Efficacy of Lenalidomide in Myelodysplastic Syndromes
Alan List, M.D., Sandy Kurtin, C.N.P., M.S., Denise J. Roe, Dr.P.H., Andrew Buresh, M.D., Daruka Mahadevan, M.D., Ph.D., Deborah Fuchs, M.D., Lisa Rimsza, M.D., Ruth Heaton, B.S., Robert Knight, M.D., and Jerome B. Zeldis, M.D.
Background Ineffective erythropoiesis is the hallmark of myelodysplasticsyndromes. Management of the anemia caused by ineffective erythropoiesisis difficult. In patients with myelodysplastic syndromes andsymptomatic anemia, we evaluated the safety and hematologicactivity of lenalidomide, a novel analogue of thalidomide.
Methods Forty-three patients with transfusion-dependent or symptomaticanemia received lenalidomide at doses of 25 or 10 mg per dayor of 10 mg per day for 21 days of every 28-day cycle. All patientseither had had no response to recombinant erythropoietin orhad a high endogenous erythropoietin level with a low probabilityof benefit from such therapy. The response to treatment wasassessed after 16 weeks.
Conclusions Lenalidomide has hematologic activity in patientswith low-risk myelodysplastic syndromes who have no responseto erythropoietin or who are unlikely to benefit from conventionaltherapy.
Refractory anemia resulting from ineffective hematopoiesis isthe principal therapeutic challenge for patients with myelodysplasticsyndromes.1 Recombinant erythropoietin alone or in combinationwith myeloid growth factors ameliorates anemia in some patientsbut is generally ineffective in patients who require two ormore red-cell transfusions per month; its use rarely inducescytogenetic remissions.2,3
Hematopoietic precursors in patients with myelodysplastic syndromeshave an accelerated cell-cycle transition and impaired responsivenessto cytokine stimulation.1,4 Survival signals from the microenvironmentare compromised, owing in part to the presence of angiogenicmolecules, disruption of the medullary architecture, and excessproduction of inflammatory cytokines.5,6,7,8,9,10 Thalidomide,a multifunctional inhibitor of angiogenesis and an immune modulator,restores erythropoiesis and reduces transfusion dependence inapproximately 18 percent of patients who have no response torecombinant erythropoietin.11,12,13,14 However, long-term treatmentand dose escalation are limited by the drug's sedative and neurologiceffects. Lenalidomide is a novel 4-amino-glutarimide analogueof thalidomide that is more potent but does not have the neurotoxicand teratogenic effects of thalidomide.15,16,17 We report theresults of a safety and efficacy study of lenalidomide in patientswith myelodysplastic syndromes.
Methods
Patients
Eligible patients had received a histologically confirmed diagnosisof a primary myelodysplastic syndrome according to French–American–British(FAB) criteria (Figure 1)18 more than three months before enrollmentand a diagnosis of either symptomatic anemia (defined by a hemoglobinlevel of less than 10.0 g per deciliter) or transfusion-dependentanemia (defined by the need for at least 4 units of red cellswithin eight weeks before enrollment). Hematologic values obtainedduring the eight weeks preceding study treatment served as areference for the assessment of response. Patients either hadhad no response to treatment with recombinant erythropoietinor had an endogenous serum level of more than 500 mU per milliliter.Patients with severe neutropenia (defined by an absolute neutrophilcount of less than 500 per cubic millimeter), severe thrombocytopenia(defined by a platelet count of less than 10,000 per cubic millimeter),treatment-related myelodysplastic syndromes, or clinically significantcoexisting medical illnesses were excluded.
Figure 1. Characteristics of Myelodysplastic Syndromes.
The bone marrow aspirate in patients with myelodysplasia is hypercellular, reflecting trilineal dysplasia (Panel A; Wright–Giemsa stain). In this specimen, hypolobated megakaryocytes and hyposegmented neutrophils are prominent. Myeloid maturation is shifted to the left, and myeloblasts may be increased, as shown in Panel B in a patient with refractory anemia with excess blasts (Wright–Giemsa stain). Dyserythropoiesis accompanies the hypolobated megakaryocytes and hyposegmented neutrophils. There may be a left-sided shift in erythroid maturation, nuclear budding, megaloblastic changes, and as shown in Panel C, a decrease in the number of erythroid precursors (Wright–Giemsa stain). The cellularity of a core-biopsy specimen can approach 100 percent, with readily apparent dysplasia (Panel D; hematoxylin and eosin). (Provided by Lynn Moscinski, M.D., H. Lee Moffitt Cancer Center and Research Institute, Tampa, Fla.)
Study Design
This open-label, single-center trial evaluated the safety andefficacy of lenalidomide in patients with myelodysplastic syndromeswho had symptomatic anemia. All patients gave written informedconsent, and the study was approved by the institutional reviewboard of the University of Arizona. The principal investigatordesigned and conducted the study, analyzed the data, and wrotethe article in consultation with Celgene. Lenalidomide (Revlimid)was supplied by Celgene as 5-mg or 25-mg capsules. Three oraldosing schedules were sequentially evaluated: 25 mg daily, 10mg daily, and 10 mg daily for 21 days of every 28-day cycle.Treatment was interrupted in the event of adverse events ofgrade 3 or higher according to the Common Toxicity Criteriaof the National Cancer Institute and resumed at the next lowerdose after the resolution of these effects.19 Sequential dosereductions were as follows: 10 mg per day, 10 mg per day for21 days, 5 mg per day, 5 mg per day for 21 days, and 5 mg everyother day.
