Bolarinwa, Abiola

Abstract Measurable residual disease (MRD) is a powerful prognostic tool in multiple myeloma, but predictors of achieving MRD negativity after autologous stem cell transplantation (ASCT) are not well defined. We studied 814 patients who achieved at least a very good partial response after ASCT between January 2016 and January 2023 and underwent MRD assessment by next-generation flow cytometry. Overall, 387 (48%) achieved MRD negativity after ASCT. The presence of t(11;14) (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4–3.2; P< .01) and pretransplant response less than complete remission (OR, 2.1; 95% CI, 1.2-3.7; P< .01) independently predicted MRD positivity. Patients who were MRD positive had inferior progression-free survival (PFS; hazard ratio [HR], 1.99; 95% CI, 1.53-2.58; P< .001) and overall survival (HR, 1.62; 95% CI, 1.10-2.28; P = .009). Despite lower MRD-negative rate, 5-year PFS was similar among t(11;14) MRD positive (58%) and patients who were MRD negative (63%; P = .12). In patients who were MRD negative, the 5-year PFS was 73% in those without ≥2 HRCA compared with 55% in those with ≥2 HRCA (HR 1.9, 95% CI 1.2–3.3; P = .01). In the MRD-positive cohort, 5-year PFS was 53% in patients without ≥2 HRCA vs 17% in those with ≥2 HRCA (HR, 2.4; 95% CI, 1.6-3.6; P< .01). In addition, higher residual clonal plasma cell burden within MRD-positive disease was associated with inferior PFS (HR, 2.4; 95% CI, 1.2-6.9; P = .002). This study highlights that the presence of t(11;14) independently predicts MRD positivity after ASCT, although it does not significantly affect prognosis in this subgroup.

ABSTRACT The recently published BLAST clinical risk model for chronic myelomonocytic leukemia (CMML) and its molecular version (BLAST‐Mol) differentiate low, intermediate, and high‐risk groups. The objective of the current retrospective study was to examine the survival impact of allogeneic stem cell transplant (ASCT) in a consecutive series of Mayo Clinic patients ( n = 775; 68% males, median age 71 years) with CMML, overall and adjusted for baseline BLAST/BLAST‐Mol risk categories. At a median follow‐up of 77 months, 151 (20%) patients underwent ASCT. Overall survival (OS) was longer in the ASCT compared to the non‐ASCT cohorts (median 77 vs. 28 months; p < 0.01). The significant difference in OS between the ASCT and non‐ASCT cohorts was retained after adjusting for BLAST clinical risk groups: high‐risk (median 50 vs. 14 months; p < 0.01), intermediate‐risk (81 vs. 28 months; p < 0.01), and low‐risk (111 vs. 65 months; p = 0.04), respectively. The same was mostly the case when OS comparison was adjusted for BLAST‐Mol with respective p values of < 0.01, < 0.01, and 0.08, respectively. Time‐dependent cox models confirmed the favorable survival impact of ASCT in the BLAST/BLAST‐Mol high‐ and intermediate‐risk groups. The current study highlights the benefit of ASCT for BLAST/BLAST‐Mol high‐ and intermediate‐risk groups in CMML and its potential to overcome the adverse impact of some high risk cytogenetic or molecular abnormalities. These observations support the early use of ASCT in CMML, ideally before BT and regardless of genetic characteristics.

