Leukemia Research Reports最新文献

Intermittent low dose dasatinib therapy brought about a beneficial effect in elderly patients with chronic-phase chronic myeloid leukemia (CML-CP) without inducing severe adverse events (AEs). An 85-year-old male patient, who received twice-weekly, thrice-weekly, or four-times-weekly administration of 20 mg/day dasatinib after once-weekly administration, achieved a major molecular response two years after the start of dasatinib treatment and later sometimes achieved a deep molecular response, maintaining the efficacy for 11 years. The mean daily dose ranged from 5.7 mg to 11.4 mg. Furthermore, a 79-year-old male patient, who received thrice-weekly or every other day administration of 20 mg/day dasatinib after once-weekly administration, achieved a deep molecular response at four and half years after the start of dasatinib treatment. The mean daily dose is 8.6 mg. Intermittent low dose dasatinib therapy appears to be feasible in elderly patients with CML-CP. The goal of treatment in elderly patients with CML-CP appears to be different from that in younger patients, since they often suffer from serious AEs in the case of standard dose tyrosine kinase inhibitor therapy, followed by the dose reduction or cessation of treatment.

Hemophagocytic Lymphohistiocytosis is an inflammatory condition which results in over activation of the immune system. It could be either sporadic or familial. The familial subtype is linked with various genetic mutations and is commonly a disease of the young. Here we report a case of HLH in an adult, occurring in the background of a successfully treated hematological malignancy. Upon workup, he was also found to have pathogenic STXBP2 mutation, suggesting HLH of familial origin. To date, only few cases of adult-onset familial HLH have been brought to light.

Preventing central nervous system (CNS) relapse is a major challenge in the treatment of diffuse large B-cell lymphoma (DLBCL). However, no previous studies have examined the efficacy of polatuzumab vedotin (PV)-containing regimens in preventing CNS relapse in patients with DLBCL. Here, we report two cases of CNS relapse after PV-containing chemotherapy for DLBCL. CNS relapse developed during combination therapy with PV, bendamustine, and rituximab (PV-BR) in one patient and six months after PV-BR in the other patient. PV-containing chemotherapy may be ineffective as a prophylaxis against CNS relapse; therefore, additional strategies for preventing CNS relapse in DLBCL patients are required.

Introduction

While genetic aberrations are becoming increasingly critical in disease classification, morphological abnormalities defined by a 10% threshold in each lineage continue to play a significant role as a diagnostic tool for myelodysplastic neoplasms (MDS). However, erythroid lineage dysplasia has been reported in some cases of aplastic anemia (AA), a phenomenon noted as common in the UK guidelines.

Methods

We assessed the impact of erythroid dysplasia on the survival in AA patients enrolled in an ongoing prospective registry, central morphological review (blinded), and follow-up study of AA and MDS conducted by the Japanese National Research Group on Idiopathic Bone Marrow Failure Syndromes. Furthermore, we compared the prognosis of AA patients with erythroid dysplasia with that of patients diagnosed in the same study with MDS presenting with single-lineage erythroid dysplasia (“MDS-SLED”). According to this study's definition, the criteria for excluding MDS are stringent, considering both bone marrow cellularity and megakaryocyte counts. Therefore, AA is not diagnosed when a decrease is not observed in the megakaryocyte count.

Results

The study included a total of 32 cases of AA with erythroid dysplasia, 56 cases of AA without dysplasia, and 47 cases of MDS-SLED. The overall survival or leukemia-free survival showed no significant difference between AA patients with and without erythroid dysplasia (both p=0.14). Nevertheless, distinct differences were seen between AA with erythroid dysplasia and those diagnosed with MDS-SLED (both p<0.0001).

Conclusions

Erythroid dysplasia should not exclude an AA diagnosis. In particular, megakaryocyte count plays an important role in differentiating between MDS from AA.

Introduction

Accurate risk assessment of bone marrow failure syndrome (BMFS) is crucial for early diagnosis and intervention.

Methods

We used complete blood count (CBC) data to develop a predictive model for BMFS. Retrospective CBC data were collected from Seoul National University Hospital and Seoul St. Mary's Hospital of the Catholic Medical Center in South Korea. We developed binary classifiers for aplastic anaemia (AA) and myelodysplastic syndrome (MDS) and generated a BMFS classifier to determine the maximum probability. Classifiers were developed using multiple feature sets consisting of 13, 17, 25, or 28 CBC features to ensure applicability to various CBC testing settings. Performance was evaluated using the area under the receiver operating characteristic curve (AUROC).

Results

XGBoost achieved the best AUROCs, 0·953–0·961 for the AA classifier and 0·910–0·935 for the MDS classifier, across multiple CBC feature sets. The BMFS classifier, combining the AA and MDS classifiers, demonstrated an AUROC of 0·915–0·936. When using cut-off probabilities to achieve a 95% sensitivity, the specificities ranged from 68% to 79%. External validation on an independent dataset yielded an AUROC of 0·932–0·942, a sensitivity of 93–96%, and a specificity of 65–82% at the aforementioned cut-offs.

