Hanson, CA

Abstract Prognostic indices such as the CLL International Prognostic Index (CLL-IPI) and the International Prognostic Score for Early-stage CLL (IPS-E) can predict time to first treatment (TTFT) in patients with early-stage CLL. Their ability to predict risk of infection - a leading contributor to morbidity and mortality in CLL - remains uncertain. The CLL-TIM is a machine-learning model developed in Europe that integrates clinical, laboratory, and infection-related data to predict TTFT or infection risk within 2-years of diagnosis, Receiver Operating Characteristic - Area Under the Curve (ROC-AUC) 0.74; Agius et al., Nat Comm 11, 363 2020. We conducted the first validation of CLL-TIM in a US cohort of newly diagnosed CLL patients and compared its performance with the CLL-IPI and IPS-E indices. Adults with newly diagnosed CLL (2000-2020) were identified through the Rochester Epidemiology Project using International Classification of Disease (ICD) codes; all diagnoses were confirmed. We replicated the variable selection from the original CLL-TIM model and applied it to our cohort. The primary endpoint was a 2-year composite of either TTFT or incident infection (defined as having blood cultures drawn). Model performance was evaluated using ROC-AUC consistent with the original CLL-TIM methods. CLL-IPI and IPS-E performance was assessed using time-dependent ROC-AUC; pairwise differences in discrimination were tested using DeLong. We identified 454 CLL patients with a median age of 72 years [range, 30-97], 166 (37%) were female, Rai Stage was 0-II in 399 (92%) patients. IGHV genes were unmutated in 130/305 (42%) patients and TP53 disruption (either del17p by FISH or TP53 mutation) was present in 24/329 (8%) patients. At 2-years, 55 (12%) patients received CLL therapy, and 56 (12%) patients had an infection. The 2-year composite endpoint was observed in 94 (21%) patients. The ROC-AUC was 0.74 (95% CI 0.68-0.80) for CLL-TIM, 0.69 for CLL-IPI (95% CI 0.63-0.75, p=0.11 compared to CLL-TIM) , and 0.68 for IPS-E (95% CI 0.62-0.74, p=0.02 compared to CLL-TIM). We also evaluated the ROC-AUC using all the prognostic models for each individual endpoints. The corresponding ROC-AUC for TTFT at 2 years were 0.79, 0.74, and 0.76 for CLL-TIM, CLL-IPI, and IPS-E, respectively; and for infection at 2 years were 0.68, 0.57, and 0.52, respectively. This is the first validation of the CLL-TIM in a US-based cohort of newly diagnosed CLL patients. Although the CLL-TIM model exceeded the minimally meaningful discrimination threshold (AUC >0.7) for individual patient-level risk prediction, there was no statistical difference in AUC between CLL-TIM and CLL-IPI, suggesting either model can predict the composite endpoint at 2 years. Most of the observed discrimination was driven by prediction of TTFT rather than infection, underscoring the need to develop more infection-specific risk models for newly diagnosed CLL. Citation Format: Raphael Mwangi, Tait D. Shanafelt, Soren Basnet, Emily L. West, Owen Keegan, Timothy G. Call, Yao Yuan, Bryan Alexis Vallejo, Paul J. Hampel, Lindsey E. Roeker, Yucai Wang, Saad J. Kenderian, Sara J. Achenbach, Aaron D. Norman, Kari G. Rabe, Neil E. Kay, James R. Cerhan, Curtis A. Hanson, Susan L. Slager, Sameer A. Parikh. Validation of the CLL treatment infection model (CLL-TIM) in patients with newly diagnosed chronic lymphocytic leukemia (CLL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 4228.