ABSTRACT We examined the prognostic value of routine NGS data in newly diagnosed acute myeloid leukemia (AML) treated with intensive (7 + 3 backbone) induction, specified by AML subtype. A contemporary (2015–2025) series of 545 Mayo Clinic patients (median age 56 years, females 44%) was considered. Median follow‐up was 49 months with 341 (63%) allogeneic hematopoietic stem cell transplantations (AHSCT) recorded. AML subtypes included core‐binding factor (CBF; N = 72; 13%), primary non‐CBF ( N = 403; 74%), post‐myelodysplastic syndromes (MDS) or post‐myelodysplastic/myeloproliferative neoplasms (post‐MDS‐MDS/MPN; N = 28; 5%), post‐MPN ( N = 15; 3%), and therapy‐related (t‐AML; N = 27; 5%). Corresponding complete remission rates, with/without count recovery (CR/CRi), were 89%, 76%, 64%, 27%, and 78% ( p < 0.01) and 5‐year transplant‐censored survival rates 68%, 57%, 21%, 0%, and 55% ( p < 0.01). In multivariable analyses, the prognostic value of specific mutations was mostly limited to primary non‐CBF AML where adverse karyotype (OR 1.9; p = 0.04) predicted inferior and FLT3 ‐ITD (OR 0.4; p < 0.01) or NPM1 MUT / FLT3 WT (OR 0.1; p < 0.01) superior CR/CRi while KRAS MUT (HR 8.8; p < 0.01), TP53 MUT (HR 5.4; p < 0.01), and TET2 MUT (HR 2.3; p = 0.01) predicted inferior and NPM1 MUT / FLT3 WT (HR 0.3; p = 0.01) superior survival. Prognostication in intensively‐treated AML should start with subtype specification and recognition of the limited value of NGS in non‐primary AML. Post‐MPN AML is particularly associated with dismal outcomes and should be prognostically distinguished from post‐MDS‐MDS/MPN AML. In primary non‐CBF AML, in addition to previously established risk factors, the favorable impact of FLT3 ‐ITD on achieving CR/CRi and the unfavorable impact of KRAS MUT and TET2 MUT on transplant‐censored survival were noted and require confirmation from additional studies.

Abstract Introduction: CSF3R mutations (CSF3RMUT), most commonly T618I, represent the defining genomic alteration in chronic neutrophilic leukemia (CNL), present in ~80% of cases. Despite emerging real-world data, information on treatment outcomes and prognostic factors remains limited due to rarity of the disease. In this two-center retrospective study, we examined clinical and molecular predictors of treatment response, overall survival (OS), and blast transformation (BT) and outcome following allogeneic stem cell transplant (ASCT). Methods: The study was approved by the institutional review boards of the Mayo Clinic (USA) and the University of Montreal (Canada). Electronic medical records were reviewed to identify patients with CSF3R mutated CNL at both institutions and extract relevant data. Statistical analyses were conducted using JMP Pro 17.0.0 software (SAS Institute, Cary, NC, USA). Results: Forty-four patients (68% male, median age 68 years [range: 26-93]) were included. At diagnosis, 20 (56%) were asymptomatic, 13 (36%) presented with constitutional/non-specific symptoms, and 20 (50%) had antecedent leukocytosis at a median of 13 months(mo) prior. Splenomegaly (palpable or radiological) was observed in 28 (67%) patients, hepatomegaly in 7 (17%) and lymphadenopathy in 4 (9.8%). Median white blood cell count (WBC) was 52×10⁹/L (range: 17-390). CSF3RMUT/variants included 39 (89%) with T618I (7 of the 39 had additional CSF3RMUT), 2 (5%) with M696T, and 1 (2%) each for I598I, Q739* and T640N. Frequent co-mutations included ASXL1 in 25 (63%) patients, SETBP1 in 14 (36%), and SRSF2 in 8 (31%), with overlapping occurrence; 10 (38%) patients had ≥2 of these 3 mutations. Ten patients (median WBC 29 x10⁹/L [range: 19–58]), were initially observed without treatment for a median of 8.6 mo; 2 remained on observation alone at 46 and 77 mo. Hydroxyurea (HU) alone or in combinations excluding ruxolitinib (Ruxo) was the most common first-line