Lenalidomide In Acute Myeloid Leukemia Research Articles

A Randomised Evaluation of Low-Dose Cytarabine Arabinoside Plus Lenalidomide Versus Single-Agent Low-Dose Cytarabine Arabinoside in Older Patients with Acute Myeloid Leukaemia: Results from the LI-1 Trial

Background: Many patients with Acute Myeloid Leukemia (AML) diagnosed after 60 years of age are not considered suitable for intensive remission induction chemotherapy, either due to co-morbidities or frailty associated with advanced age. Despite treatment with either a hypomethylating agent or low-dose cytarabine arabinoside (LDAC), survival is usually poor, with 1-year survival after LDAC of 24-37% in NCRI AML16 and historical arms of LI-1. Combination therapy with additional agents represents an attractive option, and has the potential to improve patient outcomes without substantially increasing toxicity. Lenalidomide (Revlimid TM) is an immunomodulatory drug, used to treat myeloma, and some cases of myelodysplastic syndrome, and has potent antineoplastic, anti-angiogenic, anti-inflammatory and pro-erythropoietic properties. Early-phase trials of lenalidomide in AML have demonstrated clinical activity with acceptable toxicity.Aim: To assess the efficacy and tolerability of LDAC+lenalidomide versus LDAC alone in patients aged 60+ unsuitable for intensive therapy. The aim was to double 2-year survival from 11% to 22% (HR 0.69).Methods: LI-1 was an international multicentre, multi-arm, randomised phase II trial developed to study the efficacy and tolerability of novel non-intensive therapies in AML using a “pick a winner” design. LDAC was given at 20mg BD SC on days 1-10 of each course. Lenalidomide was administered orally once daily in a flat 10mg dose for 21 days, where day 1 is day 1 of LDAC with courses occurring at 5-week intervals for courses 1-4. Patients considered to be benefitting after 4 courses, i.e. in remission or stable disease, could continue to receive treatment until disease progression, either with LDAC+lenalidomide at 6-week intervals, or lenalidomide only at 4-week intervals if patient had experienced significant toxicity. Toxicities were recorded using CTCAEv3. Primary objectives included overall survival (OS), complete remission (CR + CRi) achievement, reasons for failure, duration of response (CR/CRi), relapse rates and deaths in first CR. Secondary objectives included toxicity, supportive care requirements, and Quality of Life assessments (measured using EORTC QLQ-30, EQ5D and HADS tools).Results: Between Jan-17 and Jun-19, 202 patients from Denmark (8%), New Zealand (16%) and the UK (76%) were randomised. Median age was 78 years (range 62-89). Overall, 58% were male; 76% de novo AML, 20% secondary AML, and 4% high risk MDS; 1% favourable, 66% intermediate, 19% adverse and 14% unknown cytogenetics; WHO performance status 0 for 15%, 1 for 58%, 2 for 22% and 3 for 5%. Median of 2 courses (range 0-24; mean 3.28) was delivered in LDAC arm and 1 course in LDAC+lenalidomide arm (range 0-25; mean 3.48).Overall response (CR/CRi) was achieved in 40/202 patients (20%), (LDAC+lenalidomide 25%, LDAC 14%, OR 0.45 (0.22, 0.93), P=0.031). 30-day mortality was not significantly increased (19% in both arms); and 2-year OS showed no significant difference (14% vs 11.5%, HR 0.94 (0.69, 1.29, P=0.719). Median OS was 3.5 vs 4.6 months; HR 0.96 (0.71, 1.30), P=0.80. 1-year OS for patients that didn't enter CR/CRi was 6.8% for LDAC+lenalidomide vs 16.9% for LDAC (P=0.028). Cause of death for the majority of patients was resistant/recurrent disease: 45(53%) vs 47(58%). Most adverse events (AEs) were grade 1/2 in both arms. During cycle 1, there were 78 vs 51 grade 3/4 AEs in the LDAC+lenalidomide and LDAC arms, respectively (P=0.02). This included 5 thrombotic events in the LDAC+lenalidomide arm (4 grade 3 and 1 grade 4) and none in the LDAC arm. In course 1, supportive care requirements were higher in terms of both days of antibiotics (7 vs 3; p=0.001) and hospitalisation days (11 vs 6.5; p=0.005) for the LDAC+lenalidomide arm. There was no difference in transfusion requirements.Conclusions: Despite improving the CR/CRi rate, the combination of lenalidomide+LDAC did not improve OS, relapse-free survival or time in remission in elderly patients with AML. The addition of lenalidomide to LDAC resulted in increased toxicity, including episodes of thrombosis, as well as increased supportive care requirements. Alternative strategies to improve survival for elderly patients with AML remain a significant clinical need.Acknowledgements: We are grateful to Blood Cancer UK for funding the trial and Celgene for providing drug and additional support for this IIS.Fig 1: OS All patients [Display omitted] DisclosuresCopland: Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria, Speakers Bureau; Cyclacel Ltd: Research Funding. Russell: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Speakers Bureau; Astellas: Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding, Speakers Bureau. OffLabel Disclosure:Off label use of lenalidomide in combination with low dose cytarabine will be discussed in the setting of elderly unfit AML.

