosomal abnormalities accompanying del(5q) did not adversely affect the frequency of erythroid or cytogenetic response despite the recognized association between cytogenetic complexity and more unfavorable natural history. Myelosuppression was more common in the del(5q) study, consistent with lenalidomide’s action to suppress the del(5q) clone. Treatment interruption for grade ≥ 3 neutropenia or thrombocytopenia was reported in 55% and 44% of the patients, respectively. A recent multivariate analysis of covariates showed that a > 50% reduction in platelet count or the need for treatment interruption for myelosuppression in the initial 8 weeks of treatment were the most powerful independent predictive variables for achievement of transfusion independence, indicating that cytopenias early in the treatment course are a surrogate marker for suppression of the del(5q) clone.13
Correlative biomarker studies offer additional insight into the agent’s contrasting karyotype-dependent mechanism of action.14 A direct cytotoxic effect leading to suppression of the del(5q) MDS clone is supported by the marked rise in apoptotic index in major erythroid responders with del(5q) compared with nondel(5q) responders (207% vs. 48%). In contrast, restoration of effective erythropoiesis in the patients without del(5q) is associated with proliferation arrest. Non-del(5q) major responders had a marked reduction in the Ki-67 index (–76%) compared with del(5q) responders (–9%). Furthermore, lenalidomide significantly suppressed elaboration of an array of inflammatory cytokines in bone marrow plasma, including TNF-A, IL-1B, interferon (IFN)-A, IFN-G, stromal cell–derived factor-1B, and IL-2 in erythroid responders by 16 weeks of treatment. Reduction in medullary microvessel density was greatest in major erythroid responders with del(5q).
Deletion of Chromosome 5q Gene Targets of Lenalidomide The critical deleted region (CDR) within del(5q) encompasses a 1.5-Mb segment between 5q31 and 5q33. Lenalidomide inhibits the in vitro growth of del(5q) erythroblasts without discernable effects on normal erythroid progenitors.15 Analysis of druginduced changes in gene expression showed that lenalidomide upregulates expression of several genes in del(5q) erythroblasts, including induction of the haplodeficient SPARC gene expression, which is encoded within the CDR. Although the SPARC gene product has antiproliferative and antiangiogenic effects, its precise role, if any, in mediating the apoptotic response to lenalidomide in del(5q) MDS has not been demonstrated. Recent investigations implicate inhibition of 2 cell-cycle regulatory dual-specificity phosphatases, ie, CDC25C and PP2A-CA, which are haplodeficient in del(5q) MDS, as key targets underlying the karyotypedependent cytotoxicity of lenalidomide.16 Selective suppression of these 2 genes by shRNA promotes sensitivity to lenalidomideinduced apoptosis in both a cell line model and primary MDS bone marrow cells with normal karyotype. These findings suggest that allelic haplodeficiency for critical drug-able gene products might offer a potential strategy for therapeutic exploitation in other types of malignancies and provide opportunities to optimize treatments for patients with MDS.
Current Studies Lenalidomide was approved for the treatment of transfusiondependent patients with del(5q) MDS by the US Food and Drug
Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009
| S303
Lenalidomide in MDS Administration in December 2005. A postmarketing placebo-controlled phase III trial (MDS-004) comparing the frequency of lenalidomide-induced transfusion independence in patients with del(5q) recently completed enrollment in Europe. This trial evaluated 2 doses of lenalidomide, 5 mg and 10 mg, administered on a 21-day schedule, with cross-over allowed after 24 weeks of treatment. Although this trial will provide important new data on an alternate dose and schedule of lenalidomide administration, it will likely not address the question of the effect of lenalidomide treatment on the natural history of the disease. The ability of lenalidomide to enhance erythroid progenitor responsiveness to an ESA is the subject of the phase III Intergroup trial E2905 comparing major erythroid response rate to treatment with lenalidomide monotherapy or combined with epoetin-A in lower-risk patients who either did not respond to previous treatment with an ESA or had a poor response profile. The Southwest Oncology Group is currently investigating augmented-dose lenalidomide treatment in elderly patients with acute myeloid leukemia (AML) with a del(5q) cytogenetic abnormality. Other studies have targeted higher-risk patients with del(5q) MDS with lenalidomide monotherapy, combination treatment with azacitidine, exploitation of lenalidomide’s immune-modifying activities, MDS vaccine studies, and combination strategies in del(5q) AML with standard 7 + 3 chemotherapy induction.