treatment (68%). Second-line therapies included Ruxo (39%), HU (25%), and hypomethylating agents (14%). WBC response (≥50% reduction from baseline) was 78% with HU vs. 60% with Ruxo (p=0.2). WBC response to HU was lower with abnormal karyotype (40% vs. 94%; p=0.02). WBC response to Ruxo was lower with SETBP1MUT (0% vs. 72%; p=0.05) and with male sex (40% vs. 100%; p=0.04). Seven patients underwent ASCT, including 2 after BT; four (57%) of the 7 remain alive, including 2 without evidence of disease (both 45 mo post-ASCT; one harbored ASXL1MUT) and the other 2 with active disease (both harbored ASXL1MUT). Three patients died from veno-occlusive disease (Day+34), CNS relapse with AML (at 105 mo post-ASCT), or unrelated causes (at 44 mo post-ASCT). Median OS was longer in transplanted patients (115 vs 23 mo; p=0.03). At a median follow-up of 44 mo for living patients, disease transformation occurred in 10 patients, including 7 with BT (6 with T618I, 1 T640N) and 3 with chronic myelomonocytic leukemia (2 M696T, 1 T618I). BT rate at 2, 3, and 5 years was 15%, 31%, and 43%, respectively. Univariate analysis (UVA) identified male gender (p&lt;0.01), &gt;5% immature WBCs (p=0.02), platelets &lt;160×10⁹/L (p=0.04), higher WBC (p=0.02), and ASXL1 or SETBP1 mutation (p&lt;0.01) as risk factors for BT. On multivariable analysis (MVA), only the latter remained significant. Median OS was 26 mo (95% CI: 21-43) for the entire cohort; 24 mo for patients with T618I CSF3RMUT vs 53 mo with other CSF3RMUT, p=0.1. In UVA, age &gt;60 years (HR 5.0, p=0.03), platelets &lt;160×10⁹/L (HR 3.4, p=0.006), WBC &gt;50×10⁹/L (HR 2.6, p=0.02), and ASXL1 or SETBP1 mutations (HR 4.2, p=0.01) were associated with shorter OS. In MVA, age &gt;60 (HR 6, p=0.03), WBC &gt;50×10⁹/L (HR 12, p&lt;0.01), and the presence of ASXL1MUT or SETBP1MUT (HR 9.5, p=0.01) remained significant. Based on the HRs on MVA, one adverse point was allocated for age &gt;60 years, and two adverse points each for WBC &gt;50×10⁹/L and presence of ASXL1 or SETBP1 mutations. Patients were accordingly stratified into low (0-2 points), intermediate (3) and high (4-5) risk groups with corresponding median OS of “not reached”, 29 mo, and 16 mo (p&lt;0.01). Causes of death included disease progression (82%), infection/bleeding (9%), and ASCT complications (9%). Conclusion: The current study highlights the prognostic relevance of “SETBP1 or ASXL1” mutation for both overall survival and risk of blast transformation. The study also signifies variable natural history and potential benefit from ASCT.

Abstract Background: The primary goal of induction therapy in acute myeloid leukemia (AML) is to induce complete remission with (CR) or without (CRi) hematologic recovery. In order to accomplish this, re-induction might be necessary based on D14-residual AML. The current study examines the impact of re-induction on relapse, transplant-censored survival, and post-transplant survival in a consecutive series of AML patients who have achieved CR/CRi following intensive chemotherapy. The study also examined the impact of variations in consolidation chemotherapy including the use of anthracycline-based chemotherapy (AC) in the first consolidation cycle and the use of high (HiDAC) vs. intermediate (IDAC) dose cytarabine. Methods: The current study was conducted under IRB-approved minimum risk protocols that allowed retrospective collection and analysis of patient data. Formal criteria were used for AML diagnosis, genetic risk stratification, and adjudication of response (Blood 2022;140:1345). Patients who received less intensive induction regimens or failed to achieve CR/CRi were excluded. Relapse-free (RFS) and overall survival (OS) analysis was calculated from the date of documented CR/CRi. Patients who underwent allogeneic stem cell transplant (ASCT) were censored at the time of