ABSTRACT
In a retrospective study, we analyzed the prevalence of elevated Creactive protein (CRP) serum levels in 148 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with laboratory features. Normal, up to 10-fold, and more than 10-fold elevated CRP levels were found in 18%, 59%, and 23% of CMML patients, respectively. Using the CRP cutoff value of 10â¯mg/L of the widely used Glasgow score, high CRP values were associated with inferior survival (13 vs. 39 months, pâ¯= 0.014), which retained prognostic significance in multivariate analysis. High CRP values were associated with lower hemoglobin levels. The survival difference between patients with normal (<â¯5â¯mg/L) and elevated CRP levels persisted after exclusion of patients with clinical infection. These findings indicate that in CMML patients, the presence of an acute-phase reaction is associated with a poor outcome, independent of clinical infection.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , C-Reactive Protein , Retrospective Studies , PrognosisABSTRACT
In a retrospective study, we analyzed the prevalence of subnormal prothrombin time (PT) values in 104 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with clinicolaboratory features. Reduced PT values (<â¯70%) were found in 45/104 (43%) patients. The median survival of patients with reduced PT values was significantly shorter than in patients with normal PT (19 vs. 49 months, pâ¯= 0.006). Patients with reduced PT had higher leukocyte counts, a higher proportion of circulating blast cells, and lower platelet counts. In patients for whom clinical information was available, there was no difference in the incidence of bleeding complications between patients with or without reduced PT. Our results show a high prevalence of plasmatic coagulation abnormalities in patients with CMML, which were associated with laboratory features of advanced disease. Moreover, subnormal PT values were identified as a new prognostic marker. Reduced PT values do not seem to have a clinical impact regarding bleeding complications.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , Leukemia, Myelomonocytic, Chronic/complications , Retrospective Studies , Prognosis , Blood CoagulationABSTRACT
The impact of treatment on the outcome of chronic myelomonocytic leukemia (CMML) patients over a longer period of time and the potential role of predictive factors are not well defined. In a retrospective observational study, we analyzed 168 CMML patients regarding treatment options and survival during the past three decades. The proportion of patients treated with hydroxyurea (HU), intensive chemotherapy, and azacitidine (AZA) was 65/19/0% before 2000, 51/25/32% from 2000-2010, and 36/12/53% after 2010, respectively. Median overall survival (OS) increased from 10 months before 2000 to 23 months thereafter (pâ¯= 0.021). AZA-treated patients but not patients treated with other treatment options had improved survival as compared to CMML patients without AZA therapy (19 vs. 25 months, pâ¯= 0.041). When looking at subgroups, the following patient cohorts had a significant survival benefit in association with AZA therapy: patients with Hbâ¯> 10â¯g/dL, patients with monocytosisâ¯> 10â¯G/L, and patients with mutations in RASopathy genes.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , Leukemia, Myelomonocytic, Chronic/drug therapy , Leukemia, Myelomonocytic, Chronic/chemically induced , Antimetabolites, Antineoplastic/adverse effects , Azacitidine/therapeutic use , Azacitidine/adverse effects , Retrospective Studies , Hydroxyurea/therapeutic useABSTRACT
