T-cell Prolymphocytic Leukemia Research Articles

Leveraging machine learning for predicting acute graft-versus-host disease grades in allogeneic hematopoietic cell transplantation for T-cell prolymphocytic leukaemia

Orphan diseases, exemplified by T-cell prolymphocytic leukemia, present inherent challenges due to limited data availability and complexities in effective care. This study delves into harnessing the potential of machine learning to enhance care strategies for orphan diseases, specifically focusing on allogeneic hematopoietic cell transplantation (allo-HCT) in T-cell prolymphocytic leukemia. The investigation evaluates how varying numbers of variables impact model performance, considering the rarity of the disease. Utilizing data from the Center for International Blood and Marrow Transplant Research, the study scrutinizes outcomes following allo-HCT for T-cell prolymphocytic leukemia. Diverse machine learning models were developed to forecast acute graft-versus-host disease (aGvHD) occurrence and its distinct grades post-allo-HCT. Assessment of model performance relied on balanced accuracy, F1 score, and ROC AUC metrics. The findings highlight the Linear Discriminant Analysis (LDA) classifier achieving the highest testing balanced accuracy of 0.58 in predicting aGvHD. However, challenges arose in its performance during multi-class classification tasks. While affirming the potential of machine learning in enhancing care for orphan diseases, the study underscores the impact of limited data and disease rarity on model performance.

Circulating Monocytes Phagocytosing Lymphocytes in the Small-Cell Variant of T-Cell Prolymphocytic Leukemia

Circulating Monocytes Phagocytosing Lymphocytes in the Small-Cell Variant of T-Cell Prolymphocytic Leukemia

Alemtuzumab monotherapy for T-cell prolymphocytic leukemia: an observational study in Japan.

Alemtuzumab is recommended as first-line and second-line therapies for T-cell prolymphocytic leukemia (T-PLL). This study retrospectively evaluated the efficacy and safety of alemtuzumab in nine Japanese patients with T-PLL at five participating institutions who were treated between January 2015 and August 2023. The median age at first administration of alemtuzumab was 72 years (range, 39 to 78). Two patients were treatment naïve, and seven had been treated with a median of one (range, 1 to 3) prior systemic therapy. Six patients were refractory to their most recent therapy. Three patients completed 12 weeks of treatment. The overall response rate and the complete response (CR) rate were 78% and 11%, respectively. Among the six patients who achieved a partial response, two achieved clinical CR but did not undergo bone marrow examination. One patient also achieved clinical CR but did not undergo CT or bone marrow examination for response evaluation. The median progression-free survival time was 8.1 months (95% confidence interval, 0.9 to 18.6). Three patients received readministration of alemtuzumab monotherapy after disease progression. There were no treatment-related deaths. The grade 3 or 4 nonhematologic adverse events included infusion reaction (grade 3, n = 2), cytomegalovirus reactivation (grade 3, n = 2), and pulmonary edema (grade 3, n = 1). One patient experienced Epstein‒Barr virus-positive diffuse large B-cell lymphoma 15 months after the last dose of alemtuzumab. These results confirm that the efficacy and safety of alemtuzumab monotherapy in Japanese patients are comparable to those previously reported.

TCL1-family negative T-cell prolymphocytic leukemia with rapid progression of extranodal disease despite a normal white blood cell count

Here we describe the case of a 69-year-old man who was found to have moderate thrombocytopenia and severe splenomegaly during a medical checkup at the age of 67. At the first visit, his white blood cell (WBC) count was 7,400/µl with 80% lymphocytes, and bone marrow aspiration showed 24% atypical lymphocytes. Flow cytometry of atypical lymphocytes was positive for mature T-cell markers, and T-cell clonality was revealed by T-cell receptor gene rearrangement. TCL1 was negative on immunohistochemistry. We diagnosed TCL1-family negative T-cell prolymphocytic leukemia (T-PLL) and employed watchful waiting. Thirty months after diagnosis, the patient developed urinary retention and right lower-limb paresis despite a normal WBC count, and an extradural tumor around the thoracic vertebrae and spinal cord compression were detected. The tumor was diagnosed as extranodal involvement of TCL1-family negative T-PLL, but the patient's general condition deteriorated rapidly, and no treatment was possible. T-PLL is a rare disease characterized by leukocytosis, and the WBC count generally increases with disease progression. Although blood counts are recommended for observation, it is important to keep in mind that the disease may worsen even if blood counts do not change.

Flow Cytometry in Mature T- and NK-cell Neoplasms: A Retrospective Descriptive Study from a Tertiary Care Cancer Centre in Kerala, India

Introduction: Mature T- and NK-cell Neoplasms (MTNKN) constitute around 12% of all non-Hodgkin lymphomas. They have a variable clinical course, ranging from indolent to highly aggressive tumours. Flow cytometry immunophenotyping is crucial for the diagnosis, staging, and classification of MTNKN. Aim: To determine the frequency, morphologic, and immunophenotypic profile of various subtypes of MTNKN diagnosed by flow cytometry. Materials and Methods: This was a retrospective descriptive study conducted at the Department of Pathology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India. All cases of MTNKN diagnosed by flow cytometry in peripheral blood, bone marrow aspirates, or body fluids from January 1, 2010 to June 30, 2020 (10.5 years duration) at the cancer centre were studied. The morphology of tumour cells and immunophenotype by flow cytometry were analysed. Clinical parameters (lymphadenopathy, hepatosplenomegaly, skin lesions, effusions, B symptoms) and follow-up details, including Progression-free Survival (PFS) and Overall Survival (OS), were also noted. Descriptive statistics for continuous variables and frequencies and percentages for categorical variables were obtained. The Kaplan-Meier method for survival plots was used. Results: Mature T- and NK-cell neoplasms constituted 83 cases. The median age of patients was 56 years. The majority of patients were males (n=49). Adult T-cell Leukaemia/Lymphoma (ATLL) (n=50) constituted the most common subtype, followed by Mycosis fungoides/Sezary syndrome (MF/SS) (n=14), T-cell Large Granular Lymphocytic Leukaemia (T-LGLL) (n=7), T-cell Prolymphocytic Leukaemia (T-PLL) (n=4), Aggressive NK-cell Leukaemia (ANKL) (n=3), Hepatosplenic T-cell Lymphoma (HSTL) (n=3), and Anaplastic Large Cell Lymphoma (ALCL) (n=2). OS and PFS at three years were 22.3% and 16.6%, respectively. Conclusion: Mature T- and NK-cell neoplasms presenting as leukaemia is rare. ATLL was the most common subtype of MTNKN. Flower cells, Sezary cells, and prolymphocytes are useful morphological clues for diagnosis. Immunophenotyping by flow cytometry, along with clinicopathologic correlation, is crucial for the diagnosis and subclassification of MTNKN. All subtypes except T-LGLL show inferior PFS and OS.