transplant. Conventional statistical methods were utilized (JMP Pro 17.1.0, SAS Institute, Cary, NC, USA). Results: A total of 279 AML patients diagnosed between 2004 and 2020 were included: median age 58 years, males 60%, de novo 75%, post-chronic myeloid neoplasm (post-CMN) 16%, and therapy-related 9%. Induction regimens included idarubicin (Ida) + cytarabine (Cyt) in 183 (66%) patients, daunorubicin (Da) 60 mg/m² + Cyt in 76 (27%), and Da 90 mg/m2 + Cyt in 19 (7%). Re-induction was utilized to achieve CR/CRi in 72 (27%) at a median of 18 days from start of first induction regimen. The indication for re-induction was based on residual bone marrow blast (median 30%; range 4-90) on day14 (N=53) or day 21-28 (N=15), persistent extramedullary disease (N=2) or the presence of circulating blast (N=2). At a median transplant censored follow-up of 26 months (mos), 93 (33%) deaths, 117 (42%) relapses, and 134 (48%) ASCTs were documented; ASCTs were performed in CR1 (50%) or CR2 (50%). Median RFS was 18 mos, with respective 1-, 2-, 3- year RFS of 63%, 42% and 35%. In multivariable analysis (MVA), age ≥65 years (HR 1.5, p=0.04), European LeukemiaNet (ELN) adverse karyotype (vs. intermediate HR 1.7, p=0.02; vs. favorable HR 2.8, p&lt;0.01), and the need for re-induction to achieve CR/CRi (HR 1.7, p=0.01) were independently predictive of relapse. RFS was not impacted by NPM1 mutation ( HR 0.5, p=0.09) or FLT3-ITD (HR 1.3, p=0.3). The median OS was 80 mos, with 5-year OS of 53%. In MVA, age ≥65 years (HR 2, p=0.01), ELN adverse karyotype (vs. intermediate HR 3.3, p&lt;0.01; vs. favorable HR 4.7, p&lt;0.01), FLT3-ITD (HR 1.9, p=0.04), and the need for re-induction (HR 1.9, p=0.03) independently predicted inferior OS. RFS was similar among patients who received AC (N=84; Idarubicin 9 mg/m2 or Da 60 mg/m2 days 1 to 2/3 + 100 mg/m2 Cyt days 1 to 5/7; median 18 mos) as their first consolidation cycle vs. those who received HiDAC (N=99; 3 g/m2 q12 hours on days 1,3 and 5; median 16 mos) or IDAC (N=58; IDAC; 1-2 g/m2 q12 hours on days 1, 3 and 5; median 24 mos; p=0.9); the corresponding median OS were 125, 85, and 40 mos (p=0.4). In patients aged ≥65 years, but not younger patients, both RFS (p&lt;0.01; median 23 (N=36) vs. 8 (N=24) mos) and OS (median 40 vs. 12 mos, p&lt;0.01) were significantly longer with IDAC vs. AC as their first consolidation cycle. In the AC consolidation cohort, patients who received 2-3 additional HiDAC/IDAC cycles displayed longer OS (p&lt;0.01) and RFS (p=0.047), compared to those who received less. In both the HiDAC and IDAC cohorts, RFS and OS were not significantly different between those who received 3-4 versus 1-2 consolidation cycles. The need for re-induction did not affect post-transplant survival (p=0.5), which was superior in patients receiving Ida + Cyt induction (vs. Da 60mg/m2 + Cyt, HR 0.6, p=0.04) and in those transplanted in CR1 (HR 0.5, p&lt;0.01). Conclusions: The current study signals the need for re-induction to achieve CR1 as a negative predictor of outcome in AML patients achieving CR/CRi following intensive induction chemotherapy. The particular information is potentially actionable in terms of the choice of consolidation strategy.

Abstract Background: Sickle cell disease (SCD) is marked by wide variability in clinical phenotypes and severity due to environmental, clinical, and genetic factors. Variants in iron-regulatory genes are well described modifiers of clinical presentation in different diseases, but their role in modulating SCD phenotype has been sparsely studied in African populations. In this cross-sectional study, we investigated the role of single nucleotide polymorphisms (SNPs) in iron-regulatory genes in SCD severity and lifetime transfusion(Tx) requirement. Methods: The study was approved by the institutional review board of Lagos University Teaching