Leukemia & Lymphoma最新文献

Despite increasing utilization of CAR T-cell therapy, data are lacking regarding long term follow up and risk of infectious complications after the early period following CAR T-cell infusion. In this study, we sought to compare epidemiology and risk factors for early (≤ 3 months) and late (3 months to 1 year) infections. Data were retrospectively collected at six time points: pre-CAR T, day of infusion, and at 3, 6, 9, and 12 months post CAR-T infusion for all consecutive adult patients treated at our institution. In this cohort, the cumulative incidence of any infection was 73.2% in the first year. Bridging therapy, CRS, neurotoxicity and steroid use were identified as contributing risk factors for early bacterial infections. After 3 months, community acquired respiratory infections were common. We characterize bacterial, viral and fungal pathogens based on time elapsed after CAR T-cell infusion.

The diagnosis of myeloid neoplasms with plasmacytoid dendritic cell (pDC) differentiation can be challenging due to immunophenotypic overlap requiring detailed characterization by flow cytometry and immunohistochemistry. We describe two patients with a history of myeloproliferative neoplasm (MPN) and myelodysplastic/myeloproliferative neoplasm (MDS/MPN) who presented years later with leukocytosis, lymphadenopathy, splenomegaly, and cachexia, with rapid clinical deterioration and death. Lymph node biopsy specimens revealed involvement by myeloid sarcoma with prominent pDC differentiation. Furthermore, concomitant bone marrow aspiration and biopsy showed involvement by the underlying myeloid neoplasm but no parallel expansion of pDC, as seen in the lymph node specimens, suggesting that pDC differentiation is fostered in the lymph node microenvironment. These two cases could represent the "myeloid sarcoma" counterpart of the recently described acute myeloid leukemia with pDC differentiation (pDC-AML). Although patients with pDC-AML have an inferior outcome when treated with conventional therapies, the recognition of a pDC component in these neoplasms potentially expands the therapeutic options.

Chimeric antigen receptor (CAR) T-cell therapy has changed treatment landscape of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and more older patients have been treated with curative intent for R/R disease, including patients previously deemed unfit for autologous stem-cell transplant with a broader application of CAR T-cell therapy. Due to the unique CAR T-cell-related toxicity and special attention needed in treating older patients, optimal patient selection and management of CAR T-cell therapy in older patients are becoming more critical. More data are emerging in the field; multiple approaches, such as geriatric and frailty assessment and multi-disciplinary work with geriatrics, are being studied for CAR T-cell therapy application. Studies support the safe use of CAR T-cell therapy in older patients, however, application of geriatric assessment tools and maximizing multi-disciplinary approach to tailor supportive care are critical to reduce morbidity and improve outcomes in older patients.

In this multicenter phase Ib trial, we investigated the combination of CPX-351 and gemtuzumab ozogamicin (GO) in relapsed/refractory acute myeloid leukemia (AML). Cohort A received CPX-351 plus a single dose of GO, while cohort B received two doses of GO. Thirteen participants received investigational treatment. Dose-limiting toxicities (DLTs) occurred in one participant in each cohort, with manageable adverse events. No cases of hepatic sinusoidal obstructive syndrome occurred. Out of 12 evaluable participants, four achieved complete remission (CR), three of whom were negative for measurable residual disease. The median time to recovery of hematopoiesis for responders was 37 days. CPX-351 with GO was feasible with acceptable toxicity and marrow recovery kinetics. Further evaluation in a larger patient cohort is necessary to assess the efficacy of this regimen in relapsed/refractory AML.

Dual productive B-cell receptor (BCR) rearrangements have been repeatedly reported for chronic lymphocytic leukemia (CLL), but the standard population-based PCR analyses cannot distinguish whether these are bi-clonal CLL, or a monoclonal CLL with bi-allelic productive rearrangements. We investigated CLL cells by combined single-cell RNA and BCR sequencing. We identified two CLL clones using different immunoglobulin (Ig) heavy-chain V region genes (IGHV) genes and distinct Ig λ light chains. One clone is classified as Ig unmutated the other as mutated. The two CLL clones have distinct transcriptomes: Numerous genes were differentially expressed, with genes typical for unmutated or mutated CLL showing the expected representation in the two clones. Using PCR, cloning and Sanger sequencing of the IGHV rearrangements we detected both CLL clones over a period of three years without clinical progression of the CLL and thus giving insights into the disease biology of multi-clonal CLL.