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response.

A Phase 1 Study of Lenalidomide in Combination with Mitoxantrone, Etoposide, and Ara-C in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Background: The prognosis for patients with relapsed acute myeloid leukemia (AML) remains extremely poor. Standard reinduction regimens, such as mitoxantrone, etoposide, and ara-C (MEC), have been associated with complete remission rates in the 23 to 30% range. Lenalidomide (Len), an immunomodulatory drug, has efficacy in relapsed AML and has been shown to augment the effects of standard chemotherapies (anthracyclines and ara-C) in preclinical AML studies. These data prompted the current phase 1 study of Len in combination with MEC in pts with relapsed AML.Methods: The trial included pts (≥ 18 yrs) with relapsed or refractory AML. The primary objective was determination of the maximum tolerated dose (MTD) of Len when given in combination with MEC. Secondary objectives included safety, efficacy and time to count recovery. The study examined escalating doses (5-10 mg) of Len given daily for the first 14 days in combination with standard MEC doses of mitoxantrone (8 mg/m2/d), etoposide (100 mg/m2/d), and ara-C (1000 mg/m2/d) on days 4 through 8. Due to observations of prolonged count recovery, the Len dosing schedule was amended by reducing the duration of treatment to 10 days starting on Day 1. The dose of len was then re-escalated starting at 5 mg/d (5-10-25-50). A standard 3+3 dose-escalation design was used. Dose limiting toxicity was defined as Grade IV rash or Grade IV neuropathy during the first 28 day period, or delayed neutrophil (ANC <500/mL) or platelet (platelet count <20,000/mL) recovery beyond Day 45 after start of re-induction chemotherapy in the absence of persistent AML. Pts achieving a complete remission (CR) or complete remission with incomplete blood count recovery (CRi) went on to consolidation chemotherapy or hematopoietic stem cell transplantation at the discretion of the treating physician.Results: A total of 33 pts have been enrolled in the study (25 escalation phase [5 mg days 1-14, n=3; 10 mg days 1-14, n=6; 5 mg days 1-10, n=3; 10 mg days 1-10, n=3; 25 mg days 1-10, n=3; 50 mg days 1-10, n=6] and 8 expansion phase pts at 50 mg/d days 1-10). One patient was enrolled, found to be ineligible, and not treated. The median age was 62 years (range, 28-74), 45% were male and the median number of prior treatments was 2. Three dose limiting toxicities, all due to delayed count recovery past day 45, were observed in the escalation phase (n = 2/6 pts in the 10 mg/d day1-14 dose group and n = 1/6 in the in the 50 mg/d day1-10 dose group). The RP2D of Len in combination with MEC was 50 mg/d on days 1-10. Among the 14 pts treated at the RP2D, common grade 3/4 adverse events (AEs) regardless of causality were mainly hematologic including febrile neutropenia (36%). Overall 4 pts including none treated at the RP2D died during treatment. All of the on-treatment deaths, (grade 5 sepsis, n =1; infection, n=1; respiratory failure, n =2), were determined to be unrelated to the study drug. 32 pts were evaluable for response (one pt too early for assessment) with 12 pts achieving a CR and 1 pt a CRi with a total CR/CRi rate of 41% (95% CI: 24-59%). The median time to a neutrophil count of 1500/mL was 30 days and to a platelet count of 100,000/mL was 22 days.Conclusions: Len in combination with MEC re-induction chemotherapy for pts with relapsed or refractory AML was generally well tolerated and associated with an improved response rate as compared to historical controls. The safety profile was consistent with reported events in other MEC chemotherapy trials. Overall, these data suggest further exploration of high-dose Len in combination with MEC. DisclosuresDeAngelo:Celgene: Consultancy; Agios: Consultancy; Incyte: Consultancy; Amgen: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy; Ariad: Consultancy; Novartis: Consultancy. Off Label Use: lenalidomide in AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy. Steensma:Incyte: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Onconova: Consultancy. Attar:Agios: Employment. Stone:Abbvie: Consultancy; Amgen: Consultancy; Agios: Consultancy; Celator: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Novartis: Research Funding; Celgene: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Roche/Genetech: Consultancy; Pfizer: Consultancy; AROG: Consultancy; Juno: Consultancy.