Complete blood counts were obtained every two weeks, with theresponse to treatment and adverse events assessed every fourweeks. Bone marrow aspiration, biopsy, and cytogenetic analysiswere repeated every eight weeks. The final response was assessedafter 16 weeks of therapy. Patients with a response continuedtaking lenalidomide until disease progression, treatment failure,or dose-limiting adverse events occurred. Patients with hematologicimprovement that did not qualify as a protocol-defined responseafter 16 weeks could receive 8 additional weeks of treatmentbefore the final assessment of response, whereas patients withouta response who had been following the 21-day treatment schedulewere offered continual dosing. Red-cell transfusions were administeredaccording to prestudy clinical indicators with the followingguidelines: 2 units were given to patients with a hematocritof less than 25 percent, 3 units to those with a hematocritof less than 21 percent, and 4 units to those with a hematocritof less than 18 percent. Myeloid growth factors for the managementof an exacerbation of neutropenia were the only cytokines permitted.
Assessment of Response and Adverse Events
The hematologic response was assessed according to the modifiedcriteria of the International Working Group, with the requirementthat an improvement had to be sustained for at least eight consecutiveweeks.20 A major erythroid response was defined as freedom fromthe need for transfusion or an increase in the hemoglobin levelof more than 2 g per deciliter in patients with transfusion-independentanemia. A minor response was defined as at least a 50 percentreduction in transfusions or a sustained elevation in the hemoglobinlevel of 1 to 2 g per deciliter. A major cytogenetic responsewas defined by the absence of the pretreatment cytogenetic abnormalityon standard metaphase analysis (e.g., at least 20 cells in metaphase),and a minor response by a reduction in the number of abnormalcells in metaphase of at least 50 percent. Cytogenetic progressionwas defined as the sustained acquisition of a new chromosomalabnormality.
Responses were compared by means of the International PrognosticScoring System (IPSS), which assesses the percentage of blastsin bone marrow, the karyotype, and the number of cytopenias.21Blinded review of bone marrow specimens was performed by twoinvestigators. Immunohistochemical staining of biopsy specimensand clot sections used monoclonal antibodies against IgG2a (VentanaMedical Systems) recognizing CD3 (PSI clone) and CD20 (L26 clone)antigens. Cytologic dysplasia was graded with the use of a 10percent threshold. Adverse events were graded with the use ofthe Common Toxicity Criteria of the National Cancer Institute.19
Statistical Analysis
The duration of transfusion independence was calculated fromthe date of the last red-cell transfusion to the resumptionof transfusion through April 1, 2004, according to the methodof Kaplan and Meier.22 The duration of major responses in transfusion-independentpatients was recorded from the initial date of the sustainedelevation in hemoglobin levels of more than 2 g per deciliter.The analyses of adverse events and response were carried outaccording to the intention-to-treat principle. Univariate comparisonswere performed with the use of Fisher's exact test, a two-sampleindependent t-test, or a Wilcoxon rank-sum test. The durationof transfusion independence was compared among the groups bymeans of the log-rank test. All reported P values are two-sided.Data are reported as medians ±SD.
Results
From March 2002 to August 2003, 55 candidates were screenedand 43 were enrolled. Thirty-three patients (77 percent) hadrefractory anemia or refractory anemia with ringed sideroblasts,and 38 (88 percent) had IPSS risk scores of low or intermediate1 (Table 1). Overall, 74 percent were transfusion-dependent,33 (77 percent) had had no response to treatment with erythropoietin,and 13 (30 percent) had had no response to treatment with thalidomide.None had received cytotoxic therapy. The median number of priornontransfusion treatments was 1.7 (range, 0 to 5). Moderate-to-severeneutropenia was present in 28 percent of patients, and moderate-to-severethrombocytopenia in 23 percent of patients; 37 percent had atleast two cytopenias. Twenty patients (46 percent) had clonalkaryotypic abnormalities (defined by the presence of at leasttwo abnormal cells in metaphase), including interstitial deletionsof chromosome 5q31.1 alone (11 patients) or in association withtrisomy 21 (1), an interstitial deletion of chromosome 20q11.2(2), a complex karyotype (1), and other abnormalities (5).
Table 1. Clinical and Hematologic Characteristics of the 43 Patients.
Adverse Events
Neutropenia and thrombocytopenia were the most common adverseevents (Table 2). Severe myelosuppression (grade 3 or higher)was dose-dependent and necessitated treatment interruption ordose reduction in 25 patients (58 percent). Treatment was interruptedbecause of myelosuppression in 77 percent of patients in the25-mg group after a median of 4.6 weeks (range, 3 to 9), ascompared with 62 percent of those who were receiving 10 mg daily(median, 8.5 weeks; range, 2 to 20) and 47 percent of thosewho were receiving 10 mg daily for 21 days (median, 6 weeks;range, 1 to 11) (P=0.62). The median interval between the firstinterruption of treatment and the resumption of treatment was22 days in each cohort (range, 9 to 55).
