Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Abstracts of the Cell Therapy Transplant Canada 2022 Annual Conference.

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15-18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) Basic/Translational sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support, received awards for both the oral and poster presentations. All of these were marked as "Award Recipient" with the relevant category. We congratulate all the presenters on their research and contribution to the field.

Patient age and donor HLA matching can stratify allogeneic hematopoietic cell transplantation patients into prognostic groups.

BACKGROUND: Mixed results surround the accuracy of commonly used prognostic risk scores to predict overall survival (OS) and non-relapse mortality (NRM) in allogeneic hematopoietic stem cell transplant (allo-HCT) recipients. We hypothesize that a simple prognostic score performs better than conventional scoring systems. PATIENTS AND METHODS: OS risk factors, HCT-CI, age-HCT-CI, and augmented-HCT-CI were studied in 299 patients who underwent allo-HCT for myeloid and lymphoid malignancies. A scoring system was developed based on results and validated in a different cohort of 455 patients. RESULTS: Two-year OS was 51% (95% confidence interval (CI) 0.45-0.56); 2-year NRM was 34% (95% CI 0.29-0.39). HCT-CI and associated scores were grouped into 0-2 and ≥3. Age and HLA mismatch status were the only risk factors to affect OS in multivariate analysis (p = 0.02 and 0.05, respectively). HCT-CI and associated scores were not informative for OS prediction. The weighted scoring system assigned 0 to 2 points for age < 50, 50-64, or ≥65, respectively, and 0-1 points for no HLA mismatch versus any mismatch (except HLA-DQ). Distinct 2-year OS (62%, 53%, and 38% [p = <0.001]) and NRM (24%, 34%, and 43% [p = 0.02]) groups were characterized. The scoring system was validated in a second independent cohort with similar results on OS and NRM (p < 0.001). CONCLUSIONS: A simple scoring system based on recipient's age and mismatch status accurately predict OS and NRM in two distinct cohorts of allo-HCT patients. Its simplicity makes it a helpful tool to aid clinicians and patients in clinical decision-making.

Azacitidine and its role in the upfront treatment of acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) predominantly affects elderly population. This poses challenges in management, as patients are frequently not candidates for intensive therapy given comorbidities or frailty. Currently, azacitidine (AZA), either as monotherapy or in combination regimens, is the backbone treatment in this group of patients. AREAS COVERED: We review the mechanism of action, pharmacology, clinical efficacy, and safety of AZA. It reviews current combination therapies of AZA with other targeted therapies for the treatment of newly diagnosed AML. EXPERT OPINION: AZA is a cornerstone for the treatment of patients considered ineligible for intensive chemotherapy induction, but better results and therapies are required for these patients. AZA has shown synergistic properties when combined with other medications. Its safety profile and few drug interactions make it a suitable medication to use as backbone. Newer therapies are being combined with AZA, demonstrating safety and in cases, improved responses, and survival. AZA/venetoclax has emerged as the standard of care for patients who are ineligible for intensive chemotherapy. Doublet and triplet combinations are increasingly being studied. With the results observed in elderly patients, the intensive chemotherapy paradigm might be put to test in younger populations, with AZA combinations being at the forefront.

Treatment Outcomes in Chronic Myeloid Leukemia: Does One Size Fit All?

With the success of tyrosine kinase inhibitors (TKIs) in achieving next-to-normal overall survival in chronic myeloid leukemia (CML), treatment-free remission (TFR) has become a significant goal in the management of this disease. Discontinuation of therapy is attractive to both patients and physicians because maintaining a stable BCR-ABL transcript level without therapy would imply true operational CML cure. With TFR, patients are not exposed to unknown long-term adverse effects of TKIs and common adverse effects that may affect quality of life. Several factors need to be considered before attempting TFR, because this goal is not appropriate for a significant proportion of patients with CML. Patient-related factors, CML response to therapy and its duration, monitoring capacity, patient preferences and compliance with monitoring, and economic factors influence the decision to attempt to discontinue TKIs. Unfortunately, only 50% of patients are appropriate candidates for discontinuation of treatment. Of those, another 50% maintain stable disease while off TKIs. This means that merely 25% of patients achieve TFR. Further optimization and research are required to be able to extend this treatment goal to a larger population of patients. Although TFR is attractive and desirable, this goal is not a one-size-fits-all approach, and we should continue to focus on patients with CML having a normal OS with the best quality of life possible.