Lenalidomide Promotes Degradation of Casein Kinase 1a (CK1a) through Cereblon: Implications for the Efficacy of Lenalidomide in MDS and AML

Background: Lenalidomide has broad clinical activity in hematologic malignancies, including lymphoid malignancies (multiple myeloma (MM), non-Hodgkin’s lymphomas, B cell chronic lymphocytic leukemia) and myeloid malignancies (myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML)). Lenalidomide’s molecular mechanism involves modulation of the cullin 4 RING E3 ubiquitin ligase complex (CRL4-CRBN), with downstream effects on protein homeostasis. The binding of lenalidomide to CRL4-CRBN promotes ubiquitination and degradation of Aiolos and Ikaros in B cell lineages (MM, lymphoma), and regulation of Ikaros has been shown to be a key effector of lenalidomide’s anti-myeloma tumoricidal and T cell immunomodulatory activities. Multiple mechanisms of clinical efficacy have been hypothesized for lenalidomide activity in del(5q) MDS; however, lenalidomide-regulated substrates of therapeutic relevance to myeloid malignancies have not been defined. We undertook a proteomics approach to identify such substrates.Methods: Changes in global cellular protein levels were measured by tandem-mass-tagged proteomics in a del(5q) MDS cell line (MDS-L) and an AML cell line (HNT-34), following treatment with vehicle or 10 uM lenalidomide for 8, 24 and 72 hours. Western blot analysis was used to subsequently validate proteins that were differentially regulated in these lenalidomide-sensitive cell lines. Sensitivity to lenalidomide treatment in a panel of myeloid cancer cell lines was evaluated by tritiated thymidine and/or BrdU assays.Results: Across a panel of myeloid cancer cell lines evaluated for sensitivity to lenalidomide, HNT-34 and MDS-L cells were the most sensitive to lenalidomide, with EC50’s of 0.6 and 1.5 µM, respectively, while other cell lines were predominantly insensitive (EC50 > 10 µM). Proteomic analysis of lenalidomide-regulated proteins in MDS-L cells revealed Ikaros as the most down-regulated protein at 72 hrs (5.3 fold), and CK1α was the second most down-regulated protein (2.8 fold). The decrease of Ikaros and CK1α proteins by lenalidomide was confirmed by Western blot analysis in MDS-L and HNT-34 cells. Ikaros protein levels were reduced by lenalidomide in cell lines that were sensitive or insensitive to lenalidomide, suggesting that modulation of other proteins may be responsible for lenalidomide sensitivity of myeloid cancer cells. Ikaros levels were also decreased by a CRBN-binding glutarimide analog in HNT-34 cells, which were insensitive to the analog, further suggesting that Ikaros was not a substrate of consequence to sensitivity. In contrast, an initial study of five cell lines showed that lenalidomide promoted the greatest degradation of CK1a in the most sensitive lines (HNT-34, MDS-L), but did not degrade CK1a in the most insensitive line (MOLM-13). Mechanistic studies addressing CK1α regulation in HNT-34 cells revealed that CK1α protein levels were reduced by lenalidomide treatment in a time- and dose-dependent manner, with maximal reduction of 3.3 fold observed at 4 hrs using 10 µM lenalidomide, and CK1α degradation observed with lenalidomide at a dose as low as 0.1 µM. Pre-treating HNT-34 cells with the proteasome inhibitor MG-132 stabilized CK1α protein levels in the presence of lenalidomide, demonstrating proteasome-dependent degradation. A competition experiment performed by pre-treating HNT-34 cells with the glutarimide analog that binds CRBN, but does not result in the degradation of CK1a, resulted in CK1α protein stabilization in the presence of lenalidomide, demonstrating CRBN-dependence of the lenalidomide-induced degradation. Degradation of CK1α was also observed in primary peripheral blood mononuclear cells of AML patients treated with lenalidomide.Conclusions: CK1α is a lenalidomide-induced substrate of CRL4-CRBN, with initial links to myeloid cancer cell line sensitivity to lenalidomide. As the CSNK1A1 gene is located at 5q32, a commonly deleted region in MDS, further reduction of haplo-insufficient expression of CK1α is a potential mechanism of sensitivity to lenalidomide in del(5q) MDS. The therapeutic relevance of CK1α regulation by lenalidomide in AML requires further exploration. CK1α gene silencing and additional correlative studies of lenalidomide-induced degradation of CK1α are ongoing to define mechanistic links to myeloid cancer cell sensitivity to lenalidomide. DisclosuresHollenbach:Celgene: Employment, Equity Ownership. Lu:Celgene Corp: Employment. Gandhi:Celgene Corp: Employment, Equity Ownership. Chopra:Celgene Corp: Employment, Equity Ownership. MacBeth:Celgene: Employment, Equity Ownership.