Hospital, Lagos, Nigeria. Clinical data were abstracted from medical records and patient interviews using a structured questionnaire. Participants were recruited in steady state and were stratified according to the severity score previously described by Shah et al. (Clinicoecon Outcomes Res. 2020;12:625). Biochemical analyses included serum transferrin and serum iron; transferrin saturation (TS) was calculated. Genotyping was performed using the Axiom Precision Medicine Research Array (PMRA; Thermo Fisher Scientific). Seventy-one single nucleotide polymorphisms (SNPs) in genes implicated in iron metabolism were analyzed, including SLC40A1 (ferroportin), HFE (homeostatic iron regulator), HJV (hemojuvelin), HAMP (hepcidin), and TFR2 (transferrin receptor 2). SNPs whose variants were not represented in this cohort, including HFE C282Y and H63D, were excluded. Ensembl and NCBI databases were used to describe the wild-type (WT)/variant alleles and gene consequences. Univariate and multivariate logistic regression were used to analyze binary outcomes, and age-adjusted linear regression for Tx burden. Odds ratios (OR) and regression coefficients (β) were estimated using the WT as the reference. Multiple-testing correction was performed as necessary. Statistical analyses were conducted in R version 4.4.1, with p&lt;0.05 considered significant. Results: We included 60 genotyped, confirmed HbSS patients; median age was 22 years (range: 18–43), 22 (37.3%) were female, 42 (70.0%) were classified as mild severity (Class I), 5 (8.0%) as Class II, and 13 (22.0%) as severe (Class III). Twenty-seven (45.0%) had never received a blood Tx, while 33 (55.0%) had received Tx, median of 2units (range: 1-10). On univariate analysis (UVA), five SNPs (rs10218795, rs10188230, rs114250626, rs4287798, and rs634349) were significantly associated with severe phenotype; three of these remained significant on multivariable analysis (MVA). Two were associated with higher odds of severe phenotype: rs10177654 (OR = 28.9, 95% CI: 3.0–100.0, p = 0.03) and rs10218795 (OR = 15.0, 95% CI: 2.4–327.0, p&lt;0.01), while rs10188230 was associated with lower odds (OR = 0.03, 95% CI: 0.008–0.28, p&lt;0.01). Results remained consistent after adjusting for age. For lifetime transfusion burden, both UVA and MVA identified two significant SNPs: rs4667289, associated with higher transfusion burden (β = 2.6, 95% CI: 0.04–5.2, p = 0.047) and rs11568344, associated with lower transfusion burden (β = –1.8, 95% CI: –3.5 to –0.36, p = 0.02). Genotype distributions for the five significant SNPs were as follows: rs10177654 (SLC40A1, transcription factor binding site), TT(WT) 12 (20.3%), TC 30 (50.8%), CC 17 (28.8%); rs10188230 (SLC40A1, intron variant), TT (WT) 32 (54.2%), TC 22 (37.3%), CC 5 (8.5%); rs10218795 (HJV, intron variant), CC (WT) 22 (37.3%), TC 29 (49.2%), TT 8 (13.6%); rs4667289 (SLC40A1 proximal intergenic), GG (WT) 46 (78.0%), AG 10 (16.9%), AA 3 (5.1%); rs11568344 (SLC40A1 splice region variant), GG (WT) 47 (79.7%), AG 9 (15.3%), AA 3 (5.1%). Compared with the homozygous WT, patients with rs10188230 had a lower median TS (21.65% vs. 43.3%, p = 0.04), while those with rs4667289 had a higher median TS (83% vs. 31%, p&lt;0.01). When adjusted for age and lifetime Tx, rs4667289 remained significant (β = 47.8, 95% CI 3.6-82.8, p = 0.03). No other SNPs showed association with TS. Conclusion: We present novel genetic data on iron-regulatory variants in African patients with sickle cell disease, identifying SNPs in SLC40A1 and HJV associated with disease severity. Most of these are yet to be fully described in the literature, and their intronic locations suggest possible regulatory roles. We hope to further validate these findings in larger cohorts and through functional studies to clarify their impact on iron metabolism and clinical significance.