In a retrospective study, we analyzed the prevalence of increased creatinine levels in 166 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with laboratory and molecular features. Increased creatinine values (>â¯1.1â¯mg/dl) were found in 71 of 166 (43%) patients. The median survival of patients with increased creatinine values was significantly shorter than in patients without impairment of renal function (20 vs. 52 months, pâ¯< 0.001). Patients with increased creatinine values were older, were more often male, had higher leukocyte counts, higher monocyte counts, and higher lactatdehydrogenase (LDH) values. There was a trend toward a higher prevalence of CBL and ASXL1 mutations in patients with renal impairment. Our findings show a high prevalence of renal abnormalities in patients with CMML. Increased creatinine values were identified as a new prognostic marker. These findings may be important for the individualized management of this heterogenous group of patients.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , Male , Leukemia, Myelomonocytic, Chronic/genetics , Retrospective Studies , Creatinine , Prognosis , Kidney/physiology , MutationABSTRACT
In a retrospective study, we analyzed the prevalence of common cardiovascular comorbidities in 310 patients with chronic myelomonocytic leukemia (CMML), their potential prognostic impact, and potential correlations with laboratory and molecular features. 115 (36%) patients had a documented cardiovascular comorbidity. In these patients, coronary heart disease 41/115 (36%), atrial fibrillation 34/115 (29%), and hypertension 75/115 (64%) were documented. None of these conditions had a significant impact on survival. Unexpectedly, patients with cardiovascular comorbidity had a lower number of circulating blasts and a lower prevalence of EZH2 mutations. Moreover, time to transformation was significantly longer in these patients. Cardiovascular comorbidity does not seem to have a major impact on prognosis in CMML patients. The unexpected lower transformation rate in these patients needs to be further investigated.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , Leukemia, Myelomonocytic, Chronic/epidemiology , Leukemia, Myelomonocytic, Chronic/genetics , Retrospective Studies , Prognosis , Mutation , ComorbidityABSTRACT
Chronic inflammation is often indicated by a relative increase in the gamma globulin fraction in the serum electrophoresis. In a retrospective study, we analyzed the prevalence of relative hypergammaglobulinemia in 60 patients with chronic myelomonocytic leukemia (CMML), its potential prognostic impact, and potential correlations with laboratory and molecular features. Relative hypergammaglobulinemia (>â¯20%) was found in 25/60 (42%) patients. The median survival of patients with relative hypergammaglobulinemia was significantly shorter than in patients without hypergammaglobulinemia (10 vs. 24 months, pâ¯= 0.018). There was no difference between the groups regarding leukocyte count, hemoglobin value, and platelet count, but a higher prevalence of NRAS mutations and a lower prevalence of ZRSR2 mutations in patients with hypergammaglobulinemia. Our results show that hypergammaglobulinemia is present in a proportion of CMML patients and that this abnormality is associated with poor overall survival. The role of chronic inflammation in the pathophysiology of CMML needs to be further investigated.
Subject(s)
Leukemia, Myelomonocytic, Chronic , Humans , Leukemia, Myelomonocytic, Chronic/diagnosis , Leukemia, Myelomonocytic, Chronic/genetics , Retrospective Studies , Hypergammaglobulinemia/diagnosis , Hypergammaglobulinemia/genetics , Prognosis , Mutation , InflammationABSTRACT
Next-generation sequencing technology, including whole-exome or whole-genome sequencing and target gene sequencing, has allowed the molecular characterization of somatic mutation spectrums in hematologic diseases. Mutations in Additional sex combs-like 1 (ASXL1), a chromatin regulator, are identified in clonal hematopoiesis of indeterminate potential (CHIP), indicating ASXL1 mutations as early events in leukemogenesis. Not surprisingly, they occur at high frequency in myeloid malignancies and are associated with poor prognosis. Therefore, understanding how mutant ASXL1 drives clonal expansion and leukemogenesis will serve as the basis for the future development of preventative and/or therapeutic strategies for myeloid diseases with ASXL1 mutations. Here, we discuss the biology of ASXL1 and its role in controlling normal and malignant hematopoiesis. In addition, we review the clinical relevance of ASXL1 mutations in CHIP and myeloid diseases.
