Immune checkpoint inhibitors in acute myeloid leukemia

Understanding the immune biology of AML and designing rational approaches to target or harness the immune environment to improve outcomes is an area of intense research in AML. There are two primary immune checkpoint harnessing modalities under clinical evaluation in AML: T-cell (such as PD1 inhibitors nivolumab and pembrolizumab) and macrophage (such as the anti-CD47 antibody magrolimab) These work synergistically with hypomethylating agents. Patients who do not achieve complete or partial responses based on IWG criteria often achieve durable stable disease or hematologic improvement, which may provide meaningful benefit for patients, even in the absence of traditional response unlike cytotoxic therapies. Patients should ideally be prospectively selected for CPI based therapies based on pre-treatment biomarkers, as there are definite populations that are more likely to respond. Immune toxicities are often mistaken for infection or other adverse event; however, if identified and treated early and aggressively with steroids, immune toxicity outcomes can be improved. Therefore, in the formative stage of development ideally only centers with experience in immune therapies should perform CPI studies in AML.     

What Is the Role of Chemotherapy in Patients With Chronic Lymphocytic Leukemia?

The current standard treatment for patients with chronic lymphocytic leukemia who require therapy is chemoimmunotherapy. However, the availability of an increasing number of targeted agents and combination warrants a reassessment of that approach. The high rate of durable responses with ibrutinib in relapsed refractory patients has established its role in this setting; however, because of its impressive efficacy as initial treatment, it should be considered as part of the algorithm in appropriate patients. There is virtually no role for chemotherapy in the relapsed or refractory setting, but, instead, consideration of active agents including idelalisib plus rituximab, or, particularly venetoclax. For patients with 17p-deletion, ibrutinib is the treatment of choice, with venetoclax in the setting of intolerance or relapse. Challenges include developing strategies to limit the duration of these expensive therapies, and to develop combinations with the potential to cure patients with chronic lymphocytic leukemia.     

Is the overall survival for older adults with AML finally improving?

Older adults with acute myeloid leukemia (AML) traditionally have very poor survival outcomes. Those who receive only supportive care have worse overall survival than those who undergo treatment, regardless of treatment type, and improvements in overall survival in the last several decades are largely attributable to the increasing decision to treat rather than offer only supportive care. However, there are a few newer agents that appear promising; these include CPX-351 (a liposomal product with cytarabine and daunorubicin), glasdegib (a selective Hedgehog signaling pathway inhibitor), and venetoclax (potent small molecule inhibitor of BCL2). A systematic review and meta-analysis is being completed to help clinicians optimize standard therapies for older AML patients.     

Chronic lymphocytic leukemia and infection risk in the era of targeted therapies: Linking mechanisms with infections

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the world. Patient with CLL are at particular risk for infections due to inherent disease-related immune dysfunction in addition to the effect of certain systemic therapies on the immune system. The advent of B-cell receptor (BCR) inhibitors such as ibrutinib and idelalisib has led to a practice change that utilizes these targeted agents in the treatment of CLL, either in place of chemoimmunotherapy (CIT) or in later line settings. In this paper, we review the pathophysiology of immune dysfunction in CLL, the spectrum of immunodeficiency with the various therapeutic agents along with prevention strategies with a focus on targeted therapies.     

维奈克拉治疗急性髓系白血病研究进展

维奈克拉的应用是近年来治疗急性髓系白血病（AML）的重要突破。诱导凋亡药物联合去甲基化药物这一非化疗手段应用于AML的治疗,给老年或不能耐受强化疗的患者带来了长期生存的希望,但目前仍有一部分患者会对含维奈克拉的方案出现耐药。文章结合第62届美国血液学会（ASH）年会报道对维奈克拉治疗AML的新进展进行介绍。     

Will new agents impact survival in AML?

In recent years, several drugs—including midostaurin, gilteritinib, and gemtuzumab ozogamicin, to name a few—have been approved or reapproved in the United States to treat patients with acute myeloid leukemia (AML). Yet survival rates for younger patients had improved with chemotherapy alone even before the approvals of these new agents. This begs the question whether the new therapies will actually have a positive impact on survival. The 5-year survival rate for older patients has also risen, again without the addition of these new agents. The challenge will be to incorporate new therapies and use them where they will have the greatest impact—major work for clinicians and researchers alike.     

两种方案对复发难治性急性髓系白血病患者疗效及预后的影响

目的 研究维奈托克和CAG分别联合阿扎胞苷对复发难治性急性髓系白血病(AML)患者的影响.方法 回顾性分析2019年7月～2020年12月我院65例复发难治性AML患者的临床资料,按照治疗方案不同分为维奈托克组(n=30,维奈托克+阿扎胞苷)、CAG组(n=35,CAG+阿扎胞苷).比较两组治疗4周后疗效及治疗4、12...     

Low-dose decitabine plus venetoclax is safe and effective as post-transplant maintenance therapy for high-risk acute myeloid leukemia and myelodysplastic syndrome

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are usually associated with poor outcomes, especially in high-risk AML/MDS. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative option for patients suffering from high-risk AML/MDS. However, many patients relapse after allo-HSCT. Novel therapy to prevent relapse is urgently needed. Both the BCL-2 inhibitor venetoclax (VEN) and the hypomethylating agent decitabine (DEC) possess significant antitumor activity effects against AML/MDS. Administration of DEC has been shown to ameliorate graft-versus-host disease (GVHD) and boost the graft-versus-leukemia (GVL) effect post-transplantation. We therefore conducted a prospective study (ChiCTR1900025374) to examine the tolerability and efficacy of a maintenance therapy of low-dose decitabine (LDEC) plus VEN to prevent relapse after allo-HSCT for high-risk AML/MDS patients. Twenty patients with high-risk AML (n = 17) or high-risk MDS (n = 3) post-transplantation were recruited. Approximately day 100 post-transplantation, all patients received LDEC (15 mg/m² for 3 d) followed by VEN (200 mg) on d 1-21. The cycle interval was 2 mo, and there was 10 cycles. The primary end points of this study were rates of overall survival (OS) and event-free survival (EFS). The secondary endpoints included adverse events (AEs), cumulative incidence of relapse (CIR), nonrelapse mortality (NRM), incidences of acute GVHD (aGVHD) and chronic GVHD (cGVHD), and incidences of viral infection after allo-HSCT. Survival outcomes were assessed using Kaplan-Meier analysis. The median follow-up was 598 (149-1072) d. Two patients relapsed, 1 died, and 1 is still alive after the second transplant. The 2-y OS and EFS rates were 85.2% and 84.7%, respectively. The median 2-y EFS time was 525 (149-1072) d, and 17 patients still had EFS and were alive at the time of this writing. The most common AEs were neutropenia, anemia, thrombocytopenia, neutropenic fever, and fatigue. Grade 2 or 3 AEs were observed in 35% (7/20) and 20% (4/20) of the patients, respectively. No grade >3 AEs were observed. aGVHD (any grade) and cGVHD (limited or extensive) occurred in 55% and 20% of patients, respectively. We conclude that LDEC + VEN can be administered safely after allo-HSCT with no evidence of an increased incidence of GVHD, and this combination decreases the relapse rate in high-risk AML/MDS patients. This novel maintenance therapy may be a promising way to prevent relapse in high-risk AML/MDS patients.