Development of novel therapies in MDS Mitani, Kinuko
Hematology, Transfusion and Cell Therapy,
October 2020, 2020-10-00, 2020-10-01, Volume:
42
Journal Article
The purpose of this trial was to evaluate the efficacy of 2-year consolidation therapy with nilotinib, at a dose of 300 mg twice daily, for achieving treatment-free remission in chronic myeloid ...leukemia patients with a deep molecular response (
≤0.0032%). Successful treatment-free remission was defined as no confirmed loss of deep molecular response. We recruited 96 Japanese patients, of whom 78 sustained a deep molecular response during the consolidation phase and were therefore eligible to discontinue nilotinib in the treatment-free remission phase; of these, 53 patients (67.9%; 95% confidence interval: 56.4-78.1%) remained free from molecular recurrence in the first 12 months. The estimated 3-year treatment-free survival was 62.8%. Nilotinib was readministered to all patients (n=29) who experienced a molecular recurrence during the treatment-free remission phase. After restarting treatment, rapid deep molecular response returned in 25 patients (86.2%), with 50% of patients achieving a deep molecular response within 3.5 months. Tyrosine kinase inhibitor withdrawal syndrome was reported in 11/78 patients during the early treatment-free remission phase. The treatment-free survival curve was significantly better in patients with undetectable molecular residual disease than in patients without (3-year treatment-free survival, 75.6
48.6%, respectively;
=0.0126 by the log-rank test). There were no significant differences in treatment-free survival between subgroups based on tyrosine kinase inhibitor treatment before the nilotinib consolidation phase, tyrosine kinase inhibitor-withdrawal syndrome, or absolute number of natural killer cells. The results of this study indicate that it is safe and feasible to stop tyrosine kinase inhibitor therapy in patients with chronic myeloid leukemia who have achieved a sustained deep molecular response with 2 years of treatment with nilotinib. This study was registered with UMIN-CTR (UMIN000005904).
Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study ...showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.
Acute myeloid leukemia (AML) is a hematologic malignancy that frequently relapses, even if remission can be achieved with intensive chemotherapy. One known relapse mechanism is the escape of leukemic ...cells from immune surveillance. Currently, there is no effective immunotherapy for AML because of the lack of specific antigens. Here, we aimed to elucidate the association between CD155 and CD112 in AML cell lines and primary AML samples and determine the therapeutic response. Briefly, we generated NK-92 cell lines (NK-92) with modified DNAX-associated molecule 1 (DNAM-1) and T-cell immunoglobulin and ITIM domain (TIGIT), which are receptors of CD155 and CD112, respectively. Analysis of 200 cases of AML indicated that the survival of patients with high expression of CD112 was shorter than that of patients with low expression. NK-92 DNAM-1 exhibited enhanced cytotoxic activity against AML cell lines and primary cells derived from patients with AML. DNAM-1 induction in NK-92 cells enhanced the expression of cytotoxicity-related genes, thus overcoming the inhibitory activity of TIGIT. Between CD155 and CD112, CD112 is an especially important target for natural killer (NK)-cell therapy of AML. Using a xenograft model, we confirmed the enhanced antitumor effect of NK-92 DNAM-1 compared with that of NK-92 alone. We also discovered that CD112 (Nectin-2), an immune checkpoint molecule belonging to the Nectin/Nectin-like family, functions as a novel target of immunotherapy. In conclusion, modification of the DNAM-1/CD112 axis in NK cells may be an effective novel immunotherapy for AML. Furthermore, our findings suggest that the levels of expression of these molecules are potential prognostic markers in AML.
Abstract
Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show ...that disruption of the
Gdpd3
gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that
Gdpd3
deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of
Gdpd3
also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/β-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of
Lgr4/Gpr48
, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.
