Annals of Hematology最新文献

Selected chronic myeloid leukemia (CML) patients may discontinue their tyrosine kinase inihibitor (TKI) in an attempt to achieve sustained treatment-free remission (TFR), which mitigates therapy-related side effects and limits treatment costs. TFR has been extensively studied following the discontinuation of adenosine triphosphate (ATP) - competitive TKI. However, there is minimal data concerning TFR after the discontinuation of the novel TKI asciminib. Here, we present two CML patients intolerant to multiple ATP-competitive TKIs who achieved a deep molecular response (DMR) during asciminib treatment and sustained this remission after asciminib discontinuation. One of the cases developed transient myalgia and arthralgia after asciminib discontinuation consistent with a TKI withdrawal syndrome. Both patients have been free of molecular relapse for more than at least 8 months after TKI discontinuation without increase in molecular BCR::ABL1 signal. These two cases provide proof of principle that sustained TFR after discontinuing asciminib in CML patients is feasible.

Research on the comprehensive integration of clinical and genomic characteristics in patients with core binding factor acute myeloid leukemia (CBF-AML) is limited. Clinical and genomic data from consecutive patients with CBF-AML were reviewed. A Cox regression model was used to identify the variables associated with event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). A total of 346 CBF-AML patients (211 with RUNX1::RUNX1T1 and 135 with CBFB::MYH11) were included in this study. In the RUNX1::RUNX1T1 cohort, multivariate analyses revealed that KDM6A mutations were significantly associated with poor RFS (hazard ratio = 3.1 [1.4, 7.1], p = 0.007) and OS (HR = 11.5 [3.6, 37.0], p < 0.001); FLT3-TKD mutations, poor OS (HR = 4.9 [1.7, 14.3], p = 0.004); KIT mutation VAF > 25%, poor RFS (KIT^wt as ref, HR = 2.5 [1.1, 5.3], p = 0.022); ASXL1 mutations, favorable EFS (HR = 0.4 [0.2, 0.9], p = 0.016) and OS (HR = 0.2 [0.03, 0.8], p = 0.028). In the CBFB::MYH11 cohort, multivariate analyses revealed that a high mutation burden was significantly associated with inferior OS (HR = 1.4 [1.1, 1.8], p = 0.018); FLT3-ITD mutations, inferior OS (HR = 6.8 [1.3, 36.0], p = 0.024). In addition, increasing age, nonintensive chemotherapy, and high MRD levels predict poor outcomes in the RUNX1::RUNX1T1 cohort. In addition to the adverse impact of high KIT mutation burden and FLT3-ITD or FLT3-TKD mutations on prognosis in CBF-AML, KDM6A mutations predicted poor outcomes in patients with RUNX1::RUXN1T1; however, ASXL1 mutations, favourable outcomes; high mutation burden, poor outcomes in those with CBFB::MYH11.

T-cell Acute Lymphoblastic Leukemia (T-ALL) is a subtype of acute lymphoblastic leukemia characterized by the proliferation of abnormal T-cell precursors. Nelarabine, a purine analog, has been approved as a targeted therapy for patients with refractory or relapsed T-ALL. This study aims to evaluate the efficacy and safety of Nelarabine, either as monotherapy or in combination with other therapies, in treating T-ALL. A systematic review and meta-analysis were conducted following PRISMA guidelines. We searched Cochrane CENTRAL, PubMed, and Google Scholar up to August 2024 for studies evaluating Nelarabine's efficacy and safety in T-ALL patients. The primary outcome was complete response (CR), with secondary outcomes focusing on adverse events (AEs). Data were analyzed using a random effects model, with statistical significance set at p ≤ 0.05. Sixteen studies involving 1,865 patients were included, with 1,345 receiving Nelarabine. The pooled analysis revealed a CR rate of 37.9% (95% CI: 20.5-55.4%, p < 0.001) for Nelarabine monotherapy. Significant adverse events included neutropenia at 29.1% (95% CI: 9.1-49.1%, p < 0.001), thrombocytopenia at 32.4% (95% CI: 14.8-50.0%, p < 0.001), peripheral motor neuropathy at 17.1% (95% CI: 4.2-30.1%, p = 0.001), and peripheral sensory neuropathy at 15.3% (95% CI: 5.8-24.9%, p = 0.003). For combination therapy, infections occurred in 65.0% (95% CI: 27.1-103.0%, p < 0.001) of patients, febrile neutropenia in 48.7% (95% CI: -8.8-106.3%, p < 0.001), peripheral motor neuropathy in 10.5% (95% CI: 7.9-13.0%, p < 0.001), and peripheral sensory neuropathy in 23.1% (95% CI: 10.6-35.7%, p < 0.001). Nelarabine shows significant efficacy in treating refractory or relapsed T-ALL, with notable CR rates. However, its use, both as monotherapy and in combination therapy, is associated with considerable adverse events, particularly neurotoxicity and hematologic toxicities, necessitating careful monitoring. Further research is needed to optimize its application across diverse patient populations and to better manage its associated toxicities.