Quizartinib for the treatment of acute myeloid leukemia.

INTRODUCTION: . Up to 30% of patients with acute myeloid leukemia (AML) have a mutation in the FLT3 receptor. Molecular targets have acquired a significant interest in the treatment of AML and are changing patient outcomes, including improvement of overall survival (OS) and remission rates. FLT3 inhibitors have obtained a central role in how we treat AML. AREAS COVERED: . This article reviews the mechanism of action, pharmacology, clinical efficacy, and safety of quizartinib, a FLT3 inhibitor, for the treatment of acute myeloid leukemia. EXPERT OPINION: . Quizartinib yielded an improvement in OS and complete remission (CR) rates in a phase 3 trial for relapsed/refractory FLT3-mutated AML. The toxicities are manageable; however, it is associated with significant QTc prolongation and myelosuppression. The FDA and EMA did not grant drug approval to quizartinib in the relapsed/refractory setting due to the lack of a significant benefit - to-risk ratio, safety concerns and concerns with credibility and generalizability of the trial data. Results from the frontline phase 3 study evaluating quizartinib with intensive chemotherapy are eagerly awaited. Ongoing studies are investigating its toxicity and efficacy with other therapeutic agents and will help to clarify its role in the treatment of FLT3-ITD-mutated AML.

Bloodstream infection caused by S. aureus in patients with cancer: a 10-year longitudinal single-center study.

BACKGROUND: Staphylococcus aureus bloodstream infections (SABIs) represent a significant cause of morbidity and mortality in cancer patients. In this study, we compared infection characteristics and evaluated epidemiology and risk factors associated to SABIs and 30-day attributable mortality in cancer patients. METHODS: Clinical and microbiological data from patients with cancer and positive blood cultures for S. aureus were retrieved during a 10-year period at an oncology reference center. Analyses were performed according to type of malignancy and infection with methicillin-resistant S. aureus (MRSA). Data was evaluated using competing risk analyses to identify risk factors associated to 30-day mortality and used to create a point system for mortality risk stratification. RESULTS: We included 450 patients and MRSA was documented in 21.1%. Hospital-acquired infection, healthcare-associated pneumonia, and type-2 diabetes were associated to MRSA. In patients with hematologic malignancies, MRSA was more frequent if hospital-acquired, but less likely in primary bacteremia. Variables associated to mortality included abdominal source of infection, hematologic malignancy, MRSA, glucose levels > 140 mg/dL, and infectious endocarditis; catheter removal and initiation of adequate treatment within 48 h of positive blood culture were protective factors. From our designed mortality prediction scale, patients with a score > 3 had a 70.23% (95%CI 47.2-85.3%) probability of infection-related death at 30 days. CONCLUSION: SABIs are a significant health burden for cancer patients. Risk factors for SABI-related mortality in this population are varied and impose a challenge for management to improve patient's outcomes. Risk stratification might be useful to evaluate 30-day mortality risk.

Influenza in patients with hematological malignancies: Experience at two comprehensive cancer centers.

The burden of influenza infections in patients with hematological malignancies (HMs) is not well defined. We describe the clinical presentation and associated outcomes of influenza at two comprehensive cancer centers (center 1 in the United States and center 2 in Mexico). Clinical and laboratory data on patients with HMs and influenza infection diagnosed from April 2009 to May 2014 at the two centers were reviewed retrospectively. A total of 190 patients were included, the majority were male (63%) with a median age of 49 years (range, 1-88 years), and had active or refractory HMs (76%). Compared to center 1, patients in center 2 were significantly sicker (active cancer, decreased albumin levels, elevated creatinine levels, or hypoxia at influenza diagnosis) and experienced higher lower respiratory tract infection (LRI) rate (42% vs 7%; P < 0.001). In multivariable logistic regression analysis (odds ratio, 95% confidence interval), leukemia, (3.09, 1.23-7.70), decreased albumin level (3.78, 1.55-9.20), hypoxia at diagnosis (14.98, 3.30-67.90), respiratory co-infection (5.87, 1.65-20.86), and corticosteroid use (2.71, 1.03-7.15) were significantly associated with LRI; and elevated creatinine level (3.33, 1.05-10.56), hypoxia at diagnosis (5.87, 1.12-30.77), and respiratory co-infection (6.30, 1.55-25.67) were significantly associated with 60 day mortality in both centers. HM patients with influenza are at high risk for serious complications such as LRI and death, especially if they are immunosuppressed. Patients with respiratory symptoms should seek prompt medical care during influenza season.