Lymphoid blood cancers, incidence and survival 2005-2023: A report from the UK’s Haematological Malignancy Research Network

BackgroundPopulation-based information on cancer incidence and outcome are required to inform clinical practice and research; but contemporary data are lacking for many lymphoid cancer subtypes. MethodsSet within a socio-demographically representative UK population of ∼4 million, data are from an established UK patient cohort (N = 22,414 diagnoses). Information on incidence (crude and age-standardised) and survival (overall and net) is presented for > 40 subtypes. ResultsThe median diagnostic age was 69.9 years (interquartile range 59.1–78.3), but unlike many other cancers, lymphoid malignancies can be diagnosed at any age; different subtypes dominating at different ages. Males were more likely to be diagnosed than females (age-standardised sex rate ratio: 1.55 (95% Confidence Interval: 1.50,1.59)), and most subtypes had a male predominance, some more than three-fold (e.g. Burkitt lymphoma 3.26 (2.42, 4.40)). Five-year net survival estimates varied hugely, ranging from 97.4% (95% CI: 56.5, 99.9) in patients with hairy cell leukaemia to 31.6% (95% CI: 2.5, 69.8) in those with T-cell prolymphocytic leukaemia. No significant sex difference in survival were observed for the majority of diagnoses; one exception being classical Hodgkin lymphoma, where males had a higher mortality (Excess Mortality Ratio: 1.44 (95% CI: 1.11, 1.87)). An improvement in survival over time was observed for some, but not all, of the major diagnostic groups. ConclusionsMarked incidence and survival variations by subtype, sex and age confirm the heterogeneity of lymphoid neoplasms and highlight the importance of accurately characterising disease entities. Despite recent improvements, routine cancer registration of lymphoid neoplasms remains challenging and new issues continue to emerge; including the lack of an international consensus on classification and the recording of progressions and transformations. Furthermore, the increasing need for additional molecular and genomic information required for accurate classification is likely to impact negatively on the quality of cancer registration data, especially in low income countries.

Real-World Evaluation of T-Prolymphocytic Leukemia Outcomes Using the 2019 T-PLL International Study Group Criteria

Introduction: T-Cell Prolymphocytic Leukemia (T-PLL) is a rare, aggressive T-cell malignancy with very poor prognosis. CLL criteria have historically been used for diagnostic and response criteria for T-PLL, but due to the T-PLL's distinct biology and clinical features in 2019 the International Study Group (TPLL-ISG) developed the first consensus criteria for diagnosis and response assessment to harmonize clinical research in T-PLL (Staber et al, Blood, 2019). Diagnostic criteria included both major and minor criteria, while standardized criteria were developed for complete response (CR), complete response with incomplete marrow recovery (CRi), partial response (PR), and stable disease (SD). While the TPLL-ISG consensus criteria are an important step towards uniformity in diagnosis and response assessment, the applicability of these criteria has not been assessed in a real-world population. We evaluated the diagnosis and clinical responses of the OSU T-PLL population using the TPLL-ISG criteria to evaluate the concordance of historical outcomes with previous diagnostic/response criteria. Methods: We retrospectively evaluated all patients diagnosed with T-PLL at The Ohio State University between 2009-2022. Diagnosis and response were evaluated utilizing the TPLL-ISG criteria. Overall survival (OS), progression-free survival (PFS), and duration of response (DOR) were assessed using Kaplan-Meier methods and log-rank test. Results: A total of 32 patients, with an average follow-up time of 23 months were evaluated. All patients met the TPLL-ISG criteria for the diagnosis of T-PLL with 29 (91%) meeting major criteria and 22 (69%) meeting both major and minor criteria; concordant with prior studies. 23 patients (72%) were TCL1A positive (by cytogenetics or FISH) and 18 patients (56%) had nodal involvement via PET or CT scan. For all patients, median OS and PFS were 20 months (95% CI 6-45) and 4 months (95% CI 2-17), respectively. Using TPLL-ISG criteria, the overall response rate (ORR) (CR/CRi/PR) to first line treatment was 63% with a median OS of 45 months (95% CI 8-88) and PFS of 26 months (95% CI 4-46). Median DOR was 16 months (range 1-36). The median OS and PFS for patients who achieved a CR were 45 months and 37 months, respectively. For those with a Cri, the OS/PFS was not reached and for those with PR, OS was 7 months and PFS 3 months. The median OS and PFS for patients treated with frontline alemtuzumab (n=26) was 20 months and 4 months and 8 months and 4 months for patients treated with a combination of alemtuzumab/pentostatin (n=4). The ORR for patients treated front-line with alemtuzumab or alemtuzumab/pentostatin was 63% (19/30), with a median OS of 41 months and PFS of 26 months. One patient responded to frontline pentostatin with a DOR of 16 months. The median DOR for any second line treatment (n=7) was 4 months. One patient had a DOR of 4 with alemtuzumab retreatment. Second line pentostatin (n=4) had an ORR of X, and median DOR of 3 months. Patients with CD4+CD8- disease (n=24) had a median OS of 20.4 months and a median PFS of 6 months, while CD4-CD8+ patients (n=3) had an OS of 8 months and PFS of 3 months, and CD4+CD8+ patients (n=4) did not reach median OS or PFS. Nine patients (28%) proceeded to allogeneic stem cell transplantation (allo-SCT). Patients treated with alemtuzumab first line who received allo-SCT had a significantly longer median OS (88 months vs 40 months; p=0.01) and PFS (46 months vs 9 months; p=0.04) compared to those that did not receive an allo-SCT. Response rates in this cohort were similar to published results (Table 1) suggesting no substantial difference between previously utilized response criteria and TPLL-ISG criteria (Table). Conclusions: No substantial differences in T-PLL response rates or survival were observed when using the TPLL-ISG criteria when compared to historical reports. Patients who had a CR or CRi to alemtuzumab that proceeded with allo-SCT had a significantly prolonged OS and PFS. Patients with CD4-CD8+ T-PLL had inferior survival , but this will need to be validated in a larger sample set. Consistent with previous studies, alemtuzumab produced the best responses, particularly for frontline treatment. Pentostatin provided transient responses as second line treatment but patients inevitably relapsed. Our results confirm the utility of the 2019 consensus criteria and set the basis for larger real-world studies to further assess the outcomes of patients with T-PLL.