Abstract Background: Hypogammaglobulinemia at the time of CLL diagnosis predicts shorter time to first therapy (TTFT). However, the depth of immunoparesis and its impact on TTFT in newly diagnosed MBL/CLL remains unexplored. Methods: We identified previously untreated MBL/CLL patients from Mayo Clinic CLL Database (2000-2024) who had serum immunoglobulin (Ig; IgG, IgM and IgA) and monoclonal protein assessed within 1 year of diagnosis. Immunoparesis was evaluated: a) qualitatively by classifying patients into preserved, partial and full Ig suppression, based on the number of suppressed Igs; and b) quantitatively by calculating the average relative difference (ARD), defined as the mean percentage below normal for all Igs. For both methods, only uninvolved Igs were considered for those with monoclonal protein. TTFT was estimated by Kaplan-Meier with competing risk of death. Cox models estimated hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 1420 patients, median age at diagnosis was 65 (range 28-96); 954 (67%) were male; 493 (44.8%) had unmutated IGHV, and 86 (6.8%) had TP53 disruption. The median [range, mg/dL] serum IgG, IgA, and IgM were 889 [111-5290], 132 [1-4880], and 49 [4-9480]. Low IgG was present in 472 (33.2%), low IgA in 223 (16.4%), and low IgM in 530 (37.3%) patients. An M-spike was detected in 122 (8.6%) patients; distribution was: IgG (73), IgM (30), IgA (6), or multiple (13). By qualitative assessment, preserved Ig were seen in 664 (46.8%), partial Ig suppression in 604 (42.5%), and full suppression in 152 (10.7%) patients. By quantitative assessment, median ARD was 0.6 (-0.8 to 11.3); 280 (19.7%) patients had negative ARD, and 1140 (80.3%) had positive ARD. In those with negative ARD, 128 (9%) had partial Ig suppression and 152 (10.7%) had full Ig suppression; in those with positive ARD, 664 (46.8%) had preserved Ig and 476 (33.5%) had partial Ig suppression. Median follow-up was 14.7 years; 510 patients progressed requiring therapy. Median TTFT was 9.6 years. Median TTFT for patients with preserved Ig was 12.6 years, 8.0 years for partial Ig suppression (HR 1.4, 95%CI 1.1-1.7), and 1.8 years for full Ig suppression (HR 3.1, 95%CI 2.4-4.0). The median TTFT was 2.3 and 12.1 years for patients with negative vs positive ARD; negative ARD was associated with shorter TTFT (HR 2.4, 95%CI 2.0-2.9). After adjusting for sex and CLL-International Prognostic Index (CLL-IPI) score, full Ig suppression (HR 2.9, 95%CI 2.2-3.9) and partial Ig suppression (HR 1.6, 95% CI 1.3-2.0) were associated with shorter TTFT (model 1, c-stat 0.77); and negative ARD (HR 2.4, 95%CI 2.0-2.9) was associated with shorter TTFT (model 2, c-stat 0.76). Negative ARD identified an additional 9% of patients at higher risk for shorter TTFT beyond full Ig suppression. Conclusions: The depth of immunoparesis at diagnosis predicts TTFT and enhances risk stratification in newly diagnosed MBL/CLL. Citation Format: Yuan Yao, Kari G. Rabe, Eli Muchtar, Paul Hampel, Yucai Wang, Lindsey Roeker, Saad Kenderian, Amber Koehler, Catherine Wagner, Amy Behnken, Jose F. Leis, Mazie Tsang, Talal Hilal, Ricardo Daniel Parrondo, Susan M. Schwager, Min Shi, Curtis A. Hanson, Celine M. Vachon, Shaji Kunnathu Kumar, Esteban Braggio, Neil E. Kay, Susan Slager, Sameer A. Parikh. Depth of immunoparesis predicts time to first therapy in newly diagnosed monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1191.

Abstract Background: Myelofibrosis (MF) is characterized by progressive bone marrow (BM) fibrosis resulting from aberrant megakaryopoiesis and expression of pro-inflammatory cytokines. These processes, heavily influenced by bromodomain and extraterminal domain (BET) protein-mediated gene regulation, lead to myeloproliferation and cytopenias. There is a high unmet need for a treatment that can potentially delay or reverse BM fibrosis in patients (pts) with MF. Pelabresib (CPI-0610) is a potent, first-in-class, selective, oral small-molecule BET inhibitor, which is able to modify the expression of genes involved in nuclear factor kappa B (NFκB) signaling in pts with MF. Pelabresib is currently being investigated as a monotherapy and in combination with the JAK inhibitor (JAKi) ruxolitinib (RUX), in the ongoing MANIFEST Phase 2 study (NCT02158858). Methods: In arm 1 of MANIFEST, pelabresib is administered as monotherapy to pts with MF who are intolerant/refractory to, or ineligible for RUX; in arm 2, as an 'add-on' to RUX in pts with MF who have suboptimal/lost response; and in arm 3 as combination therapy with RUX in JAKi treatment-naïve pts with MF. To evaluate the effects of pelabresib on BM biology, analyses were conducted using BM biopsy samples obtained pre-treatment and at 24 weeks post-treatment during the MANIFEST trial. Central pathology review of reticulin staining was conducted to evaluate BM fibrosis (BMF) grading and immunohistochemistry