At week 8, marrow cellularity was reduced by 75 percent amongpatients who were receiving 25 mg of lenalidomide per day, ascompared with a reduction of 12 percent in both 10-mg cohorts.Pneumonia developed in three patients, one of whom had worseningof preexisting neutropenia. One patient was removed from thestudy on day 5 because of autoimmune hemolytic anemia with escalatingtransfusion requirements that preceded enrollment in the study.There were three deaths, none of which were thought to be treatment-related:one was due to cholecystitis with rupture (day 8), one to splenicinfarct in a patient with massive splenomegaly (day 5) and ahistory of such events, and one to pneumonia without neutropenia(week 20). All other adverse events were either minor or ofmoderate severity.
Pruritus, generally self-limited and restricted to the scalp,was reported by 28 percent of patients during the first weekof treatment. Isolated and transient urticaria was reportedby 14 percent of patients, whereas a systemic rash with an urticarialcomponent developed in one patient and resolved after treatmentwas interrupted. Diarrhea occurred in 21 percent of patientsafter prolonged treatment (more than three months) but was manageablewith the use of either medication for diarrhea or the interruptionof treatment with lenalidomide. Four patients required hormonereplacement — two for hypothyroidism, and two for gonadaldysfunction. Seven patients discontinued lenalidomide prematurely(before 28 days) because of withdrawal of consent by three patients,autoimmune hemolytic anemia in one, early myelosuppression inone, and early death in two.
Hematologic Response
Twenty-four patients (56 percent) had a response (Table 3);20 of 32 transfusion-dependent patients (63 percent) achievedindependence from transfusion. Of 11 patients who required notransfusions, 1 had an increase in the hemoglobin level of morethan 2 g per deciliter. The median time to a response increasedfrom 9 weeks in the 25-mg cohort to 11.5 weeks in the cohortgiven 10 mg per day for 21 days. Patients with a major responsereached a median hemoglobin level of 13.2±1.4 g per deciliter(range, 11.5 to 15.8), with a corresponding median increasein hemoglobin from baseline of 5.3 g per deciliter (range, 4.4to 8.7). After a median follow-up of 81 weeks (range, 42 to110), the median duration of the major response had not beenreached (more than 48 weeks; range, more than 13 to more than101). Among the 21 patients with a major response, anemia recurredin 4, with the resumption of transfusions after intervals of12, 19, 56, and 74 weeks. In one of these patients, treatmentfailure was associated with karyotypic evolution and subsequentprogression to leukemia.
Of 10 patients with moderate-to-severe thrombocytopenia, 1 hada sustained improvement in the platelet count (i.e., an increaseof more than 30,000 per cubic millimeter). Of the 12 patientswith neutropenia, 2 had a sustained increase in the neutrophilcount of more than 500 per cubic millimeter.
Table 4. Relation between Clinical and Biologic Features and Erythroid Response.
Among 20 patients with clonal cytogenetic abnormalities, 11had cytogenetic responses, including 10 with a complete cytogeneticremission (Table 5). Of these 10 patients, 9 had del(5)(q31.1)and 1 had t(1;22)(q21p11.2). All cytogenetic responses occurredin patients who also had a hematologic response. Overall, 10of 12 patients (83 percent) with a 5q31.1 deletion had a cytogeneticresponse. Fluorescence in situ hybridization with the use ofthe 5q31 (EGR1X2)-specific probe (Vysis) confirmed the absenceof the 5q31.1 deletion among 200 cells in interphase in eachof five patients who had a complete response and who were evaluatedby means of standard metaphase analysis.
Table 5. Cytogenetic Responses According to Chromosomal Abnormality.
The median time to a cytogenetic response was 8 weeks (range,8 to 24). Of 10 patients with a 5q31.1 deletion, 9 had a cytogeneticresponse after 8 weeks, whereas 1 patient had a response at16 weeks. Four patients had transient emergence of karyotypicallyunrelated clones, including trisomy 8 (in two), a reciprocaltranslocation [t(12;16)(p13;p13.3)], and monosomy 7. Sustainedacquisition of karyotypically discordant clones occurred infour patients: three patients with remitting disease and a 5q31.1deletion had translocations involving the long arm of chromosome7 [t(7;11)(q22;q12), t(7;8)(q22;p21), and t(7;21)(q31q11.1)]and one patient with a normal karyotype before treatment haddeletion 20 (q21q13.1). Only one of these four patients hadan exacerbation of anemia coincident with the appearance ofthe new abnormality and subsequent evolution to acute leukemia.All others remained free of the need for transfusion.
Pathological Responses and Morphologic Findings
Among six patients with excess myeloblasts (at least 5 percent;range, 6 to 21 percent) who could be evaluated, three had morethan a 50 percent reduction in blasts, with a return to thenormal range. The percentage of ringed sideroblasts was reducedfrom 36 percent to 11 percent in 1 of 10 patients with refractoryanemia with ringed sideroblasts who could be evaluated. Allreductions in myeloblasts and sideroblasts occurred in patientswith a hematologic response. Only one patient with refractoryanemia with ringed sideroblasts had an increase in blasts duringlenalidomide treatment, and this patient was removed from thestudy after 16 weeks.