Lenalidomide as a novel treatment of acute myeloid leukemia

Introduction: Lenalidomide is an oral immunomodulatory drug derived from thalidomide. This drug has been approved by the Food and Drug Administration for transfusion-dependent anemia due to low-risk myelodysplastic syndromes (MDS) associated with deletion 5q abnormality with or without additional cytogenetic abnormalities and multiple myeloma in combination with dexamethasone. Trials have been conducted for its use in higher-risk MDS and acute myeloid leukemia (AML).Areas covered: The pharmacokinetic and mechanism of action are discussed and clinical studies of lenalidomide in AML are reported herein in detail. An overview of safety and tolerability is also presented.Expert opinion: Lenalidomide has clinical activity in AML with manageable toxicity. The population that would benefit from lenalidomide and optimal dose needs to be better defined. Recent trials have focused on combining lenalidomide with other agents active in MDS and AML and promising data are emerging.

Priming of Mir-181a in Acute Myeloid Leukemia (AML) to Increase Chemosensitivity: A Phase I Trial of Lenalidomide (LEN) Followed by Idarubicin and Cytarabine.

AbstractAbstract 2619Expression of miR-181a confers better prognosis in cytogenetically normal (CN) AML (Schwind et al, JCO 2010). Laboratory studies by our group have demonstrated that miR-181a is upregulated by C/EBPα-p30. CN AML patients (pts) harboring CEBPA mutations, the majority of which block C/EBPAα-p42 expression but allow C/EBPα-p30 expression, have elevated miR-181a and more favorable clinical outcome (Marcucci et al, JCO 2008). We hypothesized that pharmacologic potentiation of C/EBPa-p30 expression, and in turn miR-181a upregulation, would increase chemosensitivity and improve clinical outcomes in AML. Based on prior in vitro and in vivo studies, LEN was selected as a candidate agent to achieve these pharmacodynamic (PD) endpoints. Pharmacokinetic (PK) and PD studies from our prior single-agent, high-dose LEN trial demonstrated upregulation of miR-181a in leukemic blasts at tolerable doses; preclinical studies showed that this effect is dose dependent. Given these results and previously demonstrated LEN clinical activity in AML (Blum et al, JCO 2010; Fehniger et al, Blood 2011; Ades et al, ASH 2010; Lancet et al, ASH 2011), a phase I trial was conducted of LEN as miR “priming” with intensive chemotherapy in two parallel cohorts of AML: Prior Therapy (PT) Cohort for relapsed/refractory pts <65 years of age, and Untreated (U) Cohort for newly diagnosed pts >60 years. In both groups, LEN was given for 14 days(d) starting at 25mg/d; cytarabine and idarubicin (starting dose 12/mg/m2 × 3d) began on d5. PT Cohort received cytarabine at a starting dose of 1.5 g/m2/d over 24 hours for 4d; U Cohort received 100mg/m2 for 7d in standard fashion. 