Subject(s)
Leukemia , Myeloproliferative Disorders , Humans , Repressor Proteins/genetics , Hematopoiesis/genetics , Myeloproliferative Disorders/genetics , Mutation , Leukemia/geneticsABSTRACT
BACKGROUND: Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) comprise several rare hematologic malignancies with shared concomitant dysplastic and proliferative clinicopathologic features of bone marrow failure and propensity of acute leukemic transformation, and have significant impact on patient quality of life. The only approved disease-modifying therapies for any of the MDS/MPN are DNA methyltransferase inhibitors (DNMTi) for patients with dysplastic CMML, and still, outcomes are generally poor, making this an important area of unmet clinical need. Due to both the rarity and the heterogeneous nature of MDS/MPN, they have been challenging to study in dedicated prospective studies. Thus, refining first-line treatment strategies has been difficult, and optimal salvage treatments following DNMTi failure have also not been rigorously studied. ABNL-MARRO (A Basket study of Novel therapy for untreated MDS/MPN and Relapsed/Refractory Overlap Syndromes) is an international cooperation that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides the framework for collaborative studies to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response. METHODS: ABNL MARRO 001 (AM-001) is an open label, randomly allocated phase 1/2 study that will test novel treatment combinations in MDS/MPNs, beginning with the novel targeted agent itacitinib, a selective JAK1 inhibitor, combined with ASTX727, a fixed dose oral combination of the DNMTi decitabine and the cytidine deaminase inhibitor cedazuridine to improve decitabine bioavailability. DISCUSSION: Beyond the primary objectives of the study to evaluate the safety and efficacy of novel treatment combinations in MDS/MPN, the study will (i) Establish the ABNL MARRO infrastructure for future prospective studies, (ii) Forge innovative scientific research that will improve our understanding of pathogenetic mechanisms of disease, and (iii) Inform the clinical application of diagnostic criteria, risk stratification and prognostication tools, as well as response assessments in this heterogeneous patient population. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov on August 19, 2019 (Registration No. NCT04061421).
Subject(s)
Myelodysplastic-Myeloproliferative Diseases , Quality of Life , Acetonitriles , Cytidine Deaminase , DNA/therapeutic use , Decitabine/therapeutic use , Humans , Methyltransferases , Prospective Studies , Pyrazoles , Pyrimidines , Pyrroles , SyndromeABSTRACT
Background: An understanding of the experience of patients with progressive fibrosing interstitial lung disease (PF-ILD) is needed to select appropriate patient-reported outcome measures (PROMs) to evaluate treatment effect in clinical trials. Methods: A systematic literature review was conducted to develop a preliminary conceptual model of the symptoms experienced by patients with PF-ILD and the impacts the disease has on them. An online survey and consensus meetings were then conducted with 12-14 stakeholders (patients, clinicians, regulatory and payer advisors) to refine the conceptual model and critically appraise how key concepts should be measured by PROMs. PROMs assessed included Living with Idiopathic Pulmonary Fibrosis, Living with Pulmonary Fibrosis, the King's Brief Interstitial Lung Disease questionnaire, Cough and Sputum Assessment Questionnaire, Evaluating Respiratory Symptoms, Leicester Cough Questionnaire, Functional Assessment of Chronic Illness Therapy (Dyspnoea/Fatigue) and St George's Respiratory Questionnaire for Idiopathic Pulmonary Fibrosis. Results: The literature review identified 36 signs/symptoms and 43 impacts directly or indirectly related to pulmonary aspects of PF-ILD. The most relevant symptoms identified by participants included shortness of breath on exertion, fatigue and cough; relevant impacts included effects on physical functioning, activities of daily living and emotional wellbeing. These are presented in a conceptual model. Consensus opinion was that existing PROMs need further modification and validation before use in clinical trials. Conclusions: The conceptual model improves understanding of the symptoms and impacts that living with PF-ILD has on patients' wellbeing. It can help to inform the choice of PROMs in clinical trials and highlight aspects to assess in the clinical care of patients with PF-ILD.