Serial marrow preparations from 28 patients were suitable fora detailed assessment of dysplasia and architecture. The morphologiccharacteristics of megakaryocytes became normal after treatmentwith lenalidomide in 14 of 22 patients (64 percent) with pretreatmentdysplasia, including 12 patients with a response; 10 of these12 patients had a 5q31.1 deletion (Figure 2). Lymphoid aggregates,often multiple and not paratrabecular, were detected in 10 of28 patients (36 percent) after lenalidomide treatment (including5 patients with a 5q31.1 deletion) and corresponded with a hematologicresponse in 7. Lymphoid aggregates were composed of polytypicB cells and T cells. Dysplastic erythroid elements and myeloidelements were common (present in 22 and 11 patients, respectively),whereas resolution of cytologic atypia was infrequent (occurringin 2) and unrelated to hematologic response. Reticulin fibrosisresolved after lenalidomide treatment in one of two patientswith extensive fiber deposition in the pretreatment trephine-biopsyspecimen, concordant with a hematologic response. Marrow orperipheral-blood eosinophilia or both (7.5 percent to 14 percent)developed in three patients, including two with a hematologicresponse.
Figure 2. Morphologic Changes in a Bone Marrow Specimen from a Patient with a 5q31.1 Deletion.
Numerous small, mononuclear megakaryocytes are readily identified in the bone marrow specimen obtained by trephine biopsy before treatment (Panel A, hematoxylin and eosin). After 16 weeks of lenalidomide therapy, megakaryocytes appear normal in size and have multiple nuclei (Panel B, hematoxylin and eosin), and multiple aggregates of benign-appearing lymphocytes are apparent (Panel C, hematoxylin and eosin).
The persistence of ringed sideroblasts in patients with refractoryanemia with ringed sideroblasts who had a response, however,indicates that clonal suppression is selective and complementedby the restoration of erythropoiesis in susceptible myelodysplasticsyndrome progenitors. This notion is supported by the transientemergence of karyotypically distinct and unrelated clones, whichmirrors the experience reported with imatinib treatment in patientswith chronic myeloid leukemia.24,25 In addition, three patientswith a 5q31.1 deletion acquired new translocations involvingchromosome 7 despite the complete suppression of the initialkaryotypic abnormality. Despite its unfavorable prognostic implicationin primary myelodysplastic syndromes, the clinical significanceof the acquired translocations is unclear. Only one of thesepatients had cytogenetic and disease progression, whereas theothers had a sustained hematologic response. Further observationis necessary before the clinical significance of these findingscan be determined.
Several effects of lenalidomide may contribute to its activityin myelodysplastic syndromes. It suppresses the production oftumor necrosis factor (TNF-), but selective antagonists ofTNF- have minimal clinical activity in myelodysplastic syndromes.26,27,28Lenalidomide affects a broad range of ligand-induced responsesthat may be integral to its activity in myelodysplastic syndromes,including angiogenesis, inflammation, cell adhesion, and theimmune response. Indeed, vascular endothelial growth factor(VEGF) is an autocrine growth factor elaborated by myeloid precursorsin myelodysplastic syndromes that contributes to their self-renewalwhile exacerbating ineffective erythropoiesis in erythroid progenitors,which lack VEGF receptors.9,29 Lenalidomide enhances cell-mediatedimmunity by potentiating the production of interleukin-2 andinterferon- and increasing the responses of cytolytic T cellsand natural killer cells in experiments in animals.15,16 Ofparticular interest in our study was the appearance of multiplelymphoid aggregates composed of a mixture of B cells and T cellsin the trephine-biopsy specimens from patients with a response.Whether this finding represents an immune response against theineffective clone is unknown. Furthermore, lenalidomide sensitizeserythroid progenitors to the trophic effects of recombinanterythropoietin (unpublished data).
The promising activity of lenalidomide in myelodysplastic syndromesmust be balanced against its potential to cause clinically significantmyelosuppression, which necessitates close laboratory monitoringduring the initial weeks of treatment. Neutropenia or thrombocytopeniadeveloped in more than half the patients and was not limitedto patients with preexisting lineage deficits. The extent ofmyelosuppression varied according to the dose and cumulativeexposure to lenalidomide and was reversed by the interruptionof treatment or a reduction in the dose. Although early exacerbationof cytopenias may be expected with an agent that selectivelysuppresses myelodysplastic clones that dominate steady-statehematopoiesis, many patients did not have myelosuppression despiteprolonged lenalidomide treatment. A reduction in marrow cellularitycoincided with myelosuppression in patients treated with 25mg daily, indicating that lenalidomide suppresses myelopoiesisat higher doses. At lower doses, however, this effect was notapparent. Other adverse events were uncommon and generally mildin severity. Hypothyroidism or gonadal dysfunction developedin four patients, raising the possibility that the action oflenalidomide on ligand-induced responses may extend to hypophysealhormones.
We conclude that lenalidomide has substantial activity in patientswith low-risk myelodysplastic syndromes who would otherwisenot benefit from growth-factor therapy. Ongoing phase 2, multicentertrials will estimate the clinical benefits of lenalidomide ina larger number of patients.
Supported by grants (5 PO1 CA17094 and 1U54CA90821-01) fromthe National Cancer Institute.
Dr. List reports having served as a consultant and advisor forCelgene, Cell Therapeutics, Novartis Pharmaceuticals, Pharmion,and SuperGen and having served as a paid speaker on myelodysplasticsyndromes for Celgene and Cell Therapeutics. Drs. Knight andZeldis are employees of Celgene and have equity in the company.
