McClure, Rebecca F.

Abstract Background: We had previously piloted thalidomide treatment in MMM and showed an approximately 20% response in terms of both anemia and splenomegaly (Elliott et al. BJH2002;117:288). Encouraged by this experience, we undertook the current phase II study to explore the therapeutic activity of the more potent as well as less neurotoxic immunomodulatory drug, lenalidomide (CC-5013). Methods: The study group comprised a consecutive series of patients with MMM that fulfilled protocol entry criteria that included hemoglobin level ≤ 10 g/dL, platelet count ≥ 100 x 109/L, and neutrophil count ≥ 1 x 109/L. The treatment program consisted of daily oral lenalidomide (10 mg/day) for 3 consecutive 28-day cycles with a plan to continue with additional 3 cycles in case of response. Results: i. Pretreatment patient information Twenty-seven patients (median age, 66 years; range, 40–78) were accrued between March 5, 2004 and June 15, 2005. Median duration of disease prior to protocol treatment was 30 months (range, 1–245). Previous therapy was documented in all but 2 patients. Twenty patients were RBC transfusion-dependent. Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were 16 cm (0–31), 8.4 x 109/L (1.8–84.4), 299 x 109/L (124–831), 166.1 x 106/L (2.8–5176.4), and 778 U/L (267–1725), respectively. Cytogenetic abnormalities were detected in 13 patients (48%). JAK2 V617F mutation analysis was performed in 21 patients and revealed homozygous, heterozygous, and wild-type alleles in 3, 8, and 10 patients, respectively. ii. Adverse events Adverse events (any/grade 3 or 4) with definite, probable, or possible attributions to the drug included fatigue (52%/12%), neutropenia (40%/24%), pruritus (36%/0%), thrombocytopenia (28%/8%), anemia (16%/8%), rash (12%/8%), and respiratory distress with hypoxia (8%/8%). To date, 7 deaths have been reported, all occuring after discontinuation of protocol therapy, and none were directly linked to the drug. iii. Response The median post-treatment follow up is now 16 months (range 1–17 months). During this period, 6 patients (22%) have experienced either a major (3 patients normalized their hemoglobin level), minor (2 patients became transfusion-independent), or marginal response in anemia. The median time to response and response duration were 2 and 7 months, respectively. Two of the 3 major responders had a baseline der(1;18)(q10;q10) or del(5)(q13q33) cytogenetic abnormality, the latter one of which displayed a major cytogenetic remission. In the patient with der(1;18)(q10;q10), the hemoglobin level increased to a level of 19.1 g/dL from being transfusion-dependent at the start of lenalidomide therapy. Interestingly, the particular patient was homozygous for the JAK2 V617F mutation. Responses were also recorded for palpable splenomegaly (26%), constitutional symptoms (67%), and serum LDH level (70%). Seven patients normalized their LDH. Conclusion: Lenalidomide therapy improved anemia in at least 20% of patients with MMM. Some of the responses were spectacular and appeared to be associated with specific cytogenetic abnormalities. The documentation of a positive drug effect on LDH, constitutional symptoms, and splenomegaly in patients not showing early response in anemia suggests the possibility of an even higher response rate with a longer treatment schedule.