ABSTRACT
BACKGROUND: A multistep pathogenesis of myeloid leukemia including mutations in epigenetic, spliceosome, and signaling genes has been recently demonstrated in a preclinical model but is poorly validated in patients. METHODS: Clinical, phenotypic, and biologic features were compared between three distinct molecularly defined CMML cohorts including TET2 monomutated patients (T, n = 10), TET2/SRSF2 bimutated patients (TS, n = 19), and patients who had NRAS mutations in addition to TET2/SRSF2 comutations (TSN, n = 14). RESULTS: Median survival was 90, 45, and 9 months, respectively (p = .001). Whereas no patient in the T and TS group transformed into acute myeloid leukemia (AML), 6/14 patients in the TSN group had AML at study entry or transformed during follow-up. Leukocyte counts, blast cell counts, and LDH levels were significantly higher in TSN vs. TS and T, respectively, whereas hemoglobin and platelet values were not significantly different. Increased growth factor-independent myeloid colony formation was restricted to TSN but not found in T and TS, respectively. The proportion of patients showing in vitro myelomonocytic skewing in T, TS, and TSN was 0%, 56%, and 100%, respectively (p = .010). CONCLUSION: Our results demonstrate that the model of multistep pathogenesis in CMML can be recapitulated in patients regarding clinical, phenotypic, and biologic features.
Subject(s)
Biological Products , Leukemia, Myeloid, Acute , Leukemia, Myelomonocytic, Chronic , Humans , Leukemia, Myelomonocytic, Chronic/diagnosis , Leukemia, Myelomonocytic, Chronic/genetics , Mutation , PrognosisABSTRACT
Personalized medicine aims to match the right drug with the right patient by using specific features of the individual patient's tumor. However, current strategies of personalized therapy matching provide treatment opportunities for less than 10% of patients with cancer. A promising method may be drug profiling of patient biopsy specimens with single-cell resolution to directly quantify drug effects. We prospectively tested an image-based single-cell functional precision medicine (scFPM) approach to guide treatments in 143 patients with advanced aggressive hematologic cancers. Fifty-six patients (39%) were treated according to scFPM results. At a median follow-up of 23.9 months, 30 patients (54%) demonstrated a clinical benefit of more than 1.3-fold enhanced progression-free survival compared with their previous therapy. Twelve patients (40% of responders) experienced exceptional responses lasting three times longer than expected for their respective disease. We conclude that therapy matching by scFPM is clinically feasible and effective in advanced aggressive hematologic cancers. SIGNIFICANCE: This is the first precision medicine trial using a functional assay to instruct n-of-one therapies in oncology. It illustrates that for patients lacking standard therapies, high-content assay-based scFPM can have a significant value in clinical therapy guidance based on functional dependencies of each patient's cancer.See related commentary by Letai, p. 290.This article is highlighted in the In This Issue feature, p. 275.
Subject(s)
Hematologic Neoplasms/drug therapy , Adult , Aged , Aged, 80 and over , Austria , Cohort Studies , Female , Hematologic Neoplasms/mortality , Humans , Male , Middle Aged , Molecular Targeted Therapy , Precision Medicine , Progression-Free Survival , Young AdultABSTRACT
Mutations in chromatin regulator ASXL1 are frequently identified in myeloid malignancies, in particular â¼40% of patients with chronic myelomonocytic leukemia (CMML). ASXL1 mutations are associated with poor prognosis in CMML and significantly co-occur with NRAS mutations. Here, we show that concurrent ASXL1 and NRAS mutations defined a population of CMML patients who had shorter leukemia-free survival than those with ASXL1 mutation only. Corroborating this human data, Asxl1-/- accelerated CMML progression and promoted CMML transformation to acute myeloid leukemia (AML) in NrasG12D/+ mice. NrasG12D/+;Asxl1-/- (NA) leukemia cells displayed hyperactivation of MEK/ERK signaling, increased global levels of H3K27ac, upregulation of Flt3. Moreover, we find that NA-AML cells overexpressed all the major inhibitory immune checkpoint ligands: programmed death-ligand 1 (PD-L1)/PD-L2, CD155, and CD80/CD86. Among them, overexpression of PD-L1 and CD86 correlated with upregulation of AP-1 transcription factors (TFs) in NA-AML cells. An AP-1 inhibitor or short hairpin RNAs against AP-1 TF Jun decreased PD-L1 and CD86 expression in NA-AML cells. Once NA-AML cells were transplanted into syngeneic recipients, NA-derived T cells were not detectable. Host-derived wild-type T cells overexpressed programmed cell death protein 1 (PD-1) and T-cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) receptors, leading to a predominant exhausted T-cell phenotype. Combined inhibition of MEK and BET resulted in downregulation of Flt3 and AP-1 expression, partial restoration of the immune microenvironment, enhancement of CD8 T-cell cytotoxicity, and prolonged survival in NA-AML mice. Our study suggests that combined targeted therapy and immunotherapy may be beneficial for treating secondary AML with concurrent ASXL1 and NRAS mutations.