Preclinical Evaluation of T-Cell Prolymphocytic Leukemia Demonstrates Heterogeneous BCL2-Family Dependency That May be Effectively Targeted with Small Molecule Inhibitors

T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive, mature T-cell leukemia with very few treatment options and adverse prognosis. There are currently no approved therapies for patients with relapsed T-PLL, where the median OS is less than 6 months. There are limited reports suggesting clinical activity of the BCL2 inhibitor venetoclax in patients with T-PLL. We aimed to characterize the dependencies of T-PLL on members of the BCL2-family of antiapoptotic proteins using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. We then sought to experimentally exploit these dependencies with targeted therapies alone, and in combination, designed to inhibit the antiapoptotic proteins towards a therapeutic goal. Cell lines of mature T cell lymphomas/leukemias (TCL/L) including SUPT11 (T-cell leukemia with rearranged TCL1) (n=10) and bone marrow and peripheral blood samples from untreated patients with T-PLL (n=7) were analyzed by BH3 profiling. We also used a relapsed/refractory T-PLL patient sample that were able to engraft and expand in a PDX model. Finally, scRNA/ATAC seq has also been performed in a set of naïve-treated T-PLL patients. In contrast to TCL/L that demonstrated heterogeneity on BCL2 family member dependency, T-PLL samples were primed and consistently exhibited dependency on BCL2/BCL-xL and MCL1. Integration of scRNA/ATAC seq confirmed high expression of BCL2 and MCL1 in T-PLL cells from four patients supporting the premise that BCL2 and MCL1 could potentially be targeted for therapeutic benefit. Therefore, SUPT11 cells (used as a model of T-PLL) were exposed to venetoclax (25 and 50nM; BCL-2inh), fadraciclib (25 and 50nM; CDK2/9inh - indirect inhibitor of MCL-1 as it decreases mRNAs with high decay rates including MCL1 and MYC) or a combination of venetoclax and fadraciclib. We demonstrate that exposure to fadraciclib caused a rapid decline in the levels of phosphorylation on Serine 2 of RNA polymerase II C-terminal domain, as well as decline in the levels of MCL1 within 4 hours and completely depleted these proteins by 8-12 h of exposure. We also show that there was a synergistic increase both in mitochondrial dysfunction as measured by cytochrome C release by 18h and in cell death in cells exposed to the combination at 24h. These results suggest that combining venetoclax and fadraciclib might represent a potential therapeutic approach for T-PLL. In conclusion, preclinical evaluation of a T-PLL cell line and primary patient samples demonstrate BCL2-family dependency that can be effectively targeted with small molecule inhibitors of BCL2 and CDK2/9. In vivo studies in PDX models of T-PLL are underway to form the basis for clinical trials to study these combinations.

Results from the Cohort-Expansion Stage of a Phase I Trial of Tinostamustine Monotherapy in Advanced Hodgkin Lymphoma (HL), Non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) (NCT02576496)