Abstract Background: In essential thrombocythemia (ET), homozygosity for the JAK2 V617F mutant allele is rare despite the frequent (23–57%) occurrence of the heterozygous state. This is in direct contrast with the situation in polycythemia vera (PV) where homozygosity for the mutation is seen in 25–33% of the cases. The particular observation is consistent with what has been observed in vitro as well as in animal studies where JAK2 V617F has been associated with induction of erythropoietin hypersensitivity in cell lines and erythrocytosis in mice (James et al. Nature2005;434:1144). Therefore, regardless of whether or not JAK2 V617F represents a primary event in myeloproliferative disorders, it is probable that it promotes a PV phenotype. In the current study, we explore this hypothesis as well as investigate the long-term prognostic relevance of the mutation in a well defined cohort of patients with ET seen at a single institution. Methods: The diagnosis of ET was according to the WHO classification of tumors (Jaffe ES et al. Lyon, IARC press, 2001). All patients were seen at the Mayo Clinic and patient characteristics and subsequent clinical events were determined both retrospectively (chart review) and prospectively (by means of a questionnaire sent both to patients and their primary doctors). In addition date and cause of death were confirmed by probing both the social security index and the national death index. DNA for mutation screening was derived and sequenced from either archived unsorted cells from the bone marrow or prospectively collected peripheral blood granulocytes according to previously published methods (Levine et al. Cancer Cell, 2005;7:387). Results: The study cohort consisted of 150 consecutive patients with ET including 99 females and 51 males (median age 49.8 years; range 16.8–98). Overall, JAK2 V617F was detected in 73 patients (48.7%) but none were homozygous for the mutant allele. At diagnosis, ET patients with JAK2 V617F were significantly older (median age of 53.5 vs. 42.3; p=0.02) and also displayed higher readings of both hemoglobin level (p=0.0002) and leukocyte count (p=0.005). All study patients have now been followed for a median of 11.4 years from diagnosis (range 0–32.7) and follow-up period was similar between the two mutational categories (p=0.53). During this period, 32 patients have died and the median survival for the entire group was 19.3 years; 21.9 and 17.7 years in the absence and presence of the mutation, respectively (p=0.09). Disease transformation into acute leukemia, myelofibrosis, and PV occurred in 6 (4%), 15 (10%), and 8 (5.3%) patients, respectively, and the only significant difference between the two mutational categories in this regard was the higher incidence of transformation into PV in patients with the mutation (p=0.02). Multivariate analysis identified age, hemoglobin level, and thrombosis history at diagnosis but not JAK2 V617F mutational status as independent risk factors for survival. Conclusion: Although the presence of JAK2 V617F in ET appears to promote a PV phenotype, it might not carry treatment-relevant information.

Abstract Background: In both polycythemia vera (PV) and essential thrombocythemia (ET), aspirin and/or hydroxyurea therapy provide adequate protection from thrombosis but not from disease transformation into acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) or myelofibrosis (MF). In designing clinical trials with new drugs, including the use of small molecule JAK2 inhibitors, in either ET or PV, it is important to identify patients who are at a higher risk of early transformation into AML/MDS/MF as well as those in whom the long-term risk of these complications is too low to justify exposure to experimental drugs with unknown short-term and long-term toxicity profile. Methods: Information on an institutional database of 1061 patients with either PV (n=458) or ET (n=603) was updated in July of 2007. The World Health Organization criteria were used for diagnosis of PV, ET, AML, MDS, and MF. Two different approaches were used to assess both early and overall risk of AML/MDS/MF development in both ET and PV. In the first approach, three distinct groups were delineated and their presenting features compared; group A was comprised of patients who have remained AML/MDS/MF free after a minimum follow-up of 20 years whereas groups B and C included patients who developed either AML/MDS or MF, respectively, in the first decade of their disease. In the second approach, prognostic factors for AML/MDS/MF-free survival were examined among the entire cohort of 1061 patients. Results : In ET, the number of patients that fulfilled the above-mentioned criteria for inclusion in groups A, B, and C were 40, 12, and 8; the three groups displayed significant differences in the prevalence, at diagnosis, of lower than normal hemoglobin level (8% vs. 58% vs. 38%; p=0.0004), male sex (18% vs. 58% vs. 50%; p=0.01), and arterial thrombosis at diagnosis (p=0.03), respectively. However, only the former two remained significant during multivariable analysis that included age as a covariate. In PV, the number of patients in groups A, B, and C were 23, 18, and 12; the only difference between the three groups was the association between group B and leukocytosis (p=0.02). Cox regression analysis of the entire 1061 ET/PV patients cohort, including 65 AML/MDS/MF events in ET and 36 AML/MDS events in PV, confirmed the inferior AML/MDS/MF-free survival in ET associated with lower than normal hemoglobin and AML/MDS-free survival in PV associated with leukocytosis (Figure). Conclusion : The current study identifies PV patients with leukocytosis as being the most appropriate and ET patients without anemia as the least appropriate for consideration of participation in experimental drug treatment trials. Figure Figure Figure Figure