Disclosures Dr. List has received research funding from and is a member of the Speaker’s Bureau for Celgene Corporation and has served as a paid consultant or been on the Advisory Board of S*BIO Pte Ltd.
S304
| Clinical Lymphoma, Myeloma & Leukemia Supplement
September 2009
References 1. Kale V, List AF. Immunomodulatory drugs (IMiDs): a new treatment option for myelodysplastic syndromes. Curr Pharm Biotechnol 2006; 7:339-432. 2. Muller GW, Chen R, Huang SY, et al. Amino-substituted thalidomide analogs: Potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999; 9:1625-30. 3. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4:314-22. 4. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163:380-6. 5. Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 67:746-55. 6. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002; 2:927-37. 7. List AF, Estes M, Williams A, et al. Lenalidomide (CC-5013; Revlimid(R)) promotes erythropoiesis in myelodysplastic syndromes (MDS) by CD45 protein tyrosine phosphatase (PTP) inhibition. Blood 2006; 108:397a (Abstract 1360). 8. Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest 2008; 118:248-58. 9. Ebert BL, Galili N, Tamayo P, et al. An erythroid gene expression signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med 2008; 5:e35. 10. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352:549-57. 11. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456-65. 12. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111:86-93. 13. Sekeres M, Maciejewski JP, Giagounidis A, et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2008; 26:5943-9. 14. List AF, Baker AF, Green S, et al. Lenalidomide: targeted anemia therapy for myelodysplastic syndrome. Cancer Control 2006; 13(suppl):4-11. 15. Pellagatti A, Jadersten M, Forsblom AM, et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A 2007; 104:11406-11. 16. Wei S, Chen X, Rocha K, et al. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci U S A 2009 May 26. [Epub ahead of print].
Lenalidomide—A Transforming Therapeutic Agent in Myelodysplastic Syndromes Alan List Abstract Lenalidomide is an immunomodulatory drug (IMiD™) with erythropoietic activity in myelodysplastic syndromes (MDS) that is karyotype dependent. The MDS-003 multicenter registration trial in deletion of chromosome 5q (del[5q]) showed that lenalidomide suppresses the del(5q) clone in patients who achieve transfusion independence and is a prerequisite for sustained restoration of effective erythropoiesis. Long-term outcome data indicate that cytogenetic response to lenalidomide might confer a survival advantage compared with cytogenetic nonresponders, with a corresponding reduced risk for acute myeloid leukemia (AML) progression. In lower-risk, transfusion-dependent patients with MDS without del(5q), lenalidomide has significant, albeit less erythropoietic, activity that could relate to dual effects on both the MDS clone and the bone marrow environment. The most common adverse effects are neutropenia and thrombocytopenia, which occur early and with greater frequency in patients with del(5q), consistent with the drug’s action to suppress the MDS clone. Combination strategies are now in both MDS and AML that could further broaden the therapeutic potential of lenalidomide. Clinical Lymphoma & Myeloma, Vol. 9, Suppl. 3, S302-S304, 2009; DOI: 10.3816/CLM.2009.s.028 Keywords: Acute myeloid leukemia, del(5q), Erythroid response, Immunomodulatory drugs
Introduction Lenalidomide (Revlimid®, Celgene Corporation) is a member of a proprietary class of thalidomide analogues termed immunomodulatory drugs (IMiDs™) that modulate immunologic and inflammatory responses.1 Lenalidomide is a more potent inhibitor (approximately 2000-fold) of ligand-induced tumor necrosis factor (TNF)-A production than is thalidomide.2 Its immunomodulatory activities range from inhibition of cyclooxygenase-2, interleukin (IL)-1B, transforming growth factor-B, and IL-6 induction to potentiation of IL-2 generation.3,4 The complementary action of lenalidomide on both the malignant clone and the surrounding microenvironment distinguishes it from more selective therapeutic agents such as the hematopoietic cytokines. Lenalidomide has direct antitumor effects that are complimented by its inhibitory effects on supportive stroma and its inherent ability to augment tumor selective T-cell and natural killer cell immune responses.5,6 In myelodysplastic syndromes (MDS), these effects are complemented by the agent’s capacity to potentiate erythropoietin-induced hematopoietic response and restore erythroid H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL Submitted: May 8, 2009; Revised: Jul 17, 2009; Accepted: Jul 17, 2009 Address for correspondence: Alan List, MD, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, MCC-VP, Tampa, FL 33612-9497 Fax: 813-745-3727; e-mail: [email protected]
differentiation potential.7 In CD34+ selected cells from normal marrow donors, treatment with lenalidomide or its analogue, pomalidomide, induces the expansion of immature progenitors and, in particular, erythroid bursts.5,8 A recent microarray analysis of bone marrow gene expression profiles from patients treated with lenalidomide showed that responding patients display a profound decrease in expression of genes involved in erythroid differentiation.9 Moreover, following in vitro drug exposure, lenalidomide restored erythroid differentiation with corresponding upregulation of the natively suppressed erythroid gene expression signature.