Source Information
From the Department of Interdisciplinary Oncology, University of South Florida and the H. Lee Moffitt Cancer Center and Research Institute, Tampa (A.L., R.H.); the Departments of Medicine and Pathology, University of Arizona College of Medicine, Tucson (S.K., A.B., D.M., D.F., L.R.); the Mel and Enid Zuckerman Arizona College of Public Health, Tucson (D.J.R.); and Celgene, Warren, N.J. (R.K., J.B.Z.).
Address reprint requests to Dr. List at the Hematologic Malignancies Program, SRB Rm. 24038, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., Tampa, FL 33612-9497, or at listaf{at}moffitt.usf.edu.
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Mallo, M., Arenillas, L., Espinet, B., Salido, M., Hernandez, J. M{a}, Lumbreras, E., del Rey, M., Arranz, E., Ramiro, S., Font, P., Gonzalez, O., Renedo, M., Cervera, J., Such, E., Sanz, G. F., Luno, E., Sanzo, C., Gonzalez, M., Calasanz, M. J., Mayans, J., Garcia-Ballesteros, C., Amigo, V., Collado, R., Oliver, I., Carbonell, F., Bureo, E., Insunza, A., Yanez, L., Muruzabal, M. J., Gomez-Beltran, E., Andreu, R., Leon, P., Gomez, V., Sanz, A., Casasola, N., Moreno, E., Alegre, A., Martin, M. L., Pedro, C., Serrano, S., Florensa, L., Sole, F.
(2008). Fluorescence in situ hybridization improves the detection of 5q31 deletion in myelodysplastic syndromes without cytogenetic evidence of 5q-. haematol
93: 1001-1008
[Abstract][Full Text]
Ferrajoli, A., Lee, B.-N., Schlette, E. J., O'Brien, S. M., Gao, H., Wen, S., Wierda, W. G., Estrov, Z., Faderl, S., Cohen, E. N., Li, C., Reuben, J. M., Keating, M. J.
(2008). Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood
111: 5291-5297
[Abstract][Full Text]
Sloand, E. M., Wu, C. O., Greenberg, P., Young, N., Barrett, J.
(2008). Factors Affecting Response and Survival in Patients With Myelodysplasia Treated With Immunosuppressive Therapy. JCO
26: 2505-2511
[Abstract][Full Text]
Andritsos, L. A., Johnson, A. J., Lozanski, G., Blum, W., Kefauver, C., Awan, F., Smith, L. L., Lapalombella, R., May, S. E., Raymond, C. A., Wang, D.-S., Knight, R. D., Ruppert, A. S., Lehman, A., Jarjoura, D., Chen, C.-S., Byrd, J. C.
(2008). Higher Doses of Lenalidomide Are Associated With Unacceptable Toxicity Including Life-Threatening Tumor Flare in Patients With Chronic Lymphocytic Leukemia. JCO
26: 2519-2525
[Abstract][Full Text]
Nimer, S. D.
(2008). Myelodysplastic syndromes. Blood
111: 4841-4851
[Abstract][Full Text]
Gondek, L. P., Tiu, R., O'Keefe, C. L., Sekeres, M. A., Theil, K. S., Maciejewski, J. P.
(2008). Chromosomal lesions and uniparental disomy detected by SNP arrays in MDS, MDS/MPD, and MDS-derived AML. Blood
111: 1534-1542
[Abstract][Full Text]
Kurzrock, R., Kantarjian, H. M., Blascovich, M. A., Bucher, C., Verstovsek, S., Wright, J. J., Pilat, S. R., Cortes, J. E., Estey, E. H., Giles, F. J., Beran, M., Sebti, S. M.
(2008). Phase I Study of Alternate-Week Administration of Tipifarnib in Patients with Myelodysplastic Syndrome. Clin. Cancer Res.
14: 509-514
[Abstract][Full Text]
Park, S., Grabar, S., Kelaidi, C., Beyne-Rauzy, O., Picard, F., Bardet, V., Coiteux, V., Leroux, G., Lepelley, P., Daniel, M.-T., Cheze, S., Mahe, B., Ferrant, A., Ravoet, C., Escoffre-Barbe, M., Ades, L., Vey, N., Aljassem, L., Stamatoullas, A., Mannone, L., Dombret, H., Bourgeois, K., Greenberg, P., Fenaux, P., Dreyfus, F., for the GFM group (Groupe Francophone des Myelodys,
(2008). Predictive factors of response and survival in myelodysplastic syndrome treated with erythropoietin and G-CSF: the GFM experience. Blood
111: 574-582
[Abstract][Full Text]
Kroger, N.
(2008). Epigenetic Modulation and Other Options to Improve Outcome of Stem Cell Transplantation in MDS. ASH Education Book
2008: 60-67
[Abstract][Full Text]
O'Brien, S.
(2008). New Agents in the Treatment of CLL. ASH Education Book
2008: 457-464
[Abstract][Full Text]
Raza, A., Reeves, J. A., Feldman, E. J., Dewald, G. W., Bennett, J. M., Deeg, H. J., Dreisbach, L., Schiffer, C. A., Stone, R. M., Greenberg, P. L., Curtin, P. T., Klimek, V. M., Shammo, J. M., Thomas, D., Knight, R. D., Schmidt, M., Wride, K., Zeldis, J. B., List, A. F.