Background Tinostamustine, a novel alkylating deacetylase inhibitor, improves drug access to cancer cell DNA strands, breaks them and counteracts damage repair. Tinostamustine was well tolerated, with signals of efficacy, during the dose-escalation stage of a Phase I study in patients with relapsed/refractory (R/R) haematological malignancies (Zinzani et al. HemaSphere 2019;3(S1):102:PF300) and for patients with HL in the cohort-expansion stage (Ghesquières et al. Blood 2021;138(S1):2472; Sureda et al. Blood 2022;140(S1):3696). Aims We report safety and efficacy findings from patients with advanced haematological malignancies including HL, cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), T-cell prolymphocytic leukaemia (T-PLL) and MM treated with tinostamustine in the expansion cohorts of a Phase I study. Methods Patients with advanced haematological malignancies, for whom no standard treatment with proven clinical benefit was available or recommended, were recruited to receive the recommended Phase II dose of tinostamustine. Patients with HL must have received ≥2 lines of prior therapy, CTCL 1-4 prior standard systemic therapies, PTCL >1 prior line of combination therapy, T-PLL ≥1 prior line of therapy and MM ≥1 prior systemic therapy. Adverse events (AEs) were assessed for severity using US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE; version 4.03, June 2010; for QTc prolongations CTCAE version 5.0 was used). Treatment-related AEs, fatal AEs, serious adverse events (SAEs), and AEs resulting in trial discontinuation were recorded. Primary efficacy objectives were to estimate the overall response rate (ORR; complete response [CR] + partial response [PR]) and clinical benefit rate (CBR; CR + PR + stable disease ≥4 cycles [SD]) for each cohort and to evaluate the safety of tinostamustine. Secondary efficacy variables included progression-free survival (PFS) and overall survival (OS); all outcomes were evaluated from Cycle 3 until progression or toxicity. Results 48 patients with advanced haematological malignancies were enrolled to the study and received treatment with tinostamustine (HL, n=20; CTCL, n=13; PTCL, n=8; T-PLL, n=1; MM, n=6; Table). Patients with HL, CTCL, PTCL and T-PLL received 50 mg/m 2 (1 patient), 80 mg/m 2 (7 patients) and 100 mg/m 2 (34 patients) over 60 minutes on Day 1 of a 21-day cycle; patients with MM: 60 mg/m 2 over 60 minutes on Day 1 and Day 15 of a 28-day cycle. Patients received a median of 3.5 (range 1-12) cycles of tinostamustine. No unexpected AEs were observed. Treatment-emergent AEs (TEAEs) occurred in 46/48 (95.8%) patients (500 events), with 28 patients experiencing 90 events ≥Grade 3. Gastrointestinal AEs were observed in 33/48 patients, the majority of which were nausea or vomiting. Haematological AEs, including thrombocytopenia, anaemia and neutropenia, occurred in 27/48 patients. Serious TEAEs considered related to tinostamustine occurred in 11 patients with HL or CTCL ( Table) and included thrombocytopenia (n=3) and infusion-related reaction (n=1); one patient with CTCL experienced a fatal TEAE of decreased appetite. Overall, 22/48 (45.8%) patients discontinued due to progressive disease and 13/48 (21.6%) discontinued due to AEs. In the 46 patients included in the efficacy analysis, ORR was 30.4% (95% confidence interval [CI]: 17.7%, 45.8%) and CBR 52.2% (95% CI: 36.9%, 67.1%). 4 patients achieved a CR (2 patients with HL, 2 CTCL), 10 a PR (5 HL, 4 CTCL, 1 PTCL) and 14 SD (4 HL, 4 CTCL, 3 PTCL, 3 MM). Median PFS was 4.3 months (95% CI: 2.7, 6.6 months; HL, 3.8 [2.2, 9.4] months; CTCL, 7.3 [3.2, not estimable (NE)] months; PTCL, 2.6 [1.4, NE] months; T-PLL, 0.5 [NE, NE] months; MM, 2.4 [1.4, NE] months;). Median OS was 10.3 (95% CI: 2.2, NE) months for PTCL, 5.6 (95% CI: NE, NE) months for T-PLL and not estimable for HL, CTCL and MM. Conclusions Results from expansion cohorts further demonstrate that tinostamustine has manageable tolerability in patients with advanced haematological malignancies with no unexpected AEs. The principal TEAEs were haematological and gastrointestinal. An ORR of 30.4% and a median progression-free survival of 4.3 months were observed, revealing signals of efficacy in this heavily pre-treated patient population for whom no other standard therapy with proven clinical benefit was available or recommended. Funding: Mundipharma Research Limited and Purdue Pharma, LP

Outcomes of Lymphoma and Multiple Myeloma Patients Following Inpatient Antineoplastic Treatment

Introduction: Patients (pts) with hematologic malignancies receive more aggressive end-of-life care, including hospitalizations and antineoplastic therapy, compared to solid tumor. 1 In the modern era, treatment for lymphoma and multiple myeloma is mostly administered in the outpatient setting. Pts requiring inpatient treatment may have an aggressive disease course, decreased performance status, and comorbidities that impact clinical outcomes. Treatment decisions in the acute care setting are challenging due to the need to balance efficacy, toxicity, and cost. Given the paucity of data available to help guide decision-making, we sought to investigate the outcomes of inpatient administration of unplanned antineoplastic therapy. Methods: This retrospective cohort study included adults (≥18 years) with lymphoma and multiple myeloma who received unplanned inpatient antineoplastic therapy between June and October 2022. Pts who received planned chemotherapy or first cycle of treatment for newly diagnosed disease were excluded. Pts undergoing outpatient induction or salvage therapy admitted for complications who subsequently received their next cycle while admitted were included. Baseline characteristics, diagnosis, treatment, and clinical outcomes were abstracted from the electronic medical record. The primary endpoint was rate of treatment continuation or completion 60 days after first administration of inpatient therapy. Secondary endpoints included overall survival (OS); length of stay (LOS) following treatment; transfer to intensive care unit (ICU), emergency department (ED) visits, and readmissions within 30 days; and death within 30 and 60 days of inpatient treatment. Results: Of the 172 pts screened, 49 pts were included after excluding 122 pts (76 had planned chemo and 46 had newly diagnosed disease). Median age was 63 years (range, 34-88). Treatment was for a variety of diagnoses, including plasma cell neoplasm (53%), diffuse large B-cell lymphoma (18%), central nervous system lymphoma (14%), chronic lymphocytic leukemia (4%), as well as 1 pt each with T-cell prolymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, NK/T-cell lymphoma, and T-cell lymphoma. Most had relapsed/refractory disease (90%). Thirteen (26%) pts received inpatient only regimens; however, these were not planned admissions. Fifteen (31%) pts received drugs traditionally restricted to outpatient use only (daratumumab (10), carfilzomib (3), obinutuzumab (1), loncastuximab tesirine (1), polatuzumab vedotin (1)). At 60 days after first inpatient treatment, 15 (31%) pts continued or completed treatment, while treatment was discontinued in 34 (69%) pts. Of the 15 pts who continued treatment, 53% (8/15) received ≤ 3 additional cycles after discharge. Median time to discharge following inpatient treatment initiation was 5 days (range, 0-38). Fourteen (29%) pts were transferred to the ICU, 16 (33%) pts presented to the ED after discharge, and 14 (29%) were readmitted within 30 days of inpatient treatment. Overall survival was 26.5% at a median follow up of 157 days. The 30- and 60-day mortality rates were 18% and 31% respectively. Univariate and multivariate analysis to identify prognostic factors for survival will be conducted. Conclusions: In this retrospective analysis, about a quarter of pts with lymphoid and plasma cell malignancies were alive at 5 months after receiving unplanned inpatient antineoplastic therapy. Better tools are needed to select pts who may benefit from urgent inpatient treatment, as a small subset of our cohort experienced continued clinical benefit. Combining such tools with multidisciplinary discussions may help to maximize favorable outcomes while minimizing use of aggressive end-of-life antineoplastic treatment. Ongoing analysis in our population will aim to identify patient-specific factors associated with positive outcomes.