Abstract Introduction Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Blast transformation (BT) is a frequent complication of CMML with a 3-year risk of approximately 31%. MPN driver mutations (i.e., JAK2, CALR, MPL) are known to occur in CMML but their impact on overall survival (OS) or BT remains uncertain. Methods The current study was conducted under institutional review board approved minimum risk protocols that allowed retrospective collection and analysis of patient data. Diagnostic criteria were according to the International Consensus Classification (Blood 2022; 140:1200). For survival analysis, patients were censored at the time of allogeneic stem cell transplant (ASCT). All statistical analyses were conducted using JMP Pro 17.0.0 software (SAS Institute, Cary, NC, USA) and Bluesky Statistics Software (Worldwide Headquarters, Chicago, IL, USA). Results A total of 612 CMML patients were considered (median age 71 years; 68% males). MPN driver mutations (MPNMUT) were detected in 56 (9%) patients, including 43 (77%) with JAK2, 10 (18%) MPL, and 3 (5%) CALR. The median variant allele frequencies were 44% for JAK2 (range, 0.3–100%), 49% for MPL (range, 0.3–97%), and 50% for CALR (range, 20–80%). Age and sex distributions and CMML-1 vs. CMML-2 representation were similar between CMML patients with and without MPNMUT. On the other hand, CMML patients with MPNMUT were more likely to display higher hemoglobin level (p &lt;0.01), platelet count (p &lt;0.01), absolute neutrophil count (p = 0.02) and leukocytosis (≥13 ×109/L; p &lt;0.01); they were also less likely to be red blood transfusion dependent (p &lt;0.01), display platelet counts of &lt;100 ×109/L (p &lt;0.01) or abnormal karyotype (p= 0.03), present with severe anemia (p= 0.03) or harbor NRAS mutation (p = 0.02). Higher Mutational frequencies of SRSF2 (median 53% vs. 41%; p = 0.01), TP53 (median 8% vs. 2%; p = 0.02) and IDH2 (median 13% vs. 4%; p = 0.01) were noted in CMML patients with MPNMUT. During a median follow-up of 23 months (inter-quantile range 11-51 months) for all 612 CMML patients, 402 (67%) deaths, 118 (19%) BT and 108 (18%) ASCT were documented. Of these, 36 (9%) deaths, 18 (15%) BT and 13 (12%) ASCT occurred in patients with MPNMUT. Median OS for the entire group (N=612) was 32 months with 1-, 2- and 3-year OS rates of 78%, 58% and 47%, respectively. There was no significant difference in OS between CMML patients with or without MPNMUT (median 41 vs 31 months; p = 0.27). Thrombotic events were reported in 53 (9%) patients after diagnosis of CMML, including 48 venous and 5 arterial events. There was no significant difference in arterial (p = 0.10) or venous (p = 0.76) thrombosis-free survival between CMML patients with or without MPNMUT. Among all 612 patients with CMML, followed for a median of 18 months for living patients, 118 (19%) experienced BT, with 1-, 3-, and 5-year BT rates of 10.8%, 23.1%, and 31%, respectively. Cumulative incidence analysis function (CIF) was calculated in order to assess the BT-free survival while accounting for death as a competing risk; 3-year CIF was 30% for CMML patients with vs. 18% for those without MPNMUT (Gray's test; p = 0.01). This observation was confirmed in univariate analysis of time to BT (HR 1.7; p=0.03) as well as the corresponding multivariable analysis involving other mutations and clinical risk factors: MPNMUT (HR 1.8; 0.036), ASXL1MUT (HR 2.3; p&lt;0.01), DNMT3AMUT (HR 2.6; p&lt;0.01), CMML-2 vs. CMML-1 (HR 3.4; p&lt;0.01), and leukocyte count ≥13 ×109/L (HR 2.0; p&lt;0.01). SRSF2, IDH2, and TP53 mutations did not impact BT. Notably, the aforementioned risk factors for BT, including ASXL1MUT and DNMT3AMUT, were no longer significant when analysis was restricted to patients with MPNMUT. Conclusions The current study suggests a higher risk of BT in CMML patients with MPNMUT, independent of other molecular or clinical risk factors for BT. On the other hand, overall and thrombosis-free survival did not appear to be similarly influenced. The differential impact of previously recognized risk factors for BT in CMML (e.g., ASXL1MUT, DNMT3AMUT, CMML-2, CMML-MP), in the presence (lost significance) vs. absence (remained significant) of MPNMUT was intriguingly noted.