Clinical Trials in Myelodysplastic Syndromes The safety and hematologic activity of lenalidomide in MDS was first investigated in a study involving 43 patients with transfusion-dependent or symptomatic anemia (Table 1).10-12 All patients in the trial either did not respond to treatment with a recombinant erythropoietic stimulating agent (ESA) or had a poor cytokine response profile characterized by heavy transfusion burden and high serum erythropoietin concentration (> 500 mU/mL). At doses of either 25 mg/day, 10 mg/day, or 10 mg/day for 21 of every 28 days, 56% of the patients experienced durable erythroid responses according to International Working Group (IWG) 2000 criteria, with 20 of 32 transfusion-dependent patients achieving transfusion independence. Significant differences in erythroid response rate were observed in select karyotypes. Of 12 patients with deletion of
This summary may include the discussion of investigational and/or unlabeled uses of drugs and/or devices that may not be approved by the FDA. Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400.
S302
| Clinical Lymphoma, Myeloma & Leukemia Supplement
September 2009
Table 1 Phase I/II Studies of Lenalidomide in Patients With Myelodysplastic Syndromes N
Dose, mg/Day
Erythroid HI, n (%)a
Erythroid HI-Major, n (%)a
Cytogenetic Response, n (%)
I/II10
43
10-25
24 (56)
21 (49)
11/20 (55)b
Phase II Del(5q)11
148
10
112 (76)
99 (67)
62/85 (73)
214
10
92 (43)
56 (26)
9/47 (19)
Study Phase
Phase II
Non-Del(5q)12
aHI
denotes hematologic improvement according to International Working Group 2000 criteria. cytogenetic responses in 10 of 12 patients with del(5q). Abbreviation: del(5q) = deletion of chromosome 5q
bIncludes
chromosome 5q (del[5q]), 10 had an erythroid response compared with 57% of patients with a normal karyotype and 12% of patients with other chromosomal abnormalities. Responses were durable, with the median duration of major response exceeding 2 years. Myelosuppression was dose limiting, with grade ≥ 3 neutropenia occurring in 58% of the patients with del(5q) and thrombocytopenia in 50%. Two multicenter, confirmatory trials validated the karyotypedependent erythroid response rate in low/intermediate-1 risk, transfusion-dependent patients with MDS (Table 1).11,12 In both studies, patients received treatment with lenalidomide 10 mg daily or for 21 days every 4 weeks. This non-del(5q) MDS trial was limited to patients without del(5q) and included 214 patients.12 The overall transfusion response rate was 43%, with 26% of the patients achieving transfusion independence with a > 1 g/dL rise in hemoglobin that was sustained for a median of 43 weeks, and a minority of patients (19%) experienced a cytogenetic response. Myelosuppression remained the principal adverse effect responsible for dose adjustment; however, grade ≥ 3 neutropenia or thrombocytopenia developed in < 25% of the patients. As demonstrated in the initial safety and efficacy trial, the transfusion response rate was much higher in patients with del(5q) treated in the del(5q) registration study that included 148 patients with del(5q) with varied cytogenetic complexity.11 Overall, 76% of the patients experienced a transfusion response according to IWG 2000 criteria, and 67% achieved transfusion independence with a ≥ 1 g/dL rise in hemoglobin. Unlike the non-del(5q) study, cytogenetic responses were common (73% overall; 