Preliminary Safety, Pharmacokinetics, Pharmacodynamics and Clinical Activity of KT-333, a Targeted Protein Degrader of STAT3, in Patients with Relapsed or Refractory Lymphomas, Large Granular Lymphocytic Leukemia, and Solid Tumors

Background: KT-333is a first-in-class, potent, highly selective, heterobifunctional small molecule degrader of the signal transducer and activator of transcription 3 (STAT3) protein. Aberrant activation of STAT3 resulting from activating mutations or deregulated cytokine signaling underlies various malignancies including peripheral T-cell lymphomas (PTCL), cutaneous T-cell lymphoma (CTCL), and large granular lymphocytic leukemia (LGL-L). Approximately 70% of human cancers including hematological malignancies and solid tumors exhibit increased levels of phosphorylated STAT3 (pSTAT3), a biomarker of pathway activation. In non-clinical studies, treatment with KT-333 resulted in durable tumor regressions with weekly (QW) or once every two weeks IV administration in STAT3-dependent T cell lymphomas. STAT3 degradation also sensitized immunocompetent mouse models of solid and liquid cancers to anti-PD1(ASH 2021, SITC 2021). Methods: The ongoing open-label, Phase 1a/1b study is evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary clinical activity of KT-333 administered as a QW IV infusion on Day 1, 8, 15 and 22 (28-day cycle) in patients (pts) with B- and T-cell lymphomas, Hodgkin's lymphoma and advanced solid tumors (ST) relapsed/refractory (R/R) to at least two prior systemic therapies and LGL-L and T-cell prolymphocytic leukemia R/R to at least one prior therapy. Cycle 1 and 2 blood samples are collected for KT-333 plasma concentrations and to measure changes in STAT3 protein expression in peripheral blood mononuclear cells (PBMCs) using targeted mass spectrometry. Whole blood RNA sequencing measures mRNA levels of STAT3 regulated targets. Plasma levels of inflammatory biomarkers are measured with Luminex. STAT3 degradation and other related biomarker changes in tumor are assessed in patients with accessible tumors. (NCT05225584). Results: As of July 10, 2023, 21 pts were treated at five dose levels (DL) in Phase 1a with a mean number of 5.8 doses. Pts included B-cell non-Hodgkin's lymphoma (n=1: DL5), Hodgkin's lymphoma (HL) (n=1: DL4), CTCL (n=3: DL1, 2 and 4), PTCL (n=1: DL2), LGL-L (n=2: DL5) and ST (n=13: DL1-4) with median age of 61 years (range 30,77) and ECOG performance status of 0 (n=7) or 1 (n=14). No DLTs and no KT-333 related serious adverse events (SAE) were reported. The most common AEs were Grade 1 and 2 and included constipation, fatigue, nausea and anemia. Best response among pts evaluable for response at data cut-off (not including CTCL or HL pts at DL4 or any DL5 pts) included one partial response after two cycles in a CTCL pt at DL2 and SD after two cycles in three ST pts treated at DL3 and DL4. PD data in blood available for DL1-4 demonstrated robust, dose-dependent, and sustained STAT3 degradation in PBMC. The mean maximum degradation of STAT3 by targeted mass spectrometry over the first two weeks in Cycle 1 by DL was (% (range; n)): DL1: 69.9% (52.6% to 84.1%; n=4), DL2: 73.5% (65.5% to 80.7%; n=3), DL3: 79.9% (72.3% to 90.4 %; n=3) and DL4: 86.6% (78.9% to 95.9 %; n=4) with absolute quantification of STAT3 peptides falling below lower limit of quantification of the assay for one pt in DL3 and two in DL4. STAT3 pathway inhibition in blood was demonstrated via transcriptional downregulation of a canonical JAK/STAT3 target, SOCS3, which correlated with changes in STAT3 protein levels. KT-333 also resulted in dose-dependent downregulation of STAT3-regulated inflammatory biomarkers C-reactive protein and serum amyloid A protein in plasma. KT-333 demonstrated linear PK with plasma exposure increasing with dose and reaching levels close to those predicted to be efficacious. Conclusion: The emerging clinical data demonstrate that KT-333 is a potent degrader of STAT3 as demonstrated in PBMCs at doses that are well tolerated. These data provide the first evidence of STAT3 targeted protein degradation in humans with associated STAT3 pathway inhibition, along with potential early signs of antitumor activity, highlighting the potential of heterobifunctional degraders for targeting previously undruggable transcription factors implicated in diseases. Based on non-clinical data and PK/PD modeling, the high levels of degradation achieved so far are expected to be clinically efficacious in STAT3-dependent malignancies. Accrual is ongoing, and analyses from additional patients will be presented at the meeting.

Immunophenotypic Profile of Chronic Lymphoproliferative Diseases in the State of Rio Grande Do Norte, Northeast, Brazil