Nrf2 plays a critical role in regulating cytoprotective transcriptional responses and glucose metabolism while also preventing inflammation-induced carcinogenesis. However, Nrf2 can paradoxically promote carcinogenesis. Here, we aimed to elucidate the role of Nrf2 in ATL associated with HTLV-1. HTLV-1-infected T-cell lines exhibited nuclear accumulation of Nrf2. Nrf2 knockdown along with the inhibition of its activity using ML385, decreased cell proliferation and survival. Furthermore, ML385-induced G1 arrest by enhancing γH2AX and p53 expression while downregulating CDK4/6, cyclin D2/E, and c-Myc. Additionally, ML385 triggered caspase-mediated apoptosis by downregulating the expression of anti-apoptotic proteins while upregulating pro-apoptotic proteins. The compound also induced necroptosis, promoted JNK phosphorylation, and inhibited the NF-κB, AP-1, and STAT3/5 signaling. Moreover, ML385 was found to reduce the expression of LDHA, glucose uptake, and the levels of lactate derived from glycolysis. Overall, these results suggest that Nrf2 functions as an oncogene in ATL and may represent a promising therapeutic target.

Hairy cell leukemia (HCL) is an indolent malignancy of mature B-lymphocytes. While existing front-line therapies achieve excellent initial results, a significant number of patients relapse and become increasingly treatment resistant. A major molecular driver of HCL is aberrant interlocking expression of the transcription factor JunD and the intracellular signaling molecule RhoH. Here we discuss the molecular basis of how the JunD-RhoH axis contributes to HCL pathogenesis. We also discuss how leveraging the JunD-RhoH axis identifies CD23, CD38, CD66a, CD115, CD269, integrin β7, and MET as new potential therapeutic targets. Critically, preclinical studies have already demonstrated that targeting CD38 with isatuximab effectively treats preexisiting HCL. Isatuximab and therapeutics directed against each of the other six new HCL targets are currently in clinical use to treat other disorders. Consequently, leveraging the JunD-RhoH axis has identified a battery of therapies that could be repurposed as new means of treating relapsed or refractory HCL.

Mantle cell lymphoma (MCL) is a rare, incurable B-cell non-Hodgkin lymphoma and over half of patients affected are older adults (≥65 years of age). New targeted treatments for MCL have emerged over the past two decades. Nonetheless, MCL-specific death rates for older adults remain elevated compared with younger adults, demonstrating the challenge of treating this population. The older adult population is at risk for overtreatment or undertreatment. Clinicians must be mindful of how to optimize the holistic care of older adults receiving treatment for MCL. Evaluating fitness through a geriatric assessment (GA) is an important step when choosing therapy. The treatment armamentarium includes both chemotherapy and non-chemotherapy options and toxicities must be considered in the context of the patient's GA and proactively managed. Herein, the treatment of MCL in older adults is reviewed and strategies for choosing treatment are offered to assist in treatment decision-making for this challenging population.

Allogeneic stem cell transplantation (alloSCT) represents a curative option for patients with relapsed/refractory (r/r) aggressive lymphomas. We compared outcomes of alloSCT in r/r PTCL and r/r DLBCL pts (n = 150) who underwent identical myeloablative conditioning chemotherapy, GvHD prophylaxis, and relapse management. 5-year PFS and OS were significantly superior in PTCL compared to DLBCL (56% vs. 24%; 56% vs. 28%; p ≤ 0.005). A landmark analysis (day≥ +100 post-alloSCT) markedly favored outcomes in PTCL vs. DLBCL: 5-year PFS and OS of 76% vs. 30% and 76% and 35%, respectively (p ≤ 0.003). Non-relapse mortality was comparable (35% PTCL vs. 34% DLBCL, p = 0.894), whereas post-alloSCT relapse mortality was significantly higher in DLBCL (36% vs. 10%, p = 0.0007). The occurence of limited chronic GvHD did not improve outcomes in DLBCL, whereas extensive chronic GvHD was a negative risk factor for both (HR 2.09 and 2.80, p ≤ 0.006). In conclusion, we gained evidence for strong graft-versus-lymphoma activity against PTCL but not DLBCL.