Abstract Abstract 1751 Because IDH mutations are frequent in blast-phase myeloproliferative neoplasms (MPN), they might contribute to leukemic transformation. We examined this possibility in 301 consecutive patients with chronic-phase primary myelofibrosis (PMF). All study patients were fully characterized for karyotype, JAK2 and MPL mutational status, and Dynamic International Prognostic Scoring System-plus (DIPSS-plus) risk status. DNA from bone marrow or peripheral blood was used to screen for IDH1 and IDH2 mutations, by direct sequencing and/or high resolution melting (HRM) assay. Mutant IDH was detected in 12 patients (4%): seven IDH2 (five R140Q, one R140W and one R172G) and five IDH1 (three R132S and two R132C). MPL exon 10 was mutated in 18 patients (6.3%) and constituted W515L in 14 patients, W515K in 3 and a frameshift mutation in 1 patient. JAK2V617F was detected in 169 (56%) patients. Six patients displayed both JAK2V617F and IDH mutations (IDH2R140Q in 2 patients, IDH2R140W in 1 and IDH1R132S in 3); JAK2V617F allele burden was 1%, 7%, 22%, 27%, 30% and 96%, respectively. One patient displayed both IDHR140Q and MPLW515R. One-hundred and seven (36%) patients were negative for all three mutations. The 12 IDH-mutated patients were clinically compared to patients belonging to the three other molecular subgroups: mutated for JAK2 only (n=164), mutated for MPL only (n=18) and unmutated for all three (n=107). The four molecular subgroups were remarkably similar in their phenotype with few exceptions; IDH-mutated patients were significantly older than those with no mutations (p=0.04) whereas age distribution was similar between patients with mutant IDH, MPL or JAK2. In univariate analysis, overall survival (OS) for IDH-mutated patients was significantly shorter than those for JAK2-mutated (p=0.03), MPL-mutated (p=0.047) or unmutated (p=0.0009) patients. IDH-mutated patients also showed significantly shorter leukemia-free survival (LFS), compared to those with mutant JAK2 (p=0.0008), mutant MPL (p=0.02) or no mutations (p=0.001). After accounting for age, the presence of mutant IDH remained a significant disadvantage for both OS (p=0.04) and LFS (p=0.005). Multivariable analysis of OS that included risk categorization per DIPSS-plus confirmed the independent prognostic relevance of mutant IDH (p=0.03): HR for patients with no mutations =0.39, 95% CI 0.2–0.75; HR for JAK2-mutated patients =0.50, 95% CI 0.27–0.95; HR for MPL-mutated patients =0.53, 95% CI 0.23–1.2. A similar analysis for LFS that included risk factors for LT (i.e. unfavorable karyotype and platelet count <100 × 109/L) as covariates also confirmed the prognostic relevance of mutant IDH (p=0.003): HR for patients with no mutations =0.16; 95% CI 0.06–0.46; HR for JAK2-mutated patients =0.18; 95% CI 0.06–0.48; HR for MPL-mutated patients =0.09; 95% CI 0.01–0.76). Further analysis disclosed that the negative OS and LFS effect of mutant IDH was most pronounced in the presence (p=0.0002 and <0.0001, respectively) as opposed to the absence (p=0.34 and 0.64, respectively) of concomitant JAK2V617F expression. Analysis of paired samples obtained during the chronic and blast phases of the disease was possible in 2 IDH-mutated patients and showed the presence of both IDH and JAK2 mutations at both time points. Our observations suggest that IDH mutations in PMF are independent predictors of leukemic transformation and raise the possibility of leukemogenic collaboration with JAK2V617F. Disclosures: No relevant conflicts of interest to declare.

Abstract Abstract 4109 Background: In a previous study, we reported safety and efficacy of low-dose (0.5 mg/d) pomalidomide and prednisone and pomalidomide alone (2 mg/d) for the treatment of anemia associated with myelofibrosis (J Clin Oncol 2009; 27: 4563). The current study examined the value of low dose pomalidomide alone (ClinicalTrials.gov No. NCT00669578). Methods: Persons with primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF) myelofibrosis were studied. The main eligibility criterion was RBC-transfusion-dependence or hemoglobin <10 g/dL. Subjects failing lenalidomide or thalidomide were eligible whereas those with deep vein thrombosis or pulmonary-embolism <1 y pre-study entry were not. The primary endpoint was anemia response assessed by the International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria (Blood 2006; 108: 1497). Results: Pomalidomide (0.5 mg/d) was given to 58 subjects (median age 68 y; 44 males). 