(2008). Phase 2 study of lenalidomide in transfusion-dependent, low-risk, and intermediate-1 risk myelodysplastic syndromes with karyotypes other than deletion 5q. Blood
111: 86-93
[Abstract][Full Text]
Haase, D., Germing, U., Schanz, J., Pfeilstocker, M., Nosslinger, T., Hildebrandt, B., Kundgen, A., Lubbert, M., Kunzmann, R., Giagounidis, A. A. N., Aul, C., Trumper, L., Krieger, O., Stauder, R., Muller, T. H., Wimazal, F., Valent, P., Fonatsch, C., Steidl, C.
(2007). New insights into the prognostic impact of the karyotype in MDS and correlation with subtypes: evidence from a core dataset of 2124 patients. Blood
110: 4385-4395
[Abstract][Full Text]
Chen, N., Lau, H., Kong, L., Kumar, G., Zeldis, J. B., Knight, R., Laskin, O. L.
(2007). Pharmacokinetics of Lenalidomide in Subjects With Various Degrees of Renal Impairment and in Subjects on Hemodialysis. J Clin Pharmacol
47: 1466-1475
[Abstract][Full Text]
Sorror, M. L., Sandmaier, B. M., Storer, B. E., Maris, M. B., Baron, F., Maloney, D. G., Scott, B. L., Deeg, H. J., Appelbaum, F. R., Storb, R.
(2007). Comorbidity and Disease Status Based Risk Stratification of Outcomes Among Patients With Acute Myeloid Leukemia or Myelodysplasia Receiving Allogeneic Hematopoietic Cell Transplantation. JCO
25: 4246-4254
[Abstract][Full Text]
Pellagatti, A., Jadersten, M., Forsblom, A.-M., Cattan, H., Christensson, B., Emanuelsson, E. K., Merup, M., Nilsson, L., Samuelsson, J., Sander, B., Wainscoat, J. S., Boultwood, J., Hellstrom-Lindberg, E.
(2007). 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. USA
104: 11406-11411
[Abstract][Full Text]
Bacher, U., Haferlach, T., Kern, W., Haferlach, C., Schnittger, S.
(2007). A comparative study of molecular mutations in 381 patients with myelodysplastic syndrome and in 4130 patients with acute myeloid leukemia. haematol
92: 744-752
[Abstract][Full Text]
Estey, E.
(2007). Acute Myeloid Leukemia and Myelodysplastic Syndromes in Older Patients. JCO
25: 1908-1915
[Abstract][Full Text]
Thornburg, A., Abonour, R., Smith, P., Knox, K., Twigg, H. L. III
(2007). Hypersensitivity Pneumonitis-Like Syndrome Associated With the Use of Lenalidomide. Chest
131: 1572-1574
[Abstract][Full Text]
Verhelle, D., Corral, L. G., Wong, K., Mueller, J. H., Moutouh-de Parseval, L., Jensen-Pergakes, K., Schafer, P. H., Chen, R., Glezer, E., Ferguson, G. D., Lopez-Girona, A., Muller, G. W., Brady, H. A., Chan, K. W.H.
(2007). Lenalidomide and CC-4047 Inhibit the Proliferation of Malignant B Cells while Expanding Normal CD34+ Progenitor Cells. Cancer Res.
67: 746-755
[Abstract][Full Text]
Melchert, M., List, A. F.
(2007). Management of RBC-Transfusion Dependence. ASH Education Book
2007: 398-404
[Abstract][Full Text]
Shannon, K., Silverman, L. R.
(2007). Myelodysplastic syndrome and overlap syndromes. ASH-SAP
2007: 228-242
[Full Text]
Navas, T. A., Mohindru, M., Estes, M., Ma, J. Y., Sokol, L., Pahanish, P., Parmar, S., Haghnazari, E., Zhou, L., Collins, R., Kerr, I., Nguyen, A. N., Xu, Y., Platanias, L. C., List, A. A., Higgins, L. S., Verma, A.
(2006). Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors. Blood
108: 4170-4177
[Abstract][Full Text]
Chanan-Khan, A., Miller, K. C., Musial, L., Lawrence, D., Padmanabhan, S., Takeshita, K., Porter, C. W., Goodrich, D. W., Bernstein, Z. P., Wallace, P., Spaner, D., Mohr, A., Byrne, C., Hernandez-Ilizaliturri, F., Chrystal, C., Starostik, P., Czuczman, M. S.
(2006). Clinical Efficacy of Lenalidomide in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia: Results of a Phase II Study. JCO
24: 5343-5349
[Abstract][Full Text]
List, A. F., Dewald, G. W., Bennett, J. M., Giagounidis, A., Raza, A., Feldman, E. J., Powell, B. L., Greenberg, P. L., Nimer, S. D., Zeldis, J. B., Wride, K., Schmidt, M., Knight, R. D.
(2006). Long-Term Clinical Benefit of Lenalidomide (Revlimid) Treatment in Patients with Myelodysplastic Syndrome and Chromosome Deletion 5q.. ASH ANNUAL MEETING ABSTRACTS
108: 251-251
[Abstract]
List, A. F., Estes, M., Williams, A., Sekharam, M., Ozawa, U., Gao, G., Wu, J., Gao, G., Sokol, L.