31 pts enrolled, 17 with relapsed/refractory AML and 14 with previously untreated AML. PT Cohort pts had median age 53 years (range, 22–64) and median presenting WBC count of 4.2 × 109 (range, 0.9–22.7 × 109). U Cohort pts had median age 69 years (range, 48–77), median presenting WBC count of 3.1 × 109 (range, 0.5–31.9 × 109), and median marrow blasts of 36%. None of the U Cohort pts had favorable risk disease by ELN classification, 6 had adverse risk. Note that one patient <60 years of age was enrolled in U Cohort due to a recent amendment expanding eligibility. Dose limiting toxicities included rash (4), delayed hematologic recovery (1), mucositis (1), and cardiomyopathy (1). One pt died within 30d of starting treatment (surgical complication unrelated to treatment); however, two additional pts died of therapy-related complications within 60d of induction [intracranial hemorrhage with refractory thrombocytopenia (1) and cardiomyopathy (1)]. The maximum administered dose of LEN was 30mg/d, and we are currently expanding the 25mg dose level in both groups. PT Cohort is being expanded at LEN 25mg with idarubicin 8mg/m2/d and cytarabine at 1mg/m2/d. U Cohort is being expanded at the MTD of LEN 25mg with idarubicin 12mg/m2/d and cytarabine at 100mg/m2/d. Complete remission (CR) was achieved in 41% (7/17) in the PT Cohort and 69% (9/13, all >60 years) in the U Cohort. One pt in U Cohort was not evaluable for response as the pt discontinued treatment before chemotherapy was given. Preliminary PK parameters and LEN exposure (Figure 1) are consistent with what we reported previously. Observed PK of idarubicin was similar to expected and did not suggest an interaction with LEN. There was no apparent difference in PK of LEN in those who experienced skin rash (or other toxicities/clinical outcomes) compared with those that did not. Preliminary PD testing of LEN-induced modulation of miR-181a expression was consistent with the hypothesis of the trial. Results in a small subset of pts (N=6) tested to date showed a trend for greater post-LEN increase in miR-181a(pretreatment vs. d5 before chemotherapy began) in pts who achieved CR compared with those who did not (Figure 2). In conclusion, LEN priming with chemotherapy is reasonably well tolerated and active in AML. We are planning a randomized phase II study in previously untreated patients to test the hypotheses and compare efficacy of LEN priming vs. post-chemotherapy LEN. For the current trial, an amendment to shorten the course of LEN in order to facilitate dose escalation above 25mg is planned. Updated correlative results for all enrollees will be presented. Supported by NCI U01 CA 76576-05, NIH/NCI K23CA120708, Leukemia and Lymphoma Society SCOR 7004-11, and SPORE P50-CA140158. [Display omitted] [Display omitted] Disclosures:Off Label Use: Lenalidomide in AML.

2-Hydroxyglutarate in IDH mutant AML: Predicting Patient Responses, Minimal Residual Disease and Correlations with Methylcytosine and Hydroxymethylcytosine Levels