Subject(s)
Disease Models, Animal , GTP Phosphohydrolases/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myelomonocytic, Chronic/pathology , Membrane Proteins/genetics , Mutation , Repressor Proteins/genetics , Tumor Microenvironment , Animals , Humans , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/immunology , Leukemia, Myelomonocytic, Chronic/genetics , Leukemia, Myelomonocytic, Chronic/immunology , Mice , Monomeric GTP-Binding Proteins/genetics , Phenotype , Signal TransductionABSTRACT
Numerous examples in oncology have shown that better understanding the pathophysiology of a malignancy may be followed by the development of targeted treatment concepts with higher efficacy and lower toxicity as compared to unspecific treatment. The pathophysiology of chronic myelomonocytic leukemia (CMML) is heterogenous and complex but applying different research technologies have yielded a better and more comprehensive understanding of this disease. At the moment treatment for CMML is largely restricted to the unspecific use of cytotoxic drugs and hypomethylating agents (HMA). Numerous potential molecular targets have been recently detected by preclinical research which may ultimately lead to treatment concepts that will provide meaningful benefits for certain subgroups of patients.
ABSTRACT
BACKGROUND: Corticosteroid therapy (CST) prior to biopsy may hinder histopathological diagnosis in primary central nervous system lymphoma (PCNSL). Therefore, preoperative CST in patients with suspected PCNSL should be avoided if clinically possible. The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST. METHODS: A multicenter retrospective study including all immunocompetent patients diagnosed with PCNSL between 1/2004 and 9/2018 at four neurosurgical centers in Austria was conducted and the results were compared to literature. RESULTS: A total of 143 patients were included in this study. All patients showed visible contrast enhancement on preoperative MRI. There was no statistically significant difference in the rate of diagnostic surgeries with and without preoperative CST with 97.1% (68/70) and 97.3% (71/73), respectively (p = 1.0). Tapering and pause of CST did not influence the diagnostic rate. Including our study, there are 788 PCNSL patients described in literature with an odds ratio for inconclusive surgeries after CST of 3.3 (CI 1.7-6.4). CONCLUSIONS: Preoperative CST should be avoided as it seems to diminish the diagnostic rate of biopsy in PCNSL patients. Yet, if CST has been administered preoperatively and there is still a contrast enhancing lesion to target for biopsy, surgeons should try to keep the diagnostic delay to a minimum as the likelihood for acquiring diagnostic tissue seems sufficiently high.
Subject(s)
Adrenal Cortex Hormones/therapeutic use , Adrenal Cortex Hormones/pharmacology , Adult , Aged , Aged, 80 and over , Central Nervous System Neoplasms/pathology , Female , Humans , Lymphoma/pathology , Male , Middle Aged , Preoperative Period , Retrospective Studies , Young AdultABSTRACT
Proliferative chronic myelomonocytic leukemia (pCMML), an aggressive CMML subtype, is associated with dismal outcomes. RAS pathway mutations, mainly NRASG12D, define the pCMML phenotype as demonstrated by our exome sequencing, progenitor colony assays and a Vav-Cre-NrasG12D mouse model. Further, these mutations promote CMML transformation to acute myeloid leukemia. Using a multiomics platform and biochemical and molecular studies we show that in pCMML RAS pathway mutations are associated with a unique gene expression profile enriched in mitotic kinases such as polo-like kinase 1 (PLK1). PLK1 transcript levels are shown to be regulated by an unmutated lysine methyl-transferase (KMT2A) resulting in increased promoter monomethylation of lysine 4 of histone 3. Pharmacologic inhibition of PLK1 in RAS mutant patient-derived xenografts, demonstrates the utility of personalized biomarker-driven therapeutics in pCMML.