INTRODUCTION: Chronic lymphoproliferative diseases (CLPD) are considered as a heterogeneous group of diseases characterized by monoclonal expansion and accumulation of apparently mature lymphocytes, which have a proliferative and/or survival advantage over normal lymphocytes in different organs such as bone marrow, peripheral blood and lymph nodes. This translates into the progressive accumulation of clonal cells and their products, causing peripheral blood and bone marrow lymphocytosis, in addition to lymphadenopathy, splenomegaly or other organomegaly. According to the World Health Organization, which reflects the international consensus and is based on pathological, genetic and clinical factors, lymphoproliferative neoplasms are classified according to the stage of maturation and the lineage where the neoplastic transformation occurs through flow cytometry (FC). OBJECTIVES: The aim of this study was to demonstrate the immunophenotypic diagnostic profiles of patients with CLPD in Rio Grande do Norte, Brazil by FC. METHODOLOGY: Were investigated 884 patients with CLPD of both sexes through CF with a panel of monoclonal antibodies directed to CLPD. In addition, other patient information, such as age, gender, and clinical and hematological data were also collected. RESULTS: The results showed that 89.7% of the cases were B Cell CLPD (B-CLPD) and 10.3% T and natural killer cells (T/NK-CLPD). The distribution of B-CLPD cases were as follows: 487 Chronic lymphocytic leukemia; 18 B-Cell Pro-lymphocytic leukemia; 25 Hairy cell leukemia; 6 variant Hairy cell leukemia; 6 Follicular lymphoma leukemized; 4 Splenic lymphoma with villous lymphocytes; 33 Mantle cell lymphoma; 4 Waldenstrom's macroglobulinemia; 69 Multiple myeloma; 14 Plasma cell leukemia; 11 Burkitt's lymphoma and 117 Leukemic Non-Hodgkin lymphoma (Table 1). The distribution of CLPD-T/NK was as follows: 12 Large granular lymphocytic leukemia; 14 T-Cell prolymphocytic leukemia; 18 Adult T-cell leukemia; 20 Sézary syndrome; and 24 Peripheral T-Cell lymphoma and 2 DLPC-NK (Table 1). DISCUSSION: The B-CLPD are the most commonly observed corresponding to more than 85% of all cases and are characterized by the presence of clonal B lymphocytes with expression of a single type of immunoglobulin light chain (kappa or lambda) in a proportion greater than 1/10, associated the strong positivity of Pam-B antigens such as CD19, CD22 and CD20 and the absence or low expression of Pam-T antigens. However, other antigens such as CD200, CD5, FMC7, CD79b and CD103, among others, may be present or absent, specifically characterizing these entities as Chronic lymphocytic leukemia (weak CD22+; CD200+, CD5+, FMC7-, CD79b-), Hairy cells leukemia (strong CD22+; FMC7+; CD79b+; CD5-; CD200-; CD103+; CD123+; CD11c+ and Follicular lymphoma (strongCD22+/CD20+, CD10+, CD200-, CD79B+, FMC7+). T/NK-CLPD are less frequent and are characterized by the expression of Pan-T antigens CD2, CD3, CD5, CD7, CD28 and TCL-1, with clonality evidenced by strong positivity of TCRα/β in most cases and increase of TCD4+ or TCD8+ lymphocytes in a ratio above 1:10 in most cases. In this group, large granular lymphocyte leukemia (LGLG) is a rare type of T/NK cell CLPD characterized by peripheral and medullary infiltration of large hypergranular lymphocytic cells, comprising about 2-5% of all cases, the most commonly seen being CD8+ T cells. CONCLUSION: The results presented demonstrate that immunophenotyping is a defining technique for clarifying the diagnosis of patients with CPLD, clonality was also successfully characterized in the investigated cases of CPLP of B ,T and NK lineages.

Intent to Treat Allogeneic Stem Cell Transplantation Outcomes in Relapsed/Refractory T-Cell Lymphomas

Introduction T-cell lymphomas (TCL) are a heterogeneous group of lymphoproliferative malignancies with an overall poor prognosis. Despite aggressive first-line therapy, most patients experience disease relapse or progression. Allogeneic stem cell transplant (AlloSCT) is a standard of care for relapsed/refractory (R/R) TCL. However, many patients do not receive this potentially curative therapy. There is a paucity of data regarding the frequency of and barriers to undergoing AlloSCT in R/R TCL. To address this knowledge gap, we conducted a retrospective analysis of R/R TCL patients intending to undergo AlloSCT and hypothesized the primary barrier to AlloSCT to be lack of effective disease control. Methods We identified patients with a primary diagnosis of R/R TCL seen at the University of Washington/Fred Hutchinson Cancer Center (UW/FHCC) between 1/2008 and 6/2023 and linked these patients with the UW/FHCC bone marrow transplant (BMT) database to identify those who were intended for transplant. Intention to transplant (ITT) was defined as undergoing human leukocyte antigen (HLA) typing for purposes of AlloSCT. Patients with T-cell lymphoblastic leukemia/lymphoma were excluded. The primary endpoint was the rate of patients who underwent AlloSCT. Secondary endpoints included progression-free (PFS) and overall survival (OS) in patients who underwent AlloSCT and specific barriers to AlloSCT. Results Overall, 163 patients met ITT criteria. Males comprised 66% of patients. Median age was 65 (range 34-81) years and the median number of treatment regimens prior to HLA typing was 3 (range 1-10). The majority of patients (60%) were non-Hispanic whites (NHW), with Asians/Pacific Islanders (API), Hispanics/Latinos (HL), African Americans (AA) and Alaskan Natives/American Indians (ANAI) contributing 17%, 12%, 7% and 4%, respectively. Sixty-four patients (39%) had peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), 23 (14%) had angioimmunoblastic TCL (AITL), 17 (10%) had anaplastic large cell lymphoma (ALCL; 6 with ALK+), 16 (10%) had NK/TCL, 11 (7%) had hepatosplenic TCL, 12 (7%) had T-cell prolymphocytic leukemia, 5 (3%) had adult T-cell leukemia/lymphoma and 12 (7%) had primary cutaneous TCL. Twenty-two (13%) patients had secondary CNS involvement and 27 (17%) had previous autologous stem cell transplant. Of all patients who received HLA typing, 154 (94%) had a transplant consult, 54 (33%) initiated pre-AlloSCT workup and 51 (31%) underwent AlloSCT. Barriers to AlloSCT included progressive disease, patient preference, inability to identify a donor, indolent disease, poor functional status/multiple comorbidities and lack of a caregiver in 55%, 9%, 8%, 5%, 3% and 1%, respectively (Figure 1A). Six (5%) patients are currently receiving salvage therapy with plans for subsequent AlloSCT. AlloSCT occurred in NHW, API, HL, AA and ANAI patients at rates of 35%, 11%, 26%, 36% and 50%, respectively. All patients who were unable to undergo transplant due to lack of a donor were from groups other than NHW. AlloSCT rates were 30%, 39% and 17% in PTCL-NOS, AITL and ALCL, respectively. At a median follow-up time of 24.2 months, 101 (63%) patients are deceased with 83 (82%) due to disease. Twenty (39%), 17 (33%), 11 (22%) and 3 (6%) patients received an AlloSCT with a matched unrelated, matched related, mismatched unrelated and haploidentical donor, respectively. Fifteen (29%) patients underwent a myeloablative while 36 (71%) underwent a reduced intensity conditioning regimen. None of the 51 patients who underwent AlloSCT had pre-transplant measurable disease. Of transplanted patients, median PFS was 55.7 months and OS was 62.4 months (Figure 1B). Sixteen (31%) patients had eventual disease relapse. Eighty percent of relapses occurred within 3 months after AlloSCT. Seven (13%) and 6 (12%) of the transplanted patients were deceased within 12 months after AlloSCT due to disease relapse and complications of AlloSCT, respectively. Conclusions Although AlloSCT may be highly effective for R/R TCL achieving a CR, only a small minority of patients are able to undergo AlloSCT and the outcomes for the ITT population is dismal. Common barriers to undergoing AlloSCT include progressive disease and inability to identify suitable donors, particularly in minority populations. More effective pre-transplant salvage therapies and alternative AlloSCT donors are greatly needed.