Abstract 2509Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes have recently been shown to be recurrent, frequent and prognostic in acute myeloid leukemia (AML) patients. IDH1 and IDH2 encode NADP+ dependent enzymes responsible for oxidative decarboxylation of isocitrate to α-ketoglutarate (AKG). Heterozygous point mutations in IDH1 and IDH2 result in the loss of this activity, concomitant with a neomorphic ability to convert AKG to 2-hydroxyglutarate (2HG), resulting in significant elevations in this oncometabolite. The ten-eleven translocation 2 (TET2) gene converts 5-methylcytosine (5MC) to 5-hydroxymethylcytosine (5HMC), leading to DNA demethylation. TET2 encodes a dioxygenase that is dependent on AKG, and therefore, increased levels of 2HG may disrupt TET2 function. We explored the potential of 2HG to serve as a clinical biomarker of response to therapy in AML patients with IDH mutations, and correlated fluctuations of 2HG with changes in 5MC and 5HMC levels in a clinical setting.In a Phase I/II clinical trial of 44 elderly, previously untreated AML patients who received sequential azacitidine and lenalidomide, we identified 12 patients with IDH1/2 mutations (27%). Five had IDH1 mutations (all R132), and seven had IDH2 mutations (R140 N=5, R172 N=2). 2HG levels were measured by mass spectrometry from plasma obtained from bone marrow aspirations. Six patients had pre- and post-treatment samples available for comparison. Clinical responses were determined per LeukemiaNet criteria.Two of the six patients achieved a complete remission (CR), one with an IDH1 R132 and the other with an IDH2 R140. A comparison of pre- and post-treatment samples from these patients revealed decreases in 2HG levels of −16.9 and −17.9 fold after three cycles of therapy. Four patients did not achieve a CR, although some did experience decreases in the percentage of blasts. These patients had substantially smaller decreases, or increases, in 2HG levels when measured after one cycle (Figure 1). A non-parametric comparison (Mann-Whitney U test) in this small sample set showed a trend toward a significant change in pre- vs. post-treatment 2HG levels between patients who experienced a CR and those who did not (p=0.067), suggesting 2HG levels may correlate with leukemic blast clearance. [Display omitted] Both patients who achieved a CR continued to have detectable 2HG levels. Furthermore, patient 8 ultimately relapsed, and at the time of this relapse, which was unexpected based on clinical indicators or routine peripheral blood laboratory findings, there was a 1.8-fold increase in 2HG levels. Therefore, for AML patients with IDH1 and IDH2 mutations, 2HG may provide a useful, non-invasive marker of minimal residual disease.We hypothesized that decreases in 2HG would allow functional TET2 activity, resulting in increased 5HMC and decreased 5MC. Therefore, we correlated changes in 2HG levels with changes in global 5MC and 5HMC levels, as measured by mass spectrometry, in the patients who achieved a CR.Patient 8 was wild type for TET2. As predicted, after one cycle of therapy, 2HG decreased 6.1 fold, 5HMC increased 7.8 fold and 5MC decreased 1.4 fold. At relapse, when 2HG rose 1.8 fold, 5HMC decreased 5.4 fold; the expected increase in 5MC was not observed (Figure 2). Although concomitant mutations in IDH and TET2 are exceedingly rare, patient 22 did have this genotype, which allowed for an instructive negative control. After one cycle of therapy, 2HG decreased 2.6 fold. However, in contrast to patient 8, in which it appeared TET2 became functional as shown by increased 5HMC after 2HG decreased, patient 22's mutant TET2 resulted in marginal changes in 5HMC and 5MC levels (1.3-fold increase and 1.1-fold decrease, respectively) (Figure 3). These observations provide in vivo evidence for the interaction between IDH and TET2, and suggest that these interactions are dynamic and can change with therapy. [Display omitted] [Display omitted] Disclosures:Off Label Use: Lenalidomide in AML. Schenkein:Agios: Employment. Fantin:Agios: Employment. Straley:Agios: Employment. Medeiros:Celgene: Honoraria, Research Funding.

A phase 2 study of high-dose lenalidomide as initial therapy for older patients with acute myeloid leukemia

AbstractOlder patients with acute myeloid leukemia (AML) have limited treatment options and a poor prognosis, thereby warranting novel therapeutic strategies. We evaluated the efficacy of lenalidomide as front-line therapy for older AML patients. In this phase 2 study, patients 60 years of age or older with untreated AML received high-dose (HD) lenalidomide at 50 mg daily for up to 2 28-day cycles. If patients achieved a complete remission (CR)/CR with incomplete blood count recovery (CRi) or did not progress after 2 cycles of HD lenalidomide, they received low-dose lenalidomide (10 mg daily) until disease progression, an unacceptable adverse event, or completion of 12 cycles. Thirty-three AML patients (median age, 71 years) were enrolled with intermediate (55%), unfavorable (39%), or unknown (6%) cytogenetic risk. Overall CR/CRi rate was 30%, and 53% in patients completing HD lenalidomide. The CR/CRi rate was significantly higher in patients presenting with a low (< 1000/μL) circulating blast count (50%, P = .01). The median time to CR/CRi was 30 days, and duration of CR/CRi was 10 months (range, 1- ≥ 17 months). The most common grades ≥ 3 toxicities were thrombocytopenia, anemia, infection, and neutropenia. HD lenalidomide has evidence of clinical activity as initial therapy for older AML patients, and further study of lenalidomide in AML and MDS is warranted. This study is registered at www.clinicaltrials.gov as #NCT00546897.