The AML1/EVI-1 chimeric gene is generated by the t(3;21)(q26;q22) translocation and plays a pivotal role in progression of hematopoietic stem cell malignancies such as chronic myelocytic leukemia and ...myelodysplastic syndrome. In AML1/EVI-1, an N-terminal half of AML1 including a runt homology domain is fused to the entire zinc-finger EVI-1 protein. AML1 is essential for hematopoietic cell development in fetal liver and its lineage-specific differentiation in adult. In contrast, EVI-1 is barely expressed in normal hematopoietic cells, but it is overexpressed in chronic myelocytic leukemia in blastic crisis and myelodysplastic syndrome-derived leukemia. There are at least four mechanisms identified in AML1/EVI-1 fusion protein that possibly lead into malignant transformation of hematopoietic stem cells. Firstly, AML1/EVI-1 exerts dominant-negative effects over AML1-induced transcriptional activation. Although target genes repressed by AML1/EVI-1 are still not known, binding competition to a specific DNA sequence and histone deacetylase recruitment through a co-repressor CtBP in EVI-1 part are conceivable underlying mechanisms for the dominant-negative effects. Secondly, AML1/EVI-1 interferes with TGF beta signaling and antagonizes the growth-inhibitory effects of TGF beta. The first zinc-finger domain of EVI-1 associates with Smad3, a TGF beta signal transducer, and represses its transcriptional activity by recruiting histone deacetylase through CtBP that interacts with EVI-1. Thirdly, AML1/EVI-1 blocks JNK activity and prevents stress-induced apoptosis. AML1/EVI-1 associates with JNK through the first zinc-finger domain of EVI-1 and disturbs the association between JNK and its substrates. Lastly, AML1/EVI-1 enhances AP-1 activity by activating the c-Fos promoter depending on the second zinc-finger domain of EVI-1, and promotes cell proliferation. All these functions cooperatively contribute to the malignant transformation of the hematopoietic stem cells by AML1/EVI-1.
Tyrosine kinase inhibitors (TKIs) are standard therapies for chronic myeloid leukemia (CML) that can eradicate Ph-positive leukemic cells. However, disease control is not achievable in a minority of ...cases, most commonly due to evolution of TKI-resistant clones. There have also been rare cases of emergence of Ph-negative clones with other cytogenetic abnormalities, and, less commonly, development of Ph-negative acute myeloid leukemia (AML), whose molecular pathogenesis is largely unknown. Here we report molecular features of a patient with Ph + CML who developed Ph-negative AML after showing a major molecular response to dasatinib. A 55-year-old man was diagnosed with CML. He achieved a complete cytogenetic response three months after dasatinib therapy but developed AML with normal karyotype 1 year later. After receiving induction and consolidation chemotherapy for AML, the patient achieved complete remission with no evidence of CML under maintenance with bosutinib. Targeted sequencing of serial bone marrow samples identified mutations in IDH2 and NPM1 in the Ph-negative AML cells, which had not been detected in CML cells. These results suggest that Ph-negative AML in this patient originated from a preleukemic population, which might have expanded during or after the successful elimination of CML clones with TKI therapy.
Comprehensive cancer genome profiling (CGP) has been nationally reimbursed in Japan since June 2019. Less than 10% of the patients have been reported to undergo recommended treatment. Todai OncoPanel ...(TOP) is a dual DNA–RNA panel as well as a paired tumor–normal matched test. Two hundred patients underwent TOP as part of Advanced Medical Care B with approval from the Ministry of Health, Labour and Welfare between September 2018 and December 2019. Tests were carried out in patients with cancers without standard treatment or when patients had already undergone standard treatment. Data from DNA and RNA panels were analyzed in 198 and 191 patients, respectively. The percentage of patients who were given therapeutic or diagnostic recommendations was 61% (120/198). One hundred and four samples (53%) harbored gene alterations that were detected with the DNA panel and had potential treatment implications, and 14 samples (7%) had a high tumor mutational burden. Twenty‐two samples (11.1%) harbored 30 fusion transcripts or MET exon 14 skipping that were detected by the RNA panel. Of those 30 transcripts, 6 had treatment implications and 4 had diagnostic implications. Thirteen patients (7%) were found to have pathogenic or likely pathogenic germline variants and genetic counseling was recommended. Overall, 12 patients (6%) received recommended treatment. In summary, patients benefited from both TOP DNA and RNA panels while following the same indication as the approved CGP tests. (UMIN000033647).