To compare the efficacy and safety of pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) and rhG-CSF in the recovery of neutrophils after induction therapy in ALL patients, PEG-rhG-CSF was injected subcutaneously within 24 ~ 48 h after the end of intravenous infusion of daunorubicin/idarubicin during induction chemotherapy. In rhG-CSF group, patients were given rhG-CSF. The main outcome indexes were the incidence and duration of grade 4 chemotherapy-induced-neutropenia (CIN, ANC less than 0.5 × 10⁹/L), the incidence of severe agranulocytosis (ANC less than 0.2 × 10⁹/L). The incidence of grade 4 CIN in the PEG-rhG-CSF group was significantly lower than that in the rhG-CSF group (P = 0.007). There was no significant difference in the incidence of severe neutrophil deficiency and the median time of neutrophil deficiency in PEG-rhG-CSF group and rhG-CSF group. There was no significant difference in day 28 complete response (CR) rate of bone marrow cytology between the two groups (P = 0.985). Compared with rhG-CSF, PEG-rhG-CSF can reduce the incidence of agranulocytosis after induction chemotherapy in newly diagnosed ALL patients, without affecting the efficacy of chemotherapy. Meanwhile, it can reduce the pain of patients, with good safety and tolerance.

Although survival rates for patients with newly diagnosed multiple myeloma (NDMM) have improved over recent decades, multiple myeloma (MM) remains without a cure for most. There is increasing consensus that achievement of deep remissions, especially minimal residual disease negativity (MRD -), in frontline treatment is crucial and translates into improved survival. The standard of care (SOC) for NDMM consists at minimum of a triplet regimen of therapies, with or without an autologous stem cell transplant, or a doublet regimen for certain ineligible, particularly frail patients who may have specific limitations. Recently, anti-CD38 monoclonal antibodies (mAbs), such as daratumumab (Dara) or isatuximab (Isa), have been integrated into frontline SOC regimens. Seeking to further deepen and prolong responses, several clinical trials have commenced investigating the addition of anti-CD38 mAbs to carfilzomib, lenalidomide, and dexamethasone (KRd). These quadruplet regimens (Isa/Dara-KRd) are being evaluated in the context of evolving treatment considerations for the heterogeneous population of patients with NDMM. In clinical trials, the addition of Isa/Dara to KRd achieved high rates of deep responses and MRD - . Favorable outcomes were observed in patients with NDMM independent of age, transplant eligibility, and cytogenetic risk, while these treatments did not result in unexpected or emergent safety risks. The efficacy observed with intensified, yet well-tolerated therapy may offer further development of risk- and response-adapted therapy for individualized patient needs. This review summarizes the clinical outcomes of quadruplet-based therapy with Isa/Dara-KRd in NDMM.

Langerhans cell histiocytosis (LCH) is a heterogeneous histiocytosis with various pulmonary manifestations and imaging. We aim to evaluate the pulmonary response of LCH by high resolution chest computed tomography (HRCT) through continuous follow-up.We conducted a retrospective analysis of 73 adult LCH patients with pulmonary involvement. HRCT response was assessed by the change of HRCT global score (nodule score plus cyst score) between the baseline and after therapy. Among them, 69 patients (94.5%) had multi-system LCH with pulmonary involvement. 42 patients received methotrexate and cytarabine regimen, 15 received cytarabine monotherapy, 7 underwent target therapy. 14 (19.2%) achieved complete response (CR) and 45 (61.6%) achieved partial response (PR). The mean global lung-lesion score decreased from 12.2 to 10.6. The mean nodule score decreased from 4.7 to 4.1 and the mean cyst score decreased from 7.4 to 6.5. Overall, 25 (34.2%) exhibited an HRCT response and 3 (4.1%) had HRCT progression, while 45 (61.6%) maintained the same. Among patients with CR or PR, 57.1% and 40.5%, respectively, experienced an HRCT response, whereas no patient with SD or PD had an HRCT response. Multivariable analyses revealed that patients who received low dose cytarabine regimen and those with HRCT score ≥ 10 predicted a shorter PFS. Long Chang, Luo Wang, and Zheng-zheng Liu contributed equally to this work.

Chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia patients largely benefit from an expanding tyrosine kinase inhibitors (TKIs) toolbox that has improved the outcome of both diseases. However, TKI success is continuously challenged by mutation-driven acquired resistance and therefore, close monitoring of clonal genetic diversity is necessary to ensure proper clinical management and adequate response to treatment. Here, we report the case of a ponatinib-resistant Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) patient harboring a BCR::ABL1 p.I293_K294insSLLRD mutation. Using in vitro proliferation assays on newly generated Ba/F3 cell lines, we confirmed that the mutation confers moderate resistance to ponatinib, and to imatinib and nilotinib. In contrast, BCR::ABL1^SLLRD Ba/F3 cells remain highly sensitive to dasatinib. Unexpectedly, the insertion also provides resistance to asciminib with no inhibitory effect up to 1000 nM. Based on predicted structural models, we speculate that the p.I293_K294insSLLRD disrupts the interaction between the SH3 domain and the kinase domain, shifting the equilibrium toward the active conformation. This shift confers resistance to TKIs that preferentially bind to the inactive conformation, as well as to the allosteric asciminib inhibitor. However, the mutation retains sensitivity to dasatinib, which targets the active form of the kinase.