Subject(s)
Cell Cycle Proteins/genetics , GTP Phosphohydrolases/genetics , Histone-Lysine N-Methyltransferase/genetics , Leukemia, Myelomonocytic, Chronic/genetics , Membrane Proteins/genetics , Mutation , Myeloid-Lymphoid Leukemia Protein/genetics , Protein Serine-Threonine Kinases/genetics , Proto-Oncogene Proteins/genetics , Animals , Cell Cycle Proteins/metabolism , GTP Phosphohydrolases/metabolism , Gene Expression Profiling/methods , Gene Expression Regulation, Leukemic , Histone-Lysine N-Methyltransferase/metabolism , Kaplan-Meier Estimate , Leukemia, Myelomonocytic, Chronic/metabolism , Leukemia, Myelomonocytic, Chronic/therapy , Membrane Proteins/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Myeloid-Lymphoid Leukemia Protein/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/metabolism , Signal Transduction/genetics , Stem Cell Transplantation/methods , Transplantation, Homologous , Exome Sequencing/methods , Xenograft Model Antitumor Assays/methods , Polo-Like Kinase 1ABSTRACT
In older patients with chronic myelomonocytic leukaemia (CMML) and limited life expectancy due to age and or comorbidities, it is particularly important to consider the risk of transformation for individualised treatment decisions. There is limited information on potential differences between younger and older CMML patients regarding the cumulative risk of transformation as well as haematological, molecular and biologic characteristics. We analysed data from the Austrian Biodatabase for CMML (ABCMML) to compare these parameters in 518 CMML patients. Categorisation of patients into 3 age-related groups: <60 years, 60-79 years and ≥80 years, showed a significantly lower risk of transformation at higher age by competing risk analysis, with a 4-year risk of 39%, 23% and 13%, respectively (P < .0001). The lower probability of transformation was associated with a lower percentage of blast cells in the peripheral blood (PB) of older patients. Furthermore, we provide a simple score based on age, PB blasts and platelet counts that allowed us to define subgroups of CMML patients with a different cumulative transformation risk, including a low-risk group with a transformation risk of only 5%. Our findings may facilitate reasonable treatment decisions in elderly patients with CMML.
Subject(s)
Health Impact Assessment , Leukemia, Myelomonocytic, Chronic/epidemiology , Leukemia, Myelomonocytic, Chronic/pathology , Adult , Age Factors , Aged , Aged, 80 and over , Biomarkers, Tumor , Comorbidity , Disease Progression , Disease Susceptibility , Female , Humans , Leukemia, Myelomonocytic, Chronic/etiology , Leukemia, Myelomonocytic, Chronic/mortality , Male , Middle Aged , Odds Ratio , PrognosisABSTRACT
BACKGROUND: Copanlisib, an intravenous pan-class I PI3K inhibitor, showed efficacy and safety as monotherapy in patients with relapsed or refractory indolent non-Hodgkin lymphoma who had received at least two therapies. The CHRONOS-3 study aimed to assess the efficacy and safety of copanlisib plus rituximab in patients with relapsed indolent non-Hodgkin lymphoma. METHODS: CHRONOS-3 was a multicentre, double-blind, randomised, placebo-controlled, phase 3 study in 186 academic medical centres across Asia, Australia, Europe, New Zealand, North America, Russia, South Africa, and South America. Patients aged 18 years and older with an Eastern Cooperative Oncology Group performance status of no more than 2 and histologically confirmed CD20-positive indolent B-cell lymphoma relapsed after the last anti-CD20 monoclonal antibody-containing therapy and progression-free and treatment-free for at least 12 months, or at least 6 months for patients unwilling or unfit to receive chemotherapy, were randomly assigned (2:1) with an interactive voice-web response system via block randomisation (block size of six) to copanlisib (60 mg given as a 1-h intravenous infusion on an intermittent schedule on days 1, 8, and 15 [28-day cycle]) plus