46 (79%) were RBC-transfusion-dependent and 42, JAK2V617F-positive. Baseline disease-stage at time of study-entry according to the Dynamic International Prognostic Scoring System (DIPSS; Blood 2010; 115: 1703) was high-risk in 16 (28%) and intermediate-2 risk in 42 (72%). Cytogenetic findings were favorable in 46, unfavorable in 9 and not evaluable in 3. 46 (79%) had PMF and the remainder post-PV/ET MF. 49 (84%) patients completed ≥3 mo of therapy. Treatment was well-tolerated with no instances of thrombosis. There was grade-1 neuropathy possibly related to drug in 1 subject. ≥Grade-3 thrombocytopenia/neutropenia occurred in 2 subjects. There was an anemia response in 10 (17%) subjects including 9 who became RBC-transfusion-independent. Median response-duration was 8+ mo (range, 6–13 mo). 14 of 24 subjecst (58%) with platelets ≤100 × 10e9/L had a >50% increment. There were no spleen responses. Anemia response occurred only in subjects with JAK2V617F (24% vs. 0; p=0.03) but was not correlated with mutant allele burden (p=0.39). Anemia response in JAK2V617F-positive subjects was predicted by the presence of pomalidomide-induced basophilia in the 1st month of therapy (38% vs. 6%; p=0.02) or absence of marked splenomegaly (38% vs. 11%; p=0.05); response was not affected by cytogenetic risk-category (p=0.96) or WBC (p=0.27). Conclusions: These data suggest that low-dose pomalidomide is effective in the treatment for anemia associated with JAK2V617F-positive myelofibrosis, especially in the absence of marked splenomegaly. Response appears to be predicted by early drug-induced basophilia. Pomalidomide also appears to improve thrombocytopenia in most subjects with baseline platelets <100 × 10e9/L but is not active in controlling disease-associated splenomegaly. Disclosures: Mesa: SBio: Research Funding; Novartis: Research Funding; Celgene: Research Funding; Incyte: Research Funding; Roche: Research Funding; eisai: Research Funding; telik: Research Funding.

Abstract Abstract 2906 Poster Board II-882 Background: The World Health Organization (WHO) classification system recognizes indolent SM (ISM) as an entity characterized by low systemic mast cell (MC) burden but frequent skin involvement. The WHO system also recognizes 2 provisional ISM sub-variants: smoldering SM (SSM) and bone marrow (BM) mastocytosis (BMM). The two are respectively characterized by increased systemic MC burden (presence of ≥ 2 ‘B-findings') and BM MC infiltration in the absence of skin or multiorgan visceral lesions. The prognostic relevance of this sub-classification remains unclear. Methods: The study population was drawn from a larger cohort of 342 adult SM patients (Blood. 2009 Jun 4;113(23):5727). Clinical data and BM histology were reviewed, and the diagnosis of ISM and its subclassification confirmed per the 2008 WHO proposal. The primary objectives of the study were to: (i) describe the clinical characteristics of a large cohort of ISM patients, within the context of the WHO classification; (ii) evaluate the prevalence of molecular and cytogenetic abnormalities; (iii) evaluate whether ISM subclassification is prognostically relevant on the basis of survival and risk of transformation to acute leukemia or aggressive SM (ASM). Results: (i) Clinical characteristics: 159 ISM patients were evaluated (69 males; median age 49 years, range 19-84); 22 (14%) had SSM, 36 (23%) BMM, and 101 (63%) ‘ISM-other' (ISMo). By definition, ‘B-findings' were absent in BMM patients. ‘B-findings' in SSM (and ISMo) patients was as follows: hepatosplenomegaly and/or lymphadenopathy 91% (21%), BM MC >30% or serum tryptase level >200ng/mL 68% (8%), and hypercellular BM or dysmyelopoiesis without cytopenias 50% (2%). SSM patients were older (p<0.01) and more frequently displayed constitutional symptoms (p<0.01), and anemia (p<0.01). MC mediator-release symptoms (p=0.01), including anaphylaxis (p<0.01), were more frequent in BMM. The following MC-mediators were studied: serum tryptase (57%), beta prostaglandin F2alpha (45%), urine methylhistamine (32%), and urine histamine (21%) – significant differences were noted amongst the ISM subgroups with the following relationship: SSM>ISMo>BMM (p<0.01). (ii) Molecular and cytogenetic abnormalities: Complete karyotype information was available for 55 patients; only 1 patient (with ISMo) had an abnormal karyotype. Fifty nine patients were screened for KITD816V and JAK2V617F; JAK2V617F was universally absent, and distribution of KITD816V was not significantly different amongst the ISM subgroups: SSM (100%), BMM (92%), and ISMo (69%). (iii) Survival and risk of disease transformation: At a median follow of 27 months (range <1-417), 26 deaths were recorded (ISMo 14, SSM 10, and BMM 2), and the combined median survival was 198 months: ISMo 301 months, SSM 120 months, and BMM (not reached) (p<0.01; Figure). Transformation to acute leukemia and ASM was seen in 1 patient (SSM) and 3 patients (2 SSM and 1 ISMo), respectively. Conclusions: Among WHO-defined ISM patients, SSM is associated with significantly shorter survival whereas BMM and ISMo are prognostically similar. If these observations are confirmed by others, consideration may be given to classifying SSM as a distinct subcategory of SM, instead of a sub-variant of ISM as it currently stands. Disclosures: No relevant conflicts of interest to declare.