Abstract Background Neurolymphomatosis (NL) is a rare and frequently underrecognized manifestation of lymphoma, characterized by infiltration of peripheral or cranial nerves by malignant lymphocytes. Limited data exist to guide optimal management. We present the largest single-enterprise (included the 3 Mayo Clinic sites) cohort to date, evaluating disease characteristics, treatment patterns, and outcomes in patients (pts) with NL. Methods We conducted a retrospective analysis of pts ≥18 years (yrs) diagnosed with clinical, radiographic, or biopsy-confirmed NL at Mayo Clinic between January 2002 and December 2024. Baseline characteristics were compared using independent t-tests for continuous variables and Fisher's exact or Pearson's chi-square tests for categorical variables. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Objective response rate (ORR) was a secondary endpoint. Kaplan–Meier methods, log-rank tests, and Cox proportional hazards regression were used to assess survival outcomes and associated factors. Results We included 149 pts. Median age at diagnosis was 64 yrs (range 22–83), and 23% were female. Most presented with stage IV disease (89%), and NL was part of the initial lymphoma presentation in 42% (primary NL). Diagnostic confirmation was based on histopathology and imaging in 55%, imaging alone in 26%, histopathology alone in 16%, and clinical features in 4%. Diffuse large B-cell lymphoma was the most common histology (61%), followed by marginal zone lymphoma (7%), and T-cell lymphoma (7%). Clinical presentation included painful neuropathy (65%), concurrent CNS involvement (37%), systemic disease (43%), elevated LDH (46.9%), and ECOG ≥2 (38%). Pattern of involvement included cranial nerves (29%), peripheral nerves (28%), and spinal nerve roots (27%). Median follow-up was 92 months (95% CI, 63–119). Among 137 treatment-evaluable pts, first-line regimens included methotrexate-based (MTX) (62%), bendamustine-based (B) (11%), cytarabine-based (Ara-C) (4%), and rituximab-based (R) (excluding MTX, B, or Ara-C) (15%) therapies. Radiation was used in 18%, and 21% underwent autologous stem cell transplant (ASCT). Among 103 response-evaluable pts, the ORR was 67% (52% complete response [CR], 16% partial response [PR]). ORRs by regimen were 78% (MTX), 92% (B), and 86% (R). On univariate analysis, primary NL (OR 4.3) and frontline ASCT (OR 8.47) were associated with higher odds of response (p&lt;0.05), while ECOG ≥2 (OR 0.24) and localized disease (OR 0.33) were associated with lower odds. On multivariable analysis (MVA), primary NL (OR 5.0 [1.5–12.1], p=0.02) and ECOG &gt;1 (OR 0.2 [0.06–0.79], p=0.018) remained significant predictors of response. Median PFS was 13 months (95% CI, 9–36), with a 2-yr PFS of 43% (95% CI, 35–53). On MVA, concurrent CNS involvement (HR 2.4, p=0.05), systemic disease (HR 2.7, p=0.02), and ECOG &gt;1 (HR 2.4, p=0.02) were associated with inferior PFS, while primary NL was associated with improved PFS (HR 0.3, p=0.002). Patients undergoing frontline ASCT had a median PFS of 108 months (95% CI, 58–not reached) with a 7-yr PFS of 62% (95% CI, 46–84). Among those receiving second line and beyond (2+) therapy, 24 received MTX-based regimens, 10 received CAR-T, and 8 received tyrosine kinase inhibitors. Post-ASCT median PFS was 30 months (95% CI, 15–NR). Among CAR-T recipients, evaluable responses (n=8) included 4 CR, 1 PR, and 3 PD. Median OS was 56 months (95% CI, 29–133), with a 5-yr OS of 50% (95% CI, 41–60). On MVA, ECOG ≥2 (HR 2.5, p=0.02) predicted worse OS, while receipt of ASCT (HR 0.4, p=0.04) and primary NL (HR 0.5, p=0.04) were associated with improved OS. Conclusion This study represents the largest single-enterprise cohort of pts with NL, providing comprehensive insight into its clinical presentation, treatment patterns, and outcomes. Primary NL and preserved PS were independently associated with improved response rates and survival, while CNS and systemic involvement at diagnosis portended poorer PFS. MTX and bendamustine-based regimens achieved high ORR, and frontline ASCT was associated with significantly prolonged remission duration and OS. These findings highlight the prognostic importance of baseline disease burden and functional status, support the early incorporation of high-intensity regimens in eligible patients, and underscore the urgent need for prospective studies to guide evidence-based management in this rare and understudied population.