A Phase II Study of High Dose Lenalidomide as Initial Therapy for Acute Myeloid Leukemia in Patients > 60 Years Old.

Abstract 842 Background:AML pts over the age of 60 years (AML ≥ 60) have a poor prognosis and warrant novel therapeutic approaches. Lenalidomide used at the approved starting dose of 10mg/day, with dose reductions for neutropenia/thrombocytopenia, has been shown to produce clinically significant unilineage erythroid responses in pts with myelodysplastic syndromes. However, even in these trials lenalidomide was shown to reduce the bone-marrow blasts. We hypothesized that using a higher potentially myelosuppressive fixed dose for induction therapy may be active in the therapy of AML ≥ 60 yrs. Methods:Eligibility criteria: untreated AML ≥ 60 with intermediate- or poor-risk cytogenetics (chromosome 5q- excluded), ECOG PS 0-2, and adequate organ function. Treatment included 2 cycles of high dose lenalidomide (50 mg/day) x 28 days (induction), followed by low dose lenalidomide (10 mg/day) × 28 days for an additional 12 months in non-progressing pts. The primary endpoint was complete remission (CR), including cytogenetic complete remission (CRc), morphologic complete remission (CRm) and complete remission with incomplete blood count recovery (CRi). Results:33 pts were enrolled in this cohort, with a median age of 71 (range 60-88) years. 21 pts (64%) had intermediate risk and 12 (36%) poor risk cytogenetics. 23 pts (70%) had de novo AML and 10 pts (30%) had AML transformed from MDS/secondary to prior therapy. Median peripheral WBC at presentation was 4200 (range 600-44,000)/mm3. Median duration on therapy was 64 (range 3-267) days. Median follow-up from time of enrollment was 143 (range 6-401) days. In the intent-to-treat (ITT) population CR has been observed in 30%(10/33) and includes 3 CRc, 2 CRm, and 5 CRi. 45% (10/22) pts completing the entire 56 day induction regimen and 50% (10/20) pts with a presenting circulating blast count <1000/mm3 achieved CR. Responses were rapid with two pts confirmed to be in CR on day 15, five additional pts on day 28 and the 3 remaining pts on day 56. For the 7 pts that achieved a CR and had a clonal cytogenetic abnormality at diagnosis, 6 pts had resolution of the cytogenetic abnormality at the time of CR. Median CR duration was 5 (range 1 to ≥ 8) months, with 4 pts in CR currently remaining on low dose therapy at >8, >7, >7, and >4 months after achieving remission. No pt experienced bone-marrow aplasia according to biopsies performed on days 15, 28 and 56 of induction therapy. Median days of hospitalization were 6 (range 0-40). Reasons for treatment discontinuation were disease progression in 61%(20/33) and adverse events in 24%(8/33) and patient preference in 3% (1/33). The 60 day mortality was 27% (9/33) with 7 of these deaths due to disease progression. Treatment associated Grade (Gr) 3-4 hematologic toxicities included thrombocytopenia (67%), anemia (55%) and neutropenia (33%). Gr 3-4 febrile neutropenia occurred in 27%, pneumonia in 24% and bacteremia in 24%. Other Gr 3-4 non-hematologic toxicities in >10% of patients included fatigue (15%) and hypoxia (15%). Conclusions:High dose single agent lenalidomide represents a novel and effective therapeutic option with rapid onset of responses in older AML patients. Additional studies are needed to better understand the mechanism whereby lenalidomide induces CR in AML. Disclosures:Vij:CELGENE: Honoraria, Research Funding, Speakers Bureau. Off Label Use: LENALIDOMIDE IN ACUTE MYELOID LEUKEMIA. Fehniger:CELGENE: Research Funding.