Abstract BACKGROUND: Bone marrow fibrosis might represent either a primary myeloid malignancy such as myelofibrosis with myeloid metaplasia (MMM) or a reactive phenomenon associated with other malignancies or inflammatory/infectious processes. The development of myelofibrosis in the context of a plasma cell dyscrasia is uncommon and incompletely understood from the standpoint of both pathogenesis and clinical implications. We sought to determine the origin and clinical ramifications of this phenomenon based on a consecutive series of patients with plasma cell disorders (PCD). METHODS: A retrospective search of institutional databases was performed for clinical cases of PCD with the concomitant observation of myelofibrosis. Bone marrow aspirates and trephines from the time of diagnosis of both PCD and myelofibrosis were reviewed. Clinical history was abstracted for clinical manifestations as well as disease course. DNA from archived cytogenetic pellets, when available, from the time of diagnosis, was screened for the presence of JAK2V617F. RESULTS: Among 7587 patients with a PCD seen over the last 30 years at our institution, 29 (0.3%) displayed concomitant myelofibrosis (median age 59 years, range 27–77; 52% males). The specific PCD was multiple myeloma in 25 patients, smoldering myeloma in 2, plasmacytoma in 1, and heavy chain disease in 1. Four patients (14%) had organomegaly and bone marrow histological features most consistent with MMM. Otherwise, myeloproliferative disorder (MPD)-characteristic features were infrequent and included leukocytosis and/or thrombocytosis in only 2 patients. None of the patients displayed thrombohemorrhagic complications. Archived DNA was available in 7 cases without either clinical or bone marrow histological evidence of a MPD and yet revealed the presence of JAK2V617F in 6 of the 7 cases (86%). In addition, one other patient without MPD phenotype displayed a monosomy 5 abnormality. To date, 2 patients, one with and one without a MPD phenotype underwent leukemic transformation. All other causes of death were related to PCD-associated complications. Median survival (Kaplan-Meier) for the patients with multiple myeloma was 50 months. Survival stratified by the myeloma international staging system (ISS) was similar or better than expected (published controls of 62, 44, and 29 months): median survivals for this series of 73, 51 and 37 months for stage I, II, and III disease, respectively. CONCLUSIONS: Myelofibrosis that accompanies a PCD often represents an underlying MPD and does not negatively impact the natural history of the associated PCD.

Abstract Background It is widely recognized that advanced age and prior thrombosis predict recurrent thrombosis in essential thrombocythemia (ET) and are used to risk-stratify patients. However, the paucity of large sample size and long-term follow-up has limited the development of similar prognostic models for survival and leukemic transformation (LT). Methods Data was abstracted from the medical records of a consecutive cohort of patients with WHO-defined ET seen at the Mayo Clinic. Cox proportional hazards was used to determine the impact of clinical and laboratory variables on survival and LT. Overall survival and leukemia-free survival was estimated by Kaplan-Meier plots. Results i. Patient characteristics and outcome The study cohort included 605 patients of which 399 (66%) were females (median age, 57 years; range 5–91). Median follow-up was 84 months (range; 0–424). During this period, 155 patients (26%) have died and LT was documented in 20 patients (3.3%) occurring at a median of 138 months (range; 23–422) from ET diagnosis. ii. Prognostic variables for overall survival Univariate analysis of parameters at diagnosis identified age ≥ 60 years, hemoglobin less than normal (defined as < 12 g/dL in females and < 13.5 g/dL in males), leukocyte count ≥ 15 x 109/L, tobacco use, diabetes mellitus, thrombosis, male sex, and the absence of microvascular symptoms as independent predictors of inferior survival. All of the above except the last two (i.e. male sex and the absence of microvascular symptoms) sustained their prognostic significance on multivariate analysis. Based on the first three prognostic variables: age, hemoglobin level, and leukocyte count, we constructed a prognostic model for survival: low-risk (none of the risk factors), intermediate-risk (1of 3 risk factors), and high-risk (≥ 2 risk factors). The respective median survivals were 278, 200, and 111 months (p<0.0001; Figure 1) iii. Prognostic variables for leukemic transformation On univariate analysis of parameters at ET diagnosis, LT was significantly associated with platelet count ≥ 1000 x 109/L, hemoglobin less than normal, and exposure to P-32. However, on multivariate analysis, only hemoglobin less than normal and platelet count ≥ 1000 x 109/L maintained independent prognostic value. Accordingly, we utilized these two variables, to construct a prognostic model for LT: low-risk (none of the risk factors), intermediate-risk (1 risk factor), and high-risk (both risk factors). Only 1 of the 239 patients (0.4%) in the low-risk group vs. 14 of the 289 (4.8%) in the intermediate-risk and 5 of the 77 (6.5%) in the high-risk group underwent LT (p=0.0009; Figure 2). Conclusion The current study provides clinician-friendly prognostic models for both survival and LT in ET. Figure 1 Figure 1. Figure 2 Figure 2.