(2006). Lenalidomide (CC-5013; Revlimid(R)) Promotes Erythropoiesis in Myelodysplastic Syndromes (MDS) by CD45 Protein Tyrosine Phosphatase (PTP) Inhibition.. ASH ANNUAL MEETING ABSTRACTS
108: 1360-1360
[Abstract]
Epling-Burnette, P.K., Bai, F., Painter, J. S., Dana, R., Zou, J., Ku, E., Zhong, B., Wei, S., Djeu, J. Y., List, A. F.
(2006). Reduced Natural Killer Function Accompanies MDS Disease Progression and Is Restored by Lenalidomide (CC5013, Revlimid(R)) Via a Mechanism Divergent from Interleukin-2 (IL-2).. ASH ANNUAL MEETING ABSTRACTS
108: 2651-2651
[Abstract]
Kelaidi, C., Park, S., Brechignac, S., Mannone, L., Vey, N., Dombret, H., Aljassem, L., Stamatoullas, A., Ades, L., Giraudier, S., de Botton, S., Mahe, B., Lepelley, P., Picard, F., Leroux, G., Daniel, M.-T., Bouscary, D., Dreyfus, F., Fenaux, P.
(2006). Treatment of Myelodysplastic Syndromes with del 5q before the Lenalidomide Era: The GFM Experience.. ASH ANNUAL MEETING ABSTRACTS
108: 2678-2678
[Abstract]
Mesa, R. A., Tefferi, A., Steensma, D. P.
(2006). Hematologic and Cytogenetic Response to Lenalidomide Therapy in an 82 Year Old Female with Acute Myeloid Leukemia (AML) Arising from JAK2V617F Positive, del(5)(q13q33) Myelodysplastic Syndrome (MDS).. ASH ANNUAL MEETING ABSTRACTS
108: 4827-4827
[Abstract]
List, A., Dewald, G., Bennett, J., Giagounidis, A., Raza, A., Feldman, E., Powell, B., Greenberg, P., Thomas, D., Stone, R., Reeder, C., Wride, K., Patin, J., Schmidt, M., Zeldis, J., Knight, R., the Myelodysplastic Syndrome-003 Study Investigato,
(2006). Lenalidomide in the Myelodysplastic Syndrome with Chromosome 5q Deletion. NEJM
355: 1456-1465
[Abstract][Full Text]
Sviggum, H. P., Davis, M. D. P., Rajkumar, S. V., Dispenzieri, A.
(2006). Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma.. Arch Dermatol
142: 1298-1302
[Abstract][Full Text]
Tefferi, A., Barosi, G., Mesa, R. A., Cervantes, F., Deeg, H. J., Reilly, J. T., Verstovsek, S., Dupriez, B., Silver, R. T., Odenike, O., Cortes, J., Wadleigh, M., Solberg, L. A. Jr, Camoriano, J. K., Gisslinger, H., Noel, P., Thiele, J., Vardiman, J. W., Hoffman, R., Cross, N. C. P., Gilliland, D. G., Kantarjian, H.
(2006). International Working Group (IWG) consensus criteria for treatment response in myelofibrosis with myeloid metaplasia, for the IWG for Myelofibrosis Research and Treatment (IWG-MRT). Blood
108: 1497-1503
[Abstract][Full Text]
Spivak, J. L.
(2006). Lenalidomide and the 3 Ms: deja vu all over again?. Blood
108: 1118-1119
[Full Text]
Tefferi, A., Cortes, J., Verstovsek, S., Mesa, R. A., Thomas, D., Lasho, T. L., Hogan, W. J., Litzow, M. R., Allred, J. B., Jones, D., Byrne, C., Zeldis, J. B., Ketterling, R. P., McClure, R. F., Giles, F., Kantarjian, H. M.
(2006). Lenalidomide therapy in myelofibrosis with myeloid metaplasia. Blood
108: 1158-1164
[Abstract][Full Text]
Hoverson, A. R., Davis, M. D. P., Weenig, R. H., Wolanskyj, A. P.
(2006). Neutrophilic dermatosis (sweet syndrome) of the hands associated with lenalidomide.. Arch Dermatol
142: 1070-1071
[Full Text]
Chang, D. H., Liu, N., Klimek, V., Hassoun, H., Mazumder, A., Nimer, S. D., Jagannath, S., Dhodapkar, M. V.
(2006). Enhancement of ligand-dependent activation of human natural killer T cells by lenalidomide: therapeutic implications. Blood
108: 618-621
[Abstract][Full Text]
Cheson, B. D., Greenberg, P. L., Bennett, J. M., Lowenberg, B., Wijermans, P. W., Nimer, S. D., Pinto, A., Beran, M., de Witte, T. M., Stone, R. M., Mittelman, M., Sanz, G. F., Gore, S. D., Schiffer, C. A., Kantarjian, H.
(2006). Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood
108: 419-425
[Abstract][Full Text]
Traynor, B. J., Bruijn, L., Conwit, R., Beal, F., O'Neill, G., Fagan, S. C., Cudkowicz, M. E.
(2006). Neuroprotective agents for clinical trials in ALS: A systematic assessment.. Neurology
67: 20-27
[Abstract][Full Text]
Zonder, J. A., Barlogie, B., Durie, B. G. M., McCoy, J., Crowley, J., Hussein, M. A., Rajkumar, S. V., Gertz, M. A.