Abstract Cyclin D1, encoded by CCND1, is a cell cycle regulator, overexpressed in ~15% of multiple myeloma (MM) cases via CCND1::IGH super-enhancer juxtaposition through t(11;14). Cyclin D1 also plays a non-canonical role in transcriptional regulation, but in t(11;14) MM its function in gene regulation remains undefined. We investigated the global transcriptional and epigenomic consequences of CCND1overexpression in t(11;14) MM. To define a CCND1 signature, RNA-seq from two independent primary MM patient cohorts, CoMMpass and Mayo, was utilized to compare high CCND1 t(11;14) cases (≥300 transcripts-per-million [TPM], n=271) vs. low CCND1 hyperdiploid cases (&lt;30 TPM, n=233). Two CCND1 knockout (KO) clones in t(11;14) MM U266B1 were also generated by CRISPR/Cas9, introducing a frameshift insertion (A) after chr11:69641478 (hg38) in exon 1. ATAC-seq and ChIP-seq (H3K4me3, H3K4me1, and H3K27ac) were performed in duplicates, and RNA-seq in triplicates in U266B1 wild-type (WT) and KO. Libraries were sequenced on Illumina NextSeq 2000 (2x51 bp for ChIP/ATAC, 2x150 bp for RNA-seq). Reads were mapped to hg38 by BWA (ChIP/ATAC) or STAR (RNA-seq), peaks called by MACS2 (FDR&lt; 0.01), peak and gene raw counts estimated by featureCounts. Differential peaks (fold-change ≥1.5) and differentially expressed genes (fold-change ≥2) were identified by edgeR (FDR&lt;0.05), including peaks detected in ≥2 samples and genes with TPM ≥0.1 in ≥1 sample. Interactions between promoters and distal regulatory regions were identified using publicly available chromatin interaction data in blood cell types. Pathway analysis was performed using Enrichr. Co-immunoprecipitation was performed in t(11;14) KMS12BM cells. Differential analysis comparing CCND1-high t(11;14) and CCND1-low MM cases in the two patient cohorts identified 21 upregulated and 21 downregulated genes associated with CCND1 expression which were also captured in the wild-typevs. CCND1 KO U266 cells. Enriched pathways (p&lt;0.05) included Notch signaling, early/late estrogen response, epithelial-mesenchymal transition and reduced mitotic spindle and myogenesis. Dysregulated genes included those related to apoptosis, ubiquitin-proteosome, extracellular matrix, adhesion, and immune response, demonstrating a broader role for cyclin D1 in MM beyond cell cycle control. To explore the epigenomic basis of this transcriptional regulation, for each of the 42 differentially expressed genes we examined the changes of histone marks and chromatin accessibility in promoter and the interacting distal regulatory regions in the U266 KO model. Ten of the 21 genes upregulated in CCND1-high (downloaded in KO; e.g., argininosuccinate synthase 1 [ASS1], PMAIP1, MYEOV, CCR7, and DTX1) and 12 of the 21 genes downregulated in CCND1-high (upregulated in KO; e.g., UACA, RASAL2, PTPRZ1, PPT2, and IL23R) showed concordant changes in histone marks and/or chromatin accessibility, predominantly in distal regulatory regions, suggesting a chromatin-mediated mechanism of gene regulation by cyclin D1. The most prominent changes involved H3K27ac, a mark defining active enhancers. As H3K27ac is deposited by histone acetyltransferases CBP, we tested for the possible cyclin D1-CBP interaction. Co-IP confirmed this interaction, suggesting a role for this complex in chromatin remodeling and transcriptional control in t(11;14) MM. One gene notably upregulated in association with CCND1 is ASS1, which encodes a urea cycle enzyme responsible for endogenous arginine synthesis. Metabolomic studies demonstrated KO cells had elevated aspartate and citrulline and lowered arginine and ornithine compared to WT cells (p&lt;0.01) demonstrating impaired urea cycle function. Further, KO cells displayed significantly reduced ASS1 protein expression, cell growth and S-phase entry compared to WT cells in arginine-replete conditions, with both WT and KO cell types further inhibited by arginine depletion (p&lt;0.05). Together, a cyclin D1-associated gene signature was identified supporting its role in t(11;14) MM beyond the CDK4/6 mediated cell cycle control, including a role in metabolic plasticity and survival under arginine depleted conditions. These findings highlight cyclin D1 as a therapeutic vulnerability and open new avenues for personalized treatment strategies.