staining for changes in erythroids (ERY) and megakaryocytes (MK), respectively. Independent digital images of stained BM slides were also evaluated with a semi-quantitative cell-specific detection algorithm for reticulin density, percentage CD71+ ERY, mean number of CD61+ MK and mean distance between nuclei for CD61+ MK. Results: Exploratory analyses across the three treatment arms showed BM improvements after 24 weeks of treatment. Paired comparison by digital analysis of baseline and 24-week treatment BM biopsies from 29 pts showed reduction (range 67%-15.5%) in reticulin intersections per field in 45% (13/29) pts. Furthermore, digital analysis of CD71+ ERY and CD61+ MK from paired biopsies showed increased ERY progenitors in 50% (16/32) pts, decreased MK density in 57% (15/26) pts and decreased MK clustering in 46% (12/26) pts at 24 weeks. Decreased MK clustering correlated with decreased density of CD61+ MK in 75% pts (9/12). Correlative analysis between observed clinical responses and bone marrow improvements are ongoing and will be available for presentation at the conference. We previously reported (Talpaz M, et al. ASH 2020; Abstract 2163) that in pts with MF, pelabresib can reduce spleen volume, improve symptoms, improve bone marrow fibrosis, demonstrate increase in hemoglobin levels, and reduce transfusion burden. Updated 24-week data reflecting a higher number of evaluable pts and new long-term data at 48 weeks across the MANIFEST trial, will be presented. Conclusions: Treatment with pelabresib as monotherapy or in combination with RUX, in both RUX treatment-naïve and -experienced pts with MF, resulted in increased ERY progenitors, decreased MK density and reduction of BM fibrosis, as assessed by digital pathology. These data suggest possible disease-modifying potential for pelabresib by improving BM histology and function, leading to potential clinical benefits. Disclosures Verstovsek: Roche: Research Funding; Promedior: Research Funding; Blueprint Medicines Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; Genentech: Research Funding; CTI BioPharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Ital Pharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; AstraZeneca: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Constellation: Consultancy; Pragmatist: Consultancy. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Mascarenhas: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Prelude: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; Forbius: Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Talpaz: Celgene: Consultancy; Imago: Consultancy; Takeda: Other: Grant/research support ; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: La Jolla Pharma: Consultancy; Samus: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Pharma: Consultancy; CTI: Research Funding; Abbvie: Research Funding; CTI: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; AOP: Consultancy. Vannucchi: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Rampal: Incyte: Consultancy, Research Funding; Pharmaessentia: Consultancy; Blueprint: Consultancy; Disc Medicine: Consultancy; Stemline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Jazz Pharmaceuticals: Consultancy; Constellation: Research Funding; Memorial Sloan Kettering: Current Employment; Kartos: Consultancy. Oh: Abbvie: Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Membership on an entity's Board of Directors or advisory committees; Celgene Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Constellation: Membership on an entity's Board of Directors or advisory committees; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; Disc Medicine: Membership on an entity's Board of Directors or advisory committees; Geron: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Membership on an entity's Board of Directors or advisory committees; PharamaEssentia: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees. Taverna: Constellation Pharmaceuticals: Current Employment. Cui: Constellation Pharmaceuticals: Current Employment. Zavidij: Constellation Pharmaceuticals: Current Employment. Chen: Constellation Pharmaceuticals: Current Employment. Colak: Constellation Pharmaceuticals: Current Employment. Efuni: Constellation Pharmaceuticals: Current Employment. Keller: Constellation Pharmaceuticals: Current Employment. Trojer: Constellation Pharmaceuticals: Current Employment. Harrison: Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Sierra Oncology: Honoraria; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract Introduction: A new isodicentric variant of del(20q) was recently described; namely ider(20)(p11.2)del(20)(q11.2q13.3). The frequency and clinical significance of this anomaly are not yet established. This anomaly is usually missed in routine cytogenetic studies and the common commercial FISH probe, D20S108, does