Abstract Background : CC-5013 (Revlimid™) is an immunomodulatory analog of thalidomide that is substantially more potent than the parent drug in terms of both anti-angiogenic and anti-TNF-α activity. CC-5013 has shown therapeutic activity in thalidomide-responsive hematological malignancies including relapsed multiple myeloma (Blood2002;100:3063) and myelodysplastic syndrome (Blood2002;100:96a). Myelofibrosis with myeloid metaplasia (MMM) has also been shown to respond to thalidomide (BJH2002;117:288). Furthermore, both angiogenesis and altered TNF-α activity have been pathogenetically implicated in MMM. Methods : The current report considers the first 15 patients in an ongoing phase II treatment trial of single agent CC-5013 in MMM based on a minimum of 3 month follow-up from day 1 of protocol treatment. Study eligibility criteria included no concomitant MMM-directed therapy, a hemoglobin (Hgb) level of < 10 g/dL, an absolute neutrophil count (ANC) of ≥ 1 x 109/L, and a platelet count of ≥ 100 x 109/L. Previous thalidomide therapy in the absence of high-grade skin toxicity was allowed. All patients were started with daily oral CC-5013 (10 mg/day) to be taken for three 28-day treatment cycles. Three additional treament cycles were planned in case of anemia response. Results : Median age was 64 years (range, 40–75) and 10 pts were males. Twelve of the 15 study pts (80%) were red cell transfusion-dependent, 14 (93%) were previously treated including 12 with cytoreductive and 4 with thalidomide therapy. The spleen was palpably enlarged in 13 pts (median 18 cm, range 7–23). Eight of the 15 pts (53%) successfully completed 3 months of protocol treatment. Treatment was discontinued in the remaining 7 pts because of drug toxicity (2 pts), disease progression (1 pt), other co-morbid condition (3 pts), or patient discretion (1 pt). Treatment response data : Clinically relevant responses were documented in 4 patients (27%) and consisted of measurable improvements in anemia (2 pts), splenomegaly (2 pts), and/or constitutional symptoms (3 pts). One pt experienced an increase in Hgb level from 8.3 to 13.4 g/dL, a decrease in leukocyte count from 66.2 to 7.7 x 109/L, and complete resolution of myelophthisis including disapperance of circulating blasts that measured 9% before treatment. Another pt became transfusion-independent (Hgb level increased to > 10 g/dL) as well as enjoyed a profound improvement in constitutional symptoms. Interestingly, serum lactate dehydrogenase (LDH) level decreased in 11 pts (73%) to either within the normal ramge (5 pts) or by more than 30 % (6 pts). Treatment toxicity data : Grade 3 or 4 adverse events that were possibly, probably, or definitely attributed to CC-5013 included rash (2 pts), neutropenia (5 pts), thrombocytopenia (3 pts), and fatigue (2 pts). In addition, 3 patients experienced drug-associated extreme thrombocytosis while a histologically-proven disseminated extramedullary hematopoiesis was documented in one patient after one month of CC-5013 treatment. Conclusion : The current preliminary report suggests a substantial biological activity of CC-5013 in MMM with a therapeutic potential for a subset of patients. Additional studies with a longer duration of therapy, different dose schedules, and combinations of CC-5013 and corticosteroids are warranted.