rituximab (375 mg/m2 given intravenously weekly on days 1, 8, 15, and 22 during cycle 1 and day 1 of cycles 3, 5, 7, and 9) or placebo plus rituximab, stratified on the basis of histology, progression-free and treatment-free interval, presence of bulky disease, and previous treatment with PI3K inhibitors. The primary outcome was progression-free survival in the full analysis set (all randomised patients) by masked central review. Safety was assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT02367040 and is ongoing. FINDINGS: Between Aug 3, 2015, and Dec 17, 2019, 652 patients were screened for eligibility. 307 of 458 patients were randomly assigned to copanlisib plus rituximab and 151 patients were randomly assigned to placebo plus rituximab. With a median follow-up of 19·2 months (IQR 7·4-28·8) and 205 total events, copanlisib plus rituximab showed a statistically and clinically significant improvement in progression-free survival versus placebo plus rituximab; median progression-free survival 21·5 months (95% CI 17·8-33·0) versus 13·8 months (10·2-17·5; hazard ratio 0·52 [95% CI 0·39-0·69]; p<0·0001). The most common grade 3-4 adverse events were hyperglycaemia (173 [56%] of 307 patients in the copanlisib plus rituximab group vs 12 [8%] of 146 in the placebo plus rituximab group) and hypertension (122 [40%] vs 13 [9%]). Serious treatment-emergent adverse events were reported in 145 (47%) of 307 patients receiving copanlisib plus rituximab and 27 (18%) of 146 patients receiving placebo plus rituximab. One (<1%) drug-related death (pneumonitis) occurred in the copanlisib plus rituximab group and none occurred in the placebo plus rituximab group. INTERPRETATION: Copanlisib plus rituximab improved progression-free survival in patients with relapsed indolent non-Hodgkin lymphoma compared with placebo plus rituximab. To our knowledge, copanlisib is the first PI3K inhibitor to be safely combined with rituximab and the first to show broad and superior efficacy in combination with rituximab in patients with relapsed indolent non-Hodgkin lymphoma. FUNDING: Bayer.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Non-Hodgkin/drug therapy , Phosphoinositide-3 Kinase Inhibitors/administration & dosage , Pyrimidines/administration & dosage , Quinazolines/administration & dosage , Rituximab/administration & dosage , Aged , Double-Blind Method , Female , Humans , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Pyrimidines/adverse effects , Quinazolines/adverse effects , Recurrence , Rituximab/adverse effects , Rituximab/therapeutic useABSTRACT
Chronic myelomonocytic leukemia (CMML) is a stem cell-derived neoplasm characterized by dysplasia, uncontrolled expansion of monocytes, and substantial risk to transform to secondary acute myeloid leukemia (sAML). So far, little is known about CMML-initiating cells. We found that leukemic stem cells (LSC) in CMML reside in a CD34+/CD38- fraction of the malignant clone. Whereas CD34+/CD38- cells engrafted NSGS mice with overt CMML, no CMML was produced by CD34+/CD38+ progenitors or the bulk of CD34- monocytes. CMML LSC invariably expressed CD33, CD117, CD123 and CD133. In a subset of patients, CMML LSC also displayed CD52, IL-1RAP and/or CLL-1. CMML LSC did not express CD25 or CD26. However, in sAML following CMML, the LSC also expressed CD25 and high levels of CD114, CD123 and IL-1RAP. No correlations between LSC phenotypes, CMML-variant, mutation-profiles, or clinical course were identified. Pre-incubation of CMML LSC with gemtuzumab-ozogamicin or venetoclax resulted in decreased growth and impaired engraftment in NSGS mice. Together, CMML LSC are CD34+/CD38- cells that express a distinct profile of surface markers and target-antigens. During progression to sAML, LSC acquire or upregulate certain cytokine receptors, including CD25, CD114 and CD123. Characterization of CMML LSC should facilitate their enrichment and the development of LSC-eradicating therapies.