Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) ...and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.
Myelodysplastic syndromes are characterised by ineffective erythropoiesis. Luspatercept (ACE-536) is a novel fusion protein that blocks transforming growth factor beta (TGF β) superfamily inhibitors ...of erythropoiesis, giving rise to a promising new investigative therapy. We aimed to assess the safety and efficacy of luspatercept in patients with anaemia due to lower-risk myelodysplastic syndromes.
In this phase 2, multicentre, open-label, dose-finding study (PACE-MDS), with long-term extension, eligible patients were aged 18 years or older, had International Prognostic Scoring System-defined low or intermediate 1 risk myelodysplastic syndromes or non-proliferative chronic myelomonocytic leukaemia (white blood cell count <13 000/μL), and had anaemia with or without red blood cell transfusion support. Enrolled patients were classified as having low transfusion burden, defined as requiring less than 4 red blood cell units in the 8 weeks before treatment (and baseline haemoglobin <10 g/dL), or high transfusion burden, defined as requiring 4 or more red blood cell units in the 8 weeks before treatment. Patients received luspatercept subcutaneously once every 21 days at dose concentrations ranging from 0·125 mg/kg to 1·75 mg/kg bodyweight for five doses (over a maximum of 12 weeks). Patients in the expansion cohort were treated with 1·0 mg/kg luspatercept; dose titration up to 1·75 mg/kg was allowed, and patients could be treated with luspatercept for a maximum of 5 years. Patients in the base study were assessed for response and safety after 12 weeks in order to be considered for enrolment into the extension study. The primary endpoint was the proportion of patients achieving modified International Working Group-defined haematological improvement–erythroid (HI-E), defined as a haemoglobin concentration increase of 1·5 g/dL or higher from baseline for 14 days or longer in low transfusion burden patients, and a reduction in red blood cell transfusion of 4 or more red blood cell units or a 50% or higher reduction in red blood cell units over 8 weeks versus pre-treatment transfusion burden in high transfusion burden patients. Patient data were subcategorised by: luspatercept dose concentrations (0·125–0·5 mg/kg vs 0·75–1·75 mg/kg); pre-study transfusion burden (high transfusion burden vs low transfusion burden, defined as ≥4 vs <4 red blood cell units per 8 weeks); pre-study serum erythropoietin concentration (<200 IU/L, 200–500 IU/L, and >500 IU/L); presence of 15% or more ring sideroblasts; and presence of SF3B1 mutations. Efficacy analyses were carried out on the efficacy evaluable and intention-to-treat populations. This trial is currently ongoing. This study is registered with ClinicalTrials.gov, numbers NCT01749514 and NCT02268383.
Between Jan 21, 2013, and Feb 12, 2015, 58 patients with myelodysplastic syndromes were enrolled in the 12 week base study at nine treatment centres in Germany; 27 patients were enrolled in the dose-escalation cohorts (0·125–1·75 mg/kg) and 31 patients in the expansion cohort (1·0–1·75 mg/kg). 32 (63% 95% CI 48–76) of 51 patients receiving higher dose luspatercept concentrations (0·75–1·75 mg/kg) achieved HI-E versus two (22% 95% CI 3–60) of nine receiving lower dose concentrations (0·125–0·5 mg/kg). Three treatment-related grade 3 adverse events occurred in one patient each: myalgia (one 2%), increased blast cell count (one 2%), and general physical health deterioration (one 2%). Two of these treatment-related grade 3 adverse events were reversible serious grade 3 adverse events: one patient (2%) had myalgia and one patient (2%) had general physical health deterioration.
Luspatercept was well tolerated and effective for the treatment of anaemia in lower-risk myelodysplastic syndromes and so could therefore provide a novel therapeutic approach for the treatment of anaemia associated with lower-risk myelodysplastic syndromes; further studies are ongoing.
Acceleron Pharma.
Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the
like tyrosine kinase 3 gene (
...ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT.
In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with
ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first.
With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank
= .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank
= .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib.
Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for
ITD-positive AML.
Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict ...haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.
The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK–NUP214, RUNX1–RUNX1T1, CBFb–MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1–7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018.
Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44–72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5–22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32–59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82–94; hazard ratio 6·6 95% CI 3·7–11·8, p<0·0001). The most common (grade 3–4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment.
Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.
Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.
The azanucleosides azacitidine and decitabine are currently used for the treatment of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients not only eligible for intensive ...chemotherapy but are also being explored in other hematologic and solid cancers. Based on their capacity to interfere with the DNA methylation machinery, these drugs are also referred to as hypomethylating agents (HMAs). As DNA methylation contributes to epigenetic regulation, azanucleosides are further considered to be among the first true "epigenetic drugs" that have reached clinical application. However, intriguing new evidence suggests that DNA hypomethylation is not the only mechanism of action for these drugs. This review summarizes the experience from more than 10 years of clinical practice with azanucleosides and discusses their molecular actions, including several not related to DNA methylation. A particular focus is placed on possible causes of primary and acquired resistances to azanucleoside treatment. We highlight current limitations for the success and durability of azanucleoside-based therapy and illustrate that a better understanding of the molecular determinants of drug response holds great potential to overcome resistance.
Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine ...whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval CI, 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio HR, 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.
•Midostaurin plus intensive chemotherapy can be safely administered in older FLT3-ITD-positive patients with AML.•Compared with historical controls, midostaurin significantly improved event-free survival in older and younger FLT3-ITD positive patients with AML.
Erythropoiesis-stimulating agents are first choice for treating anemia in low-risk MDS. This double-blind, placebo-controlled study assessed the efficacy and safety of epoetin-α in IPSS low- or ...intermediate-1 risk (i.e., low-risk) MDS patients with Hb ≤ 10.0 g/dL, with no or moderate RBC transfusion dependence (≤4 RBC units/8 weeks). Patients were randomized, 2:1, to receive epoetin-α 450 IU/kg/week or placebo for 24 weeks, followed by treatment extension in responders. The primary endpoint was erythroid response (ER) through Week 24. Dose adjustments were driven by weekly Hb-levels and included increases, and dose reductions/discontinuation if Hb > 12 g/dL. An independent Response Review Committee (RRC) blindly reviewed all responses, applying IWG-2006 criteria but also considering dose adjustments, drug interruptions and longer periods of observation.A total of 130 patients were randomized (85 to epoetin-α and 45 to placebo). The ER by IWG-2006 criteria was 31.8% for epoetin-α vs 4.4% for placebo (p < 0.001); after RRC review, the ER was 45.9 vs 4.4% (p < 0.001), respectively. Epoetin-α reduced RBC transfusions and increased the time-to-first-transfusion compared with placebo.Thus, epoetin-α significantly improved anemia outcomes in low-risk MDS. IWG-2006 criteria for ER may require amendments to better apply to clinical studies.
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell disorders with a poor prognosis, especially for elderly patients. Increasing evidence suggests that ...alterations in the non-hematopoietic microenvironment (bone marrow niche) can contribute to or initiate malignant transformation and promote disease progression. One of the key components of the bone marrow (BM) niche are BM stromal cells (BMSC) that give rise to osteoblasts and adipocytes. It has been shown that the balance between these two cell types plays an important role in the regulation of hematopoiesis. However, data on the number of BMSC and the regulation of their differentiation balance in the context of hematopoietic malignancies is scarce. We established a stringent flow cytometric protocol for the prospective isolation of a CD73
CD105
CD271
BMSC subpopulation from uncultivated cryopreserved BM of MDS and AML patients as well as age-matched healthy donors. BMSC from MDS and AML patients showed a strongly reduced frequency of CFU-F (colony forming unit-fibroblast). Moreover, we found an altered phenotype and reduced replating efficiency upon passaging of BMSC from MDS and AML samples. Expression analysis of genes involved in adipo- and osteogenic differentiation as well as Wnt- and Notch-signalling pathways showed significantly reduced levels of DLK1, an early adipogenic cell fate inhibitor in MDS and AML BMSC. Matching this observation, functional analysis showed significantly increased in vitro adipogenic differentiation potential in BMSC from MDS and AML patients. Overall, our data show BMSC with a reduced CFU-F capacity, and an altered molecular and functional profile from MDS and AML patients in culture, indicating an increased adipogenic lineage potential that is likely to provide a disease-promoting microenvironment.
PDF
