Single-Cell CD4 and CD8 T-Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy

UNLABELLED: Acute myeloid leukemia (AML) is a heterogeneous malignancy of the blood primarily treated with intensive chemotherapy. The allogeneic T-cell antileukemic activity via donor lymphocyte infusions and stem cell transplantation suggests a potential role for checkpoint blockade therapy in AML. While clinical trials employing these treatments have fallen short of expected results, a deeper exploration into the functional states of T cells in AML could bridge this knowledge gap. In this study, we analyzed the polyfunctional activity of T cells in a cohort of patients with relapsed/refractory (RelRef) AML treated on the clinical trial (ClinicalTrials.gov identifier: NCT02397720) of combination therapy using azacitidine and nivolumab (Aza/Nivo). We utilized the single-cell polyfunctional multiplexed immune assay IsoPlexis to evaluate the CD4 and CD8 T cells in peripheral blood and bone marrow samples collected before and after immunotherapy. This revealed at a pseudobulk level that the CD4 T cells exhibited higher functional activity post-immunotherapy (post-IO), suggesting that CD4-directed therapies may play a role in RelRef AML. Additional single-cell analysis revealed significant differences in baseline polyfunctionality in bone marrows of responders as compared with nonresponders for both CD4 and CD8 T cells. Overall, this study highlights the impact of polyfunctional assessment in understanding CD4 and CD8 dynamics in contexts of therapy in AML. SIGNIFICANCE: We found T-cell polyfunctionality differs between local and systemic microenvironments. Enhanced variability in proteomic profiles of bone marrow CD4 T cells post-IO suggests their pivotal role in AML treatment response. Single-cell analysis identified novel CD4 and CD8 T-cell functional groups linked to immunotherapy response within the bone marrow

Teleworking Survey in Saudi Arabia: Reliability and Validity of Arabic Version of the Questionnaire

Objectives: This study aimed to adapt the survey questionnaire designed by Moens et al. (2021) and determine the validity and reliability of the Arabic version of the survey in a sample of the Saudi population experiencing teleworking. Methods: The questionnaire includes 2 sections. The first consists of 13 items measuring the impact of extended telework during the coronavirus disease 2019 (COVID-19) crisis. The second section includes 6 items measuring the impact of the COVID-19 crisis on self-view of telework and digital meetings. The survey instrument was translated based on the guidelines for the cultural adaptation of self-administrated measures. Results: The reliability of the questionnaire responses was measured by Cronbach’s alpha. The construct validity was checked through exploratory factor analysis followed by confirmatory factor analysis (CFA) to further assess the factor structure. CFA revealed that the model had excellent fit (root mean square error of approximation, 0.00; comparative fit index, 1.0; Tucker-Lewis index, 1; standardized root mean squared residual, 0.0). Conclusions: The Arabic version of the teleworking questionnaire had high reliability and good validity in assessing experiences and perceptions toward teleworking. While the validated survey examined perceptions and experiences during COVID-19, its use can be extended to capture experiences and perceptions during different crises

An Intriguing Case of Eosinophilia with FIP1L1/PDGFRA Rearrangement Who Presented as Thrombotic Thrombocytopenic Purpura

Myeloid neoplasm with eosinophilia and FIP1-like-1-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFRA) rearrangement is a multi-organ disease with diverse clinical presentation. Thrombotic thrombocytopenic purpura (TTP) is characterized by the concomitant occurrence of often severe thrombocytopenia, microangiopathic hemolytic anemia, and a variable degree of ischemic organ damage. To our knowledge, only one case of eosinophilia with FIP1L1-PDGFRA rearrangement presented as a case of thrombotic thrombocytopenic purpura reported in the literature. We herein report a case of a young male patient with hypereosinophilic syndrome and FIP1L1-PDGFRA rearrangement who presented with asthma, transient ischemic attacks (TIA), and confusion. He had an acquired TTP that was successfully treated with plasma exchanges (PLEX), corticosteroids, rituximab, and later with the addition of imatinib mesylate (Gleevec, Novartis). He remains in complete remission on imatinib 100 mg daily for more than 28 months of follow-up

Discontinuation of tyrosine kinase inhibitor therapy and treatment free remission (TFR) in chronic myeloid leukemia: Successful achievement of TFR in more than two-third of patients in a real-world practice

Background Discontinuation of TKI therapy and treatment-free remission (TFR) have become new goals for chronic-phase chronic myeloid leukemia (CP-CML). The aim of this study was to estimate the TFR post discontinuation of TKI therapy at three tertiary-care centers. Patients and Methods CP-CML patients aged ≥16 years who had an attempt to discontinue TKI therapy till June 2022, were eligible. The collected data included patients’ demographics, prognostic score, type and duration of TKI therapy, response dates, relapse dates, response to re-initiation of TKI therapy, and risk factors for relapse. Results Fifty-five patients (35, 63.6% females) with a median age of 40 (range 16-74) years at diagnosis discontinued therapy. Forty-eight (87.3%) patients received imatinib as first line therapy. Twenty-nine (52.7%) patients were receiving imatinib at the time of TKI-discontinuation. Median time from diagnosis to TKI discontinuation was 86 months (IQR 60;132) and median duration of TKI therapy after achieving DMR was 66 months (IQR 47;114). After a median follow up of 34 (IQR 12;68) months, 15 (27.3%) patients relapsed. Median time to relapse was 5 months (range 2-38). Most of the relapses occurred during the first 6 months except 3 (20%) patients. All the relapsed patients achieved MMR after a median of 3 (range 2-6) months after restarting TKI therapy. None of the patients progressed to advanced-phase. Conclusion Our experience confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in routine clinical practice, and can achieve TFR in more than two-third of carefully selected patients. Clinical Practice points: ● What is already known about this subject? Discontinuation of tyrosine kinase inhibitiors (TKI) and treatment free remission (TFR) has shown to be safe and feasible in clinical studies and can be achieved in 40% to 60% of CML patients. Less is known about the safety and feasibility of this approach in the real-world practice, particularly from limited-resource countries. ● What are the new findings? This real-world retrospective study found that discontinuation of TKI therapy and TFR is safe and feasible in routine clinical practice and can be achieved in around 72% of chronic-phase CML patients. Although not supported by statistical significance, most of the patients in this study received long TKI therapy after deep remission (all patients had achieved complete molecular response), usually more than 5 years. Majority of the patients (87.3%) received imatinib as the first line treatment and slightly more than half of patients were receiving imatinib at the time of TKI discontinuation. ● How might it impact on routine clinical practice? Our study provides further reassurance to the physicians treating CML that discontinuation of TKI therapy is safe and feasible in routine clinical practice and TFR can be achieved in more than two-third of patients who achieved deep remission and received longer TKI therapy. Generic imatinib is cheaper and a number of CML patients receiving imatinib can expect to discontinue therapy making this approach feasible and practical in many resource-constrained countries

Supplementary Figure 4 from Single-Cell CD4 and CD8 T-Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy

Baseline and post-therapy T cell functional activity within PB and BM.</p

Supplementary Figure 3 from Single-Cell CD4 and CD8 T-Cell Secretome Profiling Reveals Temporal and Niche Differences in Acute Myeloid Leukemia Following Immune Checkpoint Blockade Therapy

Baseline T cell individual cytokine activity in PB and BM.</p