Nour Moukalled

Immune checkpoint inhibitors in advanced non-small cell lung cancer: Immunotherapy in NSCLC

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first‐line and second‐line therapy settings for patients with advanced non–small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced‐stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue‐based and blood‐based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248‐61.

Reduced intensity is preferred over myeloablative conditioning allogeneic HCT in chronic lymphocytic leukemia whenever indicated: A systematic review/meta-analysis

Despite availability of new and more effective therapies for chronic lymphocytic leukemia, presently this disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Recent published clinical practice recommendations on behalf of the American Society for Blood and Marrow Transplantation relegated the role of for allogeneic hematopoietic cell transplantation to later stages of the disease. To our knowledge, no randomized controlled trial has been performed to date comparing myeloablative versus reduced intensity conditioning regimens in chronic lymphocytic leukemia patients eligible for the procedure. We performed a systematic review/meta-analysis to assess the efficacy of allogeneic hematopoietic cell transplantation when using myeloablative or reduced intensity conditioning regimens. We report the results in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Based on lower non-relapse mortality and slightly better overall survival rates, reduced intensity conditioning regimens appear to be the most desirable choice whenever the procedure is indicated for this disease. It appears highly unlikely that a RCT will be ever performed comparing reduced intensity vs. myeloablative allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia. In the absence of such a study, results of this systematic review/meta-analysis represent the best available evidence supporting this recommendation whenever indicated in patients with chronic lymphocytic leukemia.

Thiotepa 10 mg/kg Treatment Regimen Is Superior to Thiotepa 5 mg/kg in TBF Conditioning in Patients Undergoing Allogeneic Stem-Cell Transplantation

Micro‐Abstract A study evaluating the optimal dose of myeloablation in thiotepa, busulfan, and fludarabine (TBF) conditioning included 29 patients who received TBF conditioning before allogeneic stem‐cell transplantation. Thirteen patients received 5 mg/kg thiotepa; the remaining 16 patients received 10 mg/kg. Patients deemed fit to receive 10 mg/kg conditioning had better overall and progression‐free survival than those who received 5 mg/kg, with no additional toxicities. Introduction The optimal intensity of myeloablation with a reduced‐toxicity conditioning regimen to decrease relapse rate after allogeneic stem‐cell transplantation without increasing transplant‐related mortality (TRM) has not been well established. Materials and Methods We compared outcomes between 5 mg/kg (T5) and 10 mg/kg (T10) thiotepa‐based conditioning regimens in 29 adults who underwent allogeneic stem‐cell transplantation for hematologic malignancies. Results After a median follow‐up of 11 months, TRM was 0% and 14% at 100 days and 1 year, respectively, with TRM observed only in the T5 group (P = .016). The relapse incidence at 1 year was 20%. No patient had disease in first complete remission at the time of transplantation. At 1 year, progression‐free and overall survival were 30% versus 87% (P = .012) and 46% versus 87% (P = .008) in the T5 and T10 groups, respectively. In univariate and multivariate analysis, only age at transplantation and total dose of thiotepa had a significant impact on TRM, overall, and progression‐free survival. Conclusion Patients deemed fit to receive T10‐based conditioning for allogeneic stem‐cell transplantation to treat high‐risk hematologic malignancies had better overall and progression‐free survival than those who received T5 with no additional toxicities. Patients should be stratified before conditioning, and those judged fit should receive T10, while the others should consider alternative reduced‐intensity conditioning regimens.

Real Life Experience with Plerixafor and Granulocyte Colony-Stimulating Factor for Mobilization of Autologous Peripheral Stem Cell Transplantation

After a median follow up of 36 months, the 1-year TRM was 11% in the FB4 group, and 14% in the FB<4 group (p 1⁄40.7). The incidence of aGVHD grade II-IV was 22% in FB4 vs 14% in FB<4 (p 1⁄40.8), the incidence of cGVHD was 19%, with no significant difference between the two groups. We did not observe any significant difference at one year PFS (FB4: 87% vs FB<4: 67%) and OS (FB4: 84% vs FB<4: 87%). Conclusion: This riskadapted combined approach of selecting conditioning intensity minimizes post-transplant complications, without affecting survival. These findings need to be confirmed in larger studies.

Iron overload in patients with myelodysplastic syndromes: An updated overview: Iron Overload in MDS

Myelodysplastic syndromes (MDS) encompass a heterogeneous group of clonal hematopoietic stem cell disorders characterized by a broad clinical spectrum related to ineffective hematopoiesis leading to unilineage or multilineage cytopenias, with a high propensity for transformation to acute myeloid leukemia. Iron overload has been recently identified as one of the important conditions complicating the management of these diverse disorders. The accumulation of iron is mainly related to chronic transfusions; however, evidence suggests a possible role for ineffective erythropoiesis and increased intestinal absorption of iron, related to altered hepcidin and growth differentiation factor‐15 levels in the development of hemosiderosis in patients with MDS. In addition to its suggested role in the exacerbation of ineffective erythropoiesis, multiple reports have identified a prognostic implication for the development of iron overload in patients with MDS, with an improvement in overall survival after the initiation of iron chelation therapy. This review includes a detailed discussion of iron overload in patients with MDS whether they are undergoing supportive therapy or curative hematopoietic stem cell transplantation, with a focus on the mechanism, diagnosis, and effect on survival as well as the optimal management of this highly variable complication.

Feasibility of Venetoclax-based combinations for adult patients with acute myeloid leukemia relapsing after allogenic stem cell transplantation

To the editor, Acute myeloid leukemia relapsing after allogeneic-stemcell-transplant (allo-SCT) (R/R-AML) is associated with poor prognosis and low cure rates [1, 2], despite variable therapeutic options including hypomethylating agents, chemotherapy (standard intensive induction/salvage therapies with anthracycline-cytarabine combinations, high dose cytarabine, fludarabine and cladribine-based combinations among others), donor lymphocyte infusion (DLI), and/or a second allo-SCT [3]. The B-cell leukemia/lymphoma2 (BCL-2) family proteins are anti-apoptotic molecules overexpressed in AML cells and associated with worse prognosis [4]. Venetoclax, a selective BCL-2 inhibitor, has been shown to be efficacious as monotherapy and in combination with hypomethylating agents for treatment of relapsed/refractory-AML, among other hematologic malignancies [5, 6]. However, limited data is available on the utility of venetoclax-based combinations post-SCT. We herein present four cases of R/R-AML treated with a combination of venetoclax with a hypomethylating agent and/or a targeted therapy.