A-159 Role of TCRB1 Antibody in the Evaluation Panel of T Lymphoproliferative Diseases

Abstract Background The diagnosis of T lymphoproliferative diseases is usually a challenge due to the difficulty indifferentiating pathological T cells from reaction cells and also due to the limitation of clonalitytests currently available. TCRB1 is a monoclonal antibody specific for region 1 of the TCR T cellreceptor Beta chain constant, detecting clonal populations of TCRab positive T cells in caseswhere its expression is monotypic. Its application is similar to immunoglobulin light chainrestriction in the detection of B cell lymphoproliferations and in normal T CD3 + TCRab + cells, theexpression of this marker is polytypic. The objective of the present work is to report theexperience of including this antibody in the lymphoproliferative T panel in a private laboratoryin southern Brazil. Methods Samples received with indication of lymphoproliferative disease and lymphocytosis wereevaluated using the tube Lymphocyte Screnning Tube—LST (Euroflow) and were acquired usingFACS CANTO or FACS LYRIC cytometers. Analyzes were performed using Infinicyt software. After, all, samples that showed alteration in the CD4/CD8 ratio, or antigen alteration in the expressionof pan T markers were evaluated for the complete investigation panel according to Euroflowprotocol. This panel had the incorporation of the tube for the evaluation of clonality that hasthe TCRB1 antibody in the PE channel associated with the anchor markers CD45V500, CD3PerCpcy5, CD4V450 and CD8APCH7. The channels that were not used (FITC, APC, Pecy7) areused when necessary, to evaluate antigens that can help select the desired aberrant population,such as CD5, CD2, CD7 antibodies or to assess maturation, like CD45RA and CD27. Data werecollected from the beginning of the use of this antibody from February 2021 until the presentmoment. Results During this period, 2870 samples for immunophenotyping analysis were received, of which 17cases were T chronic lymphoproliferative diseases. Of the 17 cases found, 11 (65%) were caseswith the pathological population TCRab positive and the expression of TCRB1 could beevaluated. In these cases, the expression of the patologic cells was monotypic for the TCRB1antigen. The cases were: 4 large granular lymphocytic (LGL) leukemia, 4 Adult T-cellleukemia/lymphoma /Peripheral T-cell lymphoma, unspecified , 1 Sezary syndrome, 1 T-celllymphoblastic lymphoma in cortical/common thymocyte stage and 1 T-cell prolymphocyticleukemia (T-PLL). Recent studies have demonstrated the high specificity of this test for clonality, as long as it is associated with an expanded and standardized lymphoproliferative panel. Thepresent cases demonstrated good results for peripheral blood samples, bone marrow and lymphnode biopsy. Conclusion T-lymphoproliferative disorders remain a diagnostic challenge, due to the difficulty of a simpletest to assess clonality. The inclusion of the TCRB1 antibody in the lymphoproliferative panelincreased the specificity of the test for diagnosis, being a method of rapid execution and lowcost. Another advantage of using this marker is the possibility of evaluating small cell clonesthat may not be detected in molecular biology techniques due to the sensitivity of the test.

T-Cell Prolymphocytic Leukemia: Diagnosis, Pathogenesis, and Treatment.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells. Most patients with T-PLL present with lymphocytosis, anemia, thrombocytopenia, and hepatosplenomegaly. Correct identification of T-PLL is essential because treatment for this disease is distinct from that of other T-cell neoplasms. In 2019, the T-PLL International Study Group (TPLL-ISG) established criteria for the diagnosis, staging, and assessment of response to treatment of T-PLL with the goal of harmonizing research efforts and supporting clinical decision-making. T-PLL pathogenesis is commonly driven by T-cell leukemia 1 (TCL1) overexpression and ATM loss, genetic alterations that are incorporated into the TPLL-ISG diagnostic criteria. The cooperativity between TCL1 family members and ATM is seemingly unique to T-PLL across the spectrum of T-cell neoplasms. The role of the T-cell receptor, its downstream kinases, and JAK/STAT signaling are also emerging themes in disease pathogenesis and have obvious therapeutic implications. Despite improved understanding of disease pathogenesis, alemtuzumab remains the frontline therapy in the treatment of naïve patients with indications for treatment given its high response rate. Unfortunately, the responses achieved are rarely durable, and the majority of patients are not candidates for consolidation with hematopoietic stem cell transplantation. Improved understanding of T-PLL pathogenesis has unveiled novel therapeutic vulnerabilities that may change the natural history of this lymphoproliferative neoplasm and will be the focus of this concise review.

Delineation of clinical course, outcomes, and prognostic factors in patients with T-cell prolymphocytic leukemia.