(2006). Thrombotic complications in patients with newly diagnosed multiple myeloma treated with lenalidomide and dexamethasone: benefit of aspirin prophylaxis.. Blood
108: 403-404
[Full Text]
Pellagatti, A., Cazzola, M., Giagounidis, A. A. N., Malcovati, L., Porta, M. G. D., Killick, S., Campbell, L. J., Wang, L., Langford, C. F., Fidler, C., Oscier, D., Aul, C., Wainscoat, J. S., Boultwood, J.
(2006). Gene expression profiles of CD34+ cells in myelodysplastic syndromes: involvement of interferon-stimulated genes and correlation to FAB subtype and karyotype. Blood
108: 337-345
[Abstract][Full Text]
Nimer, S. D.
(2006). Clinical Management of Myelodysplastic Syndromes With Interstitial Deletion of Chromosome 5q. JCO
24: 2576-2582
[Abstract][Full Text]
Schiller, G. J., Slack, J., Hainsworth, J. D., Mason, J., Saleh, M., Rizzieri, D., Douer, D., List, A. F.
(2006). Phase II Multicenter Study of Arsenic Trioxide in Patients With Myelodysplastic Syndromes. JCO
24: 2456-2464
[Abstract][Full Text]
Vey, N., Bosly, A., Guerci, A., Feremans, W., Dombret, H., Dreyfus, F., Bowen, D., Burnett, A., Dennis, M., Ribrag, V., Casadevall, N., Legros, L., Fenaux, P.
(2006). Arsenic Trioxide in Patients With Myelodysplastic Syndromes: A Phase II Multicenter Study. JCO
24: 2465-2471
[Abstract][Full Text]
Stone, R. M.
(2006). Is Intravenous Arsenic Trioxide a Useful Therapy in Myelodysplastic Syndromes?. JCO
24: 2414-2416
[Full Text]
Cheson, B. D., Canellos, G. P.
(2006). The cancer and leukemia group B lymphoma committee.. Clin. Cancer Res.
12: 3572s-3575s
[Abstract][Full Text]
Tefferi, A.
(2006). Iron Chelation Therapy for Myelodysplastic Syndrome: If and When. Mayo Clin Proc.
81: 197-198
[Full Text]
Maier, S. K, Hammond, J. M
(2006). Role of Lenalidomide in the Treatment of Multiple Myeloma and Myelodysplastic Syndrome. The Annals of Pharmacotherapy
40: 286-289
[Abstract][Full Text]
Giagounidis, A. A.N., Germing, U., Aul, C.
(2006). Biological and Prognostic Significance of Chromosome 5q Deletions in Myeloid Malignancies. Clin. Cancer Res.
12: 5-10
[Abstract][Full Text]
Fenaux, P., Kelaidi, C.
(2006). Treatment of the 5q- Syndrome. ASH Education Book
2006: 192-198
[Abstract][Full Text]
Schiffer, C. A.
(2006). Clinical Issues in the Management of Patients with Myelodysplasia. ASH Education Book
2006: 205-210
[Abstract][Full Text]
Zonder, J. A.
(2006). Thrombotic Complications of Myeloma Therapy. ASH Education Book
2006: 348-355
[Abstract][Full Text]
Steensma, D. P., Bennett, J. M.
(2006). The Myelodysplastic Syndromes: Diagnosis and Treatment. Mayo Clin Proc.
81: 104-130
[Abstract][Full Text]
Tefferi, A.
(2005). Pathogenesis of Myelofibrosis With Myeloid Metaplasia. JCO
23: 8520-8530
[Abstract][Full Text]
Wang, H., Naing, A., Cheng, F., Horna, P., Suarez, I., Brayer, J., List, A. F., Sotomayor, E. M.
(2005). The Immunomodulatory Drug Lenalidomide (CC5013; Revlimid), Enhances Antigen-Presenting Cell's Function Leading to Effective Priming of CD4+ T-Lymphocytes.. ASH ANNUAL MEETING ABSTRACTS
106: 2391-2391
[Abstract]
Fenaux, P., Ades, L.
(2005). Erythropoietin for the anemia of low-risk myelodysplastic syndromes. Blood
106: 768-769
[Full Text]
Chng, W. J., Stadler, M., Ganser, A., List, A. F., Cazzola, M., Malcovati, L.
(2005). Treatment of Myelodysplastic Syndromes. NEJM
352: 2134-2135
[Full Text]
Guinan, E. C.
(2005). Aplastic Anemia: Management of Pediatric Patients. ASH Education Book
2005: 104-109
[Abstract][Full Text]
Hellstrom-Lindberg, E.
(2005). Update on Supportive Care and New Therapies: Immunomodulatory Drugs, Growth Factors and Epigenetic-Acting Agents. ASH Education Book
2005: 161-166
[Abstract][Full Text]
(TNF-
and increasing the responses of cytolytic T cells and natural killer cells in experiments in animals.15,16 Of particular interest in our study was the appearance of multiple lymphoid aggregates composed of a mixture of B cells and T cells in the trephine-biopsy specimens from patients with a response. Whether this finding represents an immune response against the ineffective clone is unknown. Furthermore, lenalidomide sensitizes erythroid progenitors to the trophic effects of recombinant erythropoietin (unpublished data). 
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