Impact of thrombophilia screening on venous thromboembolism management practices.

BACKGROUND: It is unclear whether thrombophilia testing provides any further information on risk of recurrence or guidance in management of patients with a first episode of idiopathic venous thromboembolism (VTE). Furthermore, after the introduction to clinical practice of clinical prediction rules, thrombophilia screening could be less relevant in anticoagulation decision making. We assessed the potential impact of thrombophilia screening on the decision of maintaining anticoagulation beyond the initially planned anticoagulation period in patients with an unprovoked VTE, before and after the introduction of a clinical prediction rule into practice. PATIENTS/METHODS: We conducted a single center, retrospective cohort study of consecutive patients with a diagnosis of unprovoked VTE, including a study period of 12years. Two groups were compared, before and after 2008. RESULTS: We included 1033 patients of which 85.2% were tested for thrombophilia and 26.2% were identified with any thrombophilia. A similar proportion of patients continued on anticoagulation after 6months (54.1% vs 57.1%, respectively). The proportion of patients continuing anticoagulation based on the thrombophilia screen remained small (13.9% vs 12.7%, respectively). Continuing anticoagulation beyond the initial period planned resulted in a 75% risk reduction in VTE recurrence, independent of the presence of thrombophilia (HR 0.25, 95% CI 0.12-0.55; P<0.001). CONCLUSIONS: Thrombophilia screening continues to have little relevance in clinical decision making for anticoagulation. Prolonging anticoagulation beyond 6months in an at-risk population decreased the risk of VTE recurrence regardless of their thrombophilia status.

Retinal vein thrombosis: The Internist's role in the etiologic and therapeutic management.

Retinal vein occlusion is a common and important cause of vision loss. In general, knowledge about this condition is scant within an internist's practice but the condition is relevant because of its association with other chronic ailments. A diagnosis of RVO should prompt the investigation of conditions needing chronic management in these patients. In this review we summarize the clinical presentation of RVO, its classification, associated risk factors, and treatment focused in the internist's scope of practice.

Hospital-acquired infections at an oncological intensive care cancer unit: differences between solid and hematological cancer patients.

BACKGROUND: Cancer patients have a higher risk of severe sepsis in comparison with non-cancer patients, with an increased risk for hospital-acquired infections (HAI), particularly with multidrug resistant bacteria (MDRB). The aim of the study is to describe the frequency and characteristics of HAI and MDRB in critically ill cancer patients. METHODS: We conducted an 18-month prospective study in patients admitted ≥48 h to an ICU at a cancer referral center in Mexico. Patients with hematological malignancies (HM) were compared with solid tumors. Demographic and clinical data were recorded. Mortality was evaluated at 30-days. RESULTS: There were 351 admissions during the study period, among whom 157 (66 %) met the inclusion criteria of the study as follows: 104 patients with solid tumors and 53 with HM. Sixty-four patients (40.7 %) developed 95 episodes of HAI. HAI rate was 4.6/100 patients-days. MDRB were isolated in 38 patients (24 %), with no differences between both groups. Escherichia coli was the main bacteria isolated (n = 24), 78 % were extended spectrum beta-lactamases producers. The only risk factor associated with HAI was the presence of mechanical ventilation for more than 5 days (OR 3.12, 95 % CI 1.6 - 6.2, p = 0.001). At 30-day follow-up, 61 patients (39 %) have died (38 % with solid tumors and 60 % with HM, p < 0.001). No differences were found in mortality at 30-day between patients with HAI (n = 25, 39 %) vs. non-HAI (n = 36, 38.7 %, p = 0.964); neither in those who developed a HAI with MDRB (n = 12, 35.3 %) vs. HAI with non-MDRB (n = 13, 43.3 %, p = 0.51). CONCLUSIONS: Patients with cancer who are admitted to an ICU, have a high risk of HAI, but there were no differences patients with solid or hematologic malignancies.