not distinguish between del(20q) and ider(20q). The goals of this study were to determine 1) the frequency and hematopathology of patients (pts) with ider(20q) and 2) the best cytogenetic methods to distinguish among various del(20q) anomalies. Methods: We selected 12 pts referred for chromosome studies with -20,+mar to look for evidence of ider(20q). For comparison, we also randomly selected 12 pts with classical del(20q). Up to 10 bone marrow metaphases were studied for each of these 24 pts using FISH with probes for 20pter, JAG1 (20p12), centromere 20, D20S108 (20q12) and 20qter. We also studied 200 interphase nuclei from each pt using D20S108 and 20qter probes. We reviewed cytogenetic results for a consecutive series of pts in our hematological practice between 9/1/05 and 12/31/05 to establish the frequency of ider(20q). Blood and marrow slides were available for microscopic evaluation in 9 of 12 pts. with ider(20q). Results: By metaphase FISH, each of the 12 pts with del(20q) were 20pter+, JAG1+, D20S108- and 20qter+ indicating an interstitial deletion. Each of the 12 pts with ider(20q) were 20pter-, JAG1-, D20S108-- and 20qter++ indicating an isodicentric chromosome with an interstitial del(20q) on either side of the centromere. The ider(20q) is best detected using probe for D20S108 and 20qter. By FISH each pt with ider(20q) had a mixture of cells with del(20q) and ider(20q), though cells with only del(20q) were not usually detected by chromosome studies. One pt had a subclone with two copies of ider(20q). Interphase FISH identified del(20q) and ider(20q) in each specimen. Hematopathology studies of 9 pts with ider(20q) indicated acute myeloid leukemia (AML) with multilineage dysplasia in 1 and myelodysplastic syndrome in 8 (refractory cytopenia with multilineage dysplasia (RCMD) in 3, RCMD with ringed sideroblasts in 3, atypical myelodysplastic/myeloproliferative disease in 1, and refractory anemia with excess blasts-2 (RAEB-2) in 1). Additional chromosome anomalies were detected in the pts with AML with multilineage dysplasia and RAEB-2. Six pts had dysgranulopoiesis in addition to dysmegakaryopoiesis and/or dyserythropoiesis. Among 5,744 pts in our hematological clinical practice screened by interphase FISH, ider(20q) was seen in 8, but 8 of 78 pts with del(20q) also had ider(20q). Discussion: In clinical practice ider(20q) is common in hematological disorders and occurs in 0.14% of all pts and in 10% of pts with del(20q). This figure may underestimate the true frequency of ider(20q) because novel FISH studies with D20S108 and 20qter are required to confirm its presence. When G-banding preparations indicate -20,+mar, then ider(20q) should be suspected. The literature is sparse but pts with ider(20q) appeared to have a more consistent presentation of multilineage dysplasia with additional involvement of the granulocytic series than pts with del(20q). These results suggest that it is helpful to distinguish among various forms of del(20q) in clinical practice using both chromosome and FISH studies with D20S108 and 20qter.

We studied 25 T-cell chronic lymphocytic leukemia (T-CLL) cases collected over a 15-year period. Immunophenotypic analysis was performed in each case; 12 cases were evaluated by cytogenetics, and gene rearrangement studies were performed in 14 cases. The median age was 57 years with a male predominance (M:F, 15:10). The median presenting lymphocyte count was 36.3 x 10(9)/L (range, 3.9 to 438 x 10(9)/L). Fourteen patients (56%) had shotty adenopathy and ten (40%) had mild-to-moderate splenomegaly at presentation; four (16%) had erythematous skin lesions. The lymphocytes were predominantly small; some cases had a minor component of medium-sized cells (< 10%). The nuclear: cytoplasmic ratios were uniformly high with round to oval nuclei; however, a wide spectrum of nuclear outlines could be found, ranging from minimally to markedly convoluted. Nucleoli were either absent or small and inconspicuous. These lymphocytes did not have the morphology of prolymphocytes and did not contain cytoplasmic granules. Bone marrow infiltration was generally in an interstitial pattern; the degree of involvement ranged from 15% to 90%. Immunophenotyping showed that the lymphocytes were mature T-cells with a predominant CD4+ immunophenotype. Three cases displayed a CD8+ immunophenotype. The patients were treated with a variety of chemotherapeutic regimens with only a minimal response observed in two of 20 patients. We conclude that T-CLL is an uncommon chronic lymphoproliferative disorder (CLPD) that can be morphologically similar to B-CLL, is distinct from T- prolymphocytic leukemia, and has an aggressive clinical course that is refractory to therapy. It may also be difficult to distinguish T-CLL from other T-CLPD, especially the leukemic phase of peripheral T-cell lymphoma and some cases of Sezary syndrome.