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INTRODUCTION Richter transformation (RT) is the histologic transformation of CLL/SLL into an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We previously reported an incidence of 0.5% per year of RT in patients with newly diagnosed CLL and an incidence of 1% per year following initiation of therapy (Parikh, BJH, 2013). It is unknown whether these incidences have changed in the novel agent era. METHODS We identified patients with previously untreated CLL/SLL in the Mayo Clinic CLL Database who were seen within 12 months of diagnosis. Only patients with biopsy-proven DLBCL with histopathology confirmation at Mayo Clinic were included. Cumulative incidence methodology was used to display the time to development of RT with death as a competing risk (both from time of initial CLL/SLL diagnosis, and from start of CLL directed therapy). We defined the time period prior to February 2014 (FDA approval of ibrutinib for CLL) as the pre-novel agent era and the time period starting February 2014 as the novel agent era. Using Cox regression analysis, we compared the incidence of RT, both after initial CLL diagnosis and after initiation