T-cell prolymphocytic leukemia (T-PLL) is a rare, post-thymic T-cell neoplasm with a diverse clinical course. T-PLL is typically associated with a poor prognosis; however, a subset of patients have inactive disease on initial presentation. There is a lack of accurate delineation of the disease based on initial clinical presentation and pathological assessment, hindering clinical decision-making. To characterize and delineate disease subtypes based on initial clinical presentation and pathologic assessment, we retrospectively reviewed 81 patients with T-PLL treated at our institution. We compared patients with T-PLL who initially presented with a relatively indolent or stable disease course to those with an aggressive disease course. Clinicopathologic characteristics, overall survival (OS), and prognostic factors were analyzed. Patients with inactive disease had a significantly longer OS than patients with active disease. At diagnosis, presence of B symptoms, low hemoglobin, low platelet count, lymphocyte doubling time of fewer than 3 months, and abnormal cytogenetics were associated with shorter OS. Cell morphology, immunophenotype, absolute lymphocyte count, lactate dehydrogenase levels, involvement of liver, spleen, skin or central nervous system, presence of TCL1 rearrangement or inv (14)/t(14;14), presence of chromosome 8 abnormalities, and presence of deletion of 11q were not associated with significant OS difference among the patients. Receiving alemtuzumab as first-line treatment and consolidation with allogeneic hematopoietic stem cell transplant were associated with better outcomes. T-PLL inactive and active disease subtypes can exhibit overlapping yet different clinical and pathological features. We describe several prognostic factors at diagnosis that can be used for risk stratification and aid in guiding treatment decisions.

T-Cell Prolymphocytic Leukemia With t(X;14)(q28;q11.2): A Clinicopathologic Study of 15 Cases.

T-cell prolymphocytic leukemia (T-PLL) is a rare mature T-cell leukemia usually characterized by inv(14)(q11.2q32)/t(14;14)(q11.2;q32). In this study, we aimed to investigate the clinicopathologic features and molecular profile of T-PLL associated with t(X;14)(q28;q11.2). The study group included 10 women and 5 men with a median age of 64 years. All 15 patients had a diagnosis of T-PLL with t(X;14)(q28;q11.2). All 15 patients had lymphocytosis at initial diagnosis. Morphologically, the leukemic cells had features of prolymphocytes in 11 patients, small cell variant in 3, and cerebriform variant in 1. All 15 patients had hypercellular bone marrow with an interstitial infiltrate in 12 (80%) cases. By flow cytometry, the leukemic cells were surface CD3+/CD5+/CD7+/CD26+/CD52+/TCR α/β+ in 15 (100%) cases, CD2+ in 14 (93%) cases, CD4+/CD8+ in 8 (53%) cases, CD4+/CD8- in 6 (40%) cases, and CD4-/CD8 + in 1 (7%) case. At the cytogenetic level, complex karyotypes with t(X;14)(q28;q11.2) were seen in all 15 patients assessed. Mutational analysis showed mutations of JAK3 in 5 of 6 and STAT5B p.N642H in 2 of 6 patients. Patients received variable treatments, including 12 with alemtuzumab. After a median follow-up of 17.2 months, 8 of 15 (53%) patients died. T-PLL with t(X;14)(q28;q11.2) frequently shows a complex karyotype and mutations involving JAK/STAT pathway, and it is an aggressive disease with a poor outcome.

Treatment of lymphoid malignancies in patients with primary immunodeficiencies associated with DNA repair defects

Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia (AT; Louis–Bar syndrome) are primary immunodeficiencies (PID) associated with chromosome instability and DNA repair defects that predispose individuals to an increased risk of various malignancies. In our study, we retrospectively analyzed clinical characteristics and outcomes of 28 cancer cases in 14 patients with AT and 10 patients with NBS who had been treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between January 2007 and December 2022. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The most common type of malignancy was mature B-cell non-Hodgkin lymphoma (B-NHL) (42%), with diffuse large B-cell lymphoma (DLBCL) accounting for 91% of all B-NHL cases. Other cases included T-cell acute lymphoblastic leukemia (ALL) (n = 3), B-cell ALL (n = 2), Hodgkin lymphoma (n = 3), NK/T-cell lymphoma (n = 1), T-cell lymphoblastic lymphoma (n = 1), peripheral T- cell lymphoma (n = 2), medulloblastoma (n = 1) epithelioid rhabdomyosarcoma (n = 1), T-cell prolymphocytic leukemia (n = 2). A total of 4 patients were diagnosed with second malignancies (2 children with AT and 2 children with NBS. The diagnosis of PID was suspected or confirmed before the initiation of cancer therapy in 62% of AT patients and in 100% of NBS patients. Treatment was given in accordance with standard protocols with chemotherapy dose modifications. A total of 93% of patients with AT and 80% of patients with NBS required dose reduction. The level of response was quite high: 81% of patients with AT and 58% of patients with NBS achieved complete remission. According to our data, the use of reduced-dose chemotherapy regimens helps to achieve an acceptable toxicity profile without reducing the overall effectiveness of treatment.

517 - Outcomes after Reduced-Intensity Conditioning with Pentostatin and Low-Dose TBI in Patients with T Cell Prolymphocytic Leukemia (T-PLL): A Single Institution Experience

517 - Outcomes after Reduced-Intensity Conditioning with Pentostatin and Low-Dose TBI in Patients with T Cell Prolymphocytic Leukemia (T-PLL): A Single Institution Experience

Une présentation particulière de leucémie à grands lymphocytes granuleux

T cell prolymphocytic leukemia (T-PLL) is a rare, aggressive neoplasm derived from post-thymic T cells. Patients are typically middle-aged with a slight male predominance who present with a high white blood cell count, hepatosplenomegaly, lymphadenopathy, and other symptoms typically associated with leukemia. Although cutaneous involvement has been reported in up to 30% of cases of T-PLL, to our knowledge, none have presented with a presentation resembling livedoid vasculopathy. In the correct clinical context, an underlying hematolymphoid neoplasm should be included in the differential diagnosis of a patient presenting with livedoid vasculopathy.