45% complete) and intimately linked to achievement of transfusion independence and resolution of cytologic dysplasia. Moreover, additional chromosomal abnormalities accompanying del(5q) did not adversely affect the frequency of erythroid or cytogenetic response despite the recognized association between cytogenetic complexity and more unfavorable natural history. Myelosuppression was more common in the del(5q) study, consistent with lenalidomide’s action to suppress the del(5q) clone. Treatment interruption for grade ≥ 3 neutropenia or thrombocytopenia was reported in 55% and 44% of the patients, respectively. A recent multivariate analysis of covariates showed that a > 50% reduction in platelet count or the need for treatment interruption for myelosuppression in the initial 8 weeks of treatment were the most powerful independent predictive variables for achievement of transfusion independence, indicating that cytopenias early in the treatment course are a surrogate marker for suppression of the del(5q) clone.13
Correlative biomarker studies offer additional insight into the agent’s contrasting karyotype-dependent mechanism of action.14 A direct cytotoxic effect leading to suppression of the del(5q) MDS clone is supported by the marked rise in apoptotic index in major erythroid responders with del(5q) compared with nondel(5q) responders (207% vs. 48%). In contrast, restoration of effective erythropoiesis in the patients without del(5q) is associated with proliferation arrest. Non-del(5q) major responders had a marked reduction in the Ki-67 index (–76%) compared with del(5q) responders (–9%). Furthermore, lenalidomide significantly suppressed elaboration of an array of inflammatory cytokines in bone marrow plasma, including TNF-A, IL-1B, interferon (IFN)-A, IFN-G, stromal cell–derived factor-1B, and IL-2 in erythroid responders by 16 weeks of treatment. Reduction in medullary microvessel density was greatest in major erythroid responders with del(5q).
Deletion of Chromosome 5q Gene Targets of Lenalidomide The critical deleted region (CDR) within del(5q) encompasses a 1.5-Mb segment between 5q31 and 5q33. Lenalidomide inhibits the in vitro growth of del(5q) erythroblasts without discernable effects on normal erythroid progenitors.15 Analysis of druginduced changes in gene expression showed that lenalidomide upregulates expression of several genes in del(5q) erythroblasts, including induction of the haplodeficient SPARC gene expression, which is encoded within the CDR. Although the SPARC gene product has antiproliferative and antiangiogenic effects, its precise role, if any, in mediating the apoptotic response to lenalidomide in del(5q) MDS has not been demonstrated. Recent investigations implicate inhibition of 2 cell-cycle regulatory dual-specificity phosphatases, ie, CDC25C and PP2A-CA, which are haplodeficient in del(5q) MDS, as key targets underlying the karyotypedependent cytotoxicity of lenalidomide.16 Selective suppression of these 2 genes by shRNA promotes sensitivity to lenalidomideinduced apoptosis in both a cell line model and primary MDS bone marrow cells with normal karyotype. These findings suggest that allelic haplodeficiency for critical drug-able gene products might offer a potential strategy for therapeutic exploitation in other types of malignancies and provide opportunities to optimize treatments for patients with MDS.