Todai OncoPanel (TOP) is a dual DNA‐RNA panel as well as a paired tumor‐normal matched test. Pharmaceuticals and Medical Devices Agency (PMDA) indications for comprehensive cancer genomic profiling were followed in this study. The percentage of patients who were given therapeutic or diagnostic recommendations was 61%, including patients with fusion or MET exon 14 skipping transcripts that led to recommendations.
Abstract
Background
Neurolymphomatosis (NL) is a rare manifestation of malignant lymphoma that shows selective infiltration to the peripheral nervous system primarily or secondarily. We report a ...patient with secondary NL caused by germinal center B-cell (GCB)-type diffuse large B-cell lymphoma (DLBCL) who showed selective infiltration of the lumbar plexus to the spinal cord and massive nerve enlargement resulting in severe pain.
Case presentation
A 72-year-old female exhibited asymmetric motor and sensory impairments and pain in the lower limbs that progressed for five months. Magnetic resonance imaging (MRI) showed an enlarged lumbar plexus, which continued to the cauda equina via the L3 and L4 spinal nerves. Her symptoms gradually worsened. Ten months after the onset of symptoms, the enlarged cauda equina filled the spinal canal space, and the spinal cord was swollen. A cauda equina biopsy was performed, and she was diagnosed with GCB-type DLBCL with CD10 positivity. The primary tumor was found in a mammary cyst. The autopsy study did not show apparent infiltration, except in the nervous system.
Conclusions
Although there are many neurologic phenotypes of malignant lymphoma, the association between the cytological characteristics of lymphoma and the neurological phenotypes is still unclear. Several reports of CD10-positive secondary NL are available, whereas peripheral or central nervous tissue origin lymphoma cases are mostly negative for CD10. CD10 staining may be useful for distinguishing primary NL from secondary NL. NL often has a strong organotropism for peripheral nervous tissue, which makes early diagnosis challenging.
•Lower respiratory tract infection (LRTI) is a feared complication of influenza virus infection in allogeneic hematopoietic stem cell transplantation recipients.•The risk factors and demographics of ...LRTI are discussed in a large cohort.•Early neuraminidase inhibitor therapy reduces the risk of progression to LRTI in these patients.
Influenza virus infection (IVI) occasionally causes lower respiratory tract infection (LRTI) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Although the progression to LRTI entails a high mortality, the role of early antiviral therapy for its prevention has not been fully elucidated.
This was a multicenter retrospective study using an additional questionnaire. Allo-HSCT recipients who developed IVI between 2012 and 2020 were included.
A total of 278 cases of IVI after allo-HSCT were identified from 15 institutions. The median patient age was 49 years, and the median time from allo-HSCT to IVI was 918 days. Neuraminidase inhibitors were administered within 48 hours of symptom onset (early neuraminidase inhibitor NAI) in 199 (76.9%) patients. Subsequently, 36 (12.3%) patients developed LRTI. On the multivariate analysis, age ≥50 years (hazard ratio HR, 2.16; 95% confidence interval CI, 1.02-4.58) and moderate to severe chronic graft-versus-host disease (HR, 2.28; 95% CI, 1.14-4.58) were significantly associated with progression to LRTI, whereas early NAI suppressed the progression (HR, 0.17; 95% CI, 0.06-0.46). The IVI-related mortality rate was 2.2%.
To reduce the risk of LRTI development after IVI, early NAI therapy should be considered in allo-HSCT recipients, especially with older patients and those with chronic graft-versus-host disease.
Display omitted
PDF