Conclusions

Our predictive model provides a practical guide for diagnosing BMFS based on basic demographics and CBC data available during the first clinical encounter. It provides a reliable risk assessment tool for primary physicians, facilitating a more effective triage, timely referrals, and improved patient care.

Introduction

Decitabine (DAC) is an epigenetic drug clinically used for the treatment of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, its exact mechanism of action is unclear.

Methods

To uncover the mechanisms underlying resistance to HMA, we performed genome-scale CRISPR activation screen using murine MDS/AML cells expressing ASXL1 and SETBP1 mutants (cSAM).

Results

Our genome-wide CRISPR-dCas9 activation screen using MDS-derived AML cells indicates that mitotic regulation is critical for DAC resistance. DAC strongly induces abnormal mitosis (abscission failure or tripolar mitosis) in human myeloid tumors at clinical concentrations, especially in those with TP53 mutations or antecedent hematological disorders. This DAC-induced mitotic disruption and apoptosis are significantly attenuated in DNMT1-depleted cells. In contrast, overexpression of Dnmt1, but not the catalytically inactive mutant, enhances DAC-induced mitotic defects in myeloid tumors. We also demonstrate that DAC-induced mitotic disruption is enhanced by pharmacological inhibition of the ATR-CLSPN-CHK1 pathway. In addition, transcriptome and metabolome analyses combined with our screen revealed the involvement of cholesterol metabolism in DAC resistance. Inhibition of cholesterol synthesis using statins delayed mitotic progression, suggesting that cholesterol is also important for proper mitosis. Moreover, co-treatment with DAC and statin caused mitotic catastrophe and showed synergistic growth-inhibitory effects in leukemia cells.

Conclusions

These data challenge the current assumption that DAC inhibits leukemogenesis through DNMT1 inhibition and subsequent DNA hypomethylation and highlight the potent activity of DAC to disrupt mitosis through aberrant DNMT1-DNA covalent bonds.

An 82-year-old man with Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) complicated by hepatocarcinoma was presented. Remission induction therapy of hyper-CVAD with half dose reduction achieved hematological complete remission (CR), but accompanied with elevated alanine aminotransferase and hyperbilirubinemia. The patient was thought intolerable for hyper-CVAD with half dose reduction due to liver toxicity, and treatment was switched to blinatumomab. Hematological CR was sustained after nine cycles of blinatumomab without exacerbation of liver dysfunction. After five courses of blinatumomab, hepatocarcinoma was treated successfully by trans-arterial chemoembolization. Two years after the diagnosis of ALL, the patient was alive in CR status of ALL.

The t(10;17)(p15;q21) translocation is a very rare recurrent cytogenetic aberration, and produced ZMYND11::MBTD1 fusion gene. To date, nine cases of acute leukemia with the t(10;17)(p15;q21) translocation have been reported, but the case of AML with ZMYND11::MBTD1 after chemotherapy and radiotherapy have not been reported. Epirubicin-based chemotherapy or radiotherapy for breast cancer increases the risk of developing secondary leukemia. We report a case of AML with the ZMYND11::MBTD1 fusion gene that developed after epirubicin-based chemotherapy and radiotherapy for breast cancer. previous chemotherapy and radiotherapy may be associated with poor prognosis of AML with ZMYND11/MBTD1.

Introduction

The 5q- deletion is macrocytic anemia syndrome with special clinical characteristics and relatively longer median survival with low probability of AML progression. The classification of this disease as MDS is still under debates. Molecular studies, such as tracking the leukemia-associated marker BAALC, may clarify this issue. Here we evaluated BAALC-expressing stem cells (BAALC-e SCs) in patient's with isolated 5q- syndrome and with different chromosomal abnormalities.

Methods

The study includes analysis of bone marrow (BM) from 16 patients with isolated 5q deletion and 15 samples of 5q- combined with additional non-identical chromosomal abnormalities. BMs from 10 MDS patients without 5q- but carrying other cytogenetic aberrations were studied as control group. Serial measurements of BAALC-e SCs were performed by qPCR using BAALC RQ Kit (Inogene, Russia). Cytogenetic study included standard karyotyping and FISH.

Results

The data analysis revealed that only 10% (2/16) of patients with isolated 5q- had BAALC gene overexpression. Further on, low BAALC-expressing stem cells were characteristic also in the group of 5q- combined with additional non-identical chromosomal aberrations (56%). Meanwhile, in control group this rate was higher (100%).

Conclusions

The presented data of BAALC-e SCs burdens in patients with isolated 5q- syndrome indicate that this pathology differs from typical MDS and can be considered as ribosomopathy with low risk of transformation to MDS or AML. From this position, the biological advantages of 5q deletion syndrome are obvious as an optimal clinical model for further study of MDS and AML formation at the level of leukemia-initiating cells.