Current Studies Lenalidomide was approved for the treatment of transfusiondependent patients with del(5q) MDS by the US Food and Drug
Clinical Lymphoma, Myeloma & Leukemia Supplement September 2009
| S303
Lenalidomide in MDS Administration in December 2005. A postmarketing placebo-controlled phase III trial (MDS-004) comparing the frequency of lenalidomide-induced transfusion independence in patients with del(5q) recently completed enrollment in Europe. This trial evaluated 2 doses of lenalidomide, 5 mg and 10 mg, administered on a 21-day schedule, with cross-over allowed after 24 weeks of treatment. Although this trial will provide important new data on an alternate dose and schedule of lenalidomide administration, it will likely not address the question of the effect of lenalidomide treatment on the natural history of the disease. The ability of lenalidomide to enhance erythroid progenitor responsiveness to an ESA is the subject of the phase III Intergroup trial E2905 comparing major erythroid response rate to treatment with lenalidomide monotherapy or combined with epoetin-A in lower-risk patients who either did not respond to previous treatment with an ESA or had a poor response profile. The Southwest Oncology Group is currently investigating augmented-dose lenalidomide treatment in elderly patients with acute myeloid leukemia (AML) with a del(5q) cytogenetic abnormality. Other studies have targeted higher-risk patients with del(5q) MDS with lenalidomide monotherapy, combination treatment with azacitidine, exploitation of lenalidomide’s immune-modifying activities, MDS vaccine studies, and combination strategies in del(5q) AML with standard 7 + 3 chemotherapy induction.
Disclosures Dr. List has received research funding from and is a member of the Speaker’s Bureau for Celgene Corporation and has served as a paid consultant or been on the Advisory Board of S*BIO Pte Ltd.
S304
| Clinical Lymphoma, Myeloma & Leukemia Supplement
September 2009
References 1. Kale V, List AF. Immunomodulatory drugs (IMiDs): a new treatment option for myelodysplastic syndromes. Curr Pharm Biotechnol 2006; 7:339-432. 2. Muller GW, Chen R, Huang SY, et al. Amino-substituted thalidomide analogs: Potent inhibitors of TNF-alpha production. Bioorg Med Chem Lett 1999; 9:1625-30. 3. Bartlett JB, Dredge K, Dalgleish AG. The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 2004; 4:314-22. 4. Corral LG, Haslett PA, Muller GW, et al. Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 1999; 163:380-6. 5. Verhelle D, Corral LG, Wong K, et al. Lenalidomide and CC-4047 inhibit the proliferation of malignant B cells while expanding normal CD34+ progenitor cells. Cancer Res 2007; 67:746-55. 6. Hideshima T, Anderson KC. Molecular mechanisms of novel therapeutic approaches for multiple myeloma. Nat Rev Cancer 2002; 2:927-37. 7. List AF, Estes M, Williams A, et al. Lenalidomide (CC-5013; Revlimid(R)) promotes erythropoiesis in myelodysplastic syndromes (MDS) by CD45 protein tyrosine phosphatase (PTP) inhibition. Blood 2006; 108:397a (Abstract 1360). 8. Moutouh-de Parseval LA, Verhelle D, Glezer E, et al. Pomalidomide and lenalidomide regulate erythropoiesis and fetal hemoglobin production in human CD34+ cells. J Clin Invest 2008; 118:248-58. 9. Ebert BL, Galili N, Tamayo P, et al. An erythroid gene expression signature predicts response to lenalidomide in myelodysplastic syndrome. PLoS Med 2008; 5:e35. 10. List A, Kurtin S, Roe DJ, et al. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med 2005; 352:549-57. 11. List A, Dewald G, Bennett J, et al. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355:1456-65. 12. Raza A, Reeves JA, Feldman EJ, et al. Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood 2008; 111:86-93. 13. Sekeres M, Maciejewski JP, Giagounidis A, et al. Relationship of treatment-related cytopenias and response to lenalidomide in patients with lower-risk myelodysplastic syndromes. J Clin Oncol 2008; 26:5943-9. 14. List AF, Baker AF, Green S, et al. Lenalidomide: targeted anemia therapy for myelodysplastic syndrome. Cancer Control 2006; 13(suppl):4-11. 15. Pellagatti A, Jadersten M, Forsblom AM, et al. Lenalidomide inhibits the malignant clone and up-regulates the SPARC gene mapping to the commonly deleted region in 5q- syndrome patients. Proc Natl Acad Sci U S A 2007; 104:11406-11. 16. Wei S, Chen X, Rocha K, et al. A critical role for phosphatase haplodeficiency in the selective suppression of deletion 5q MDS by lenalidomide. Proc Natl Acad Sci U S A 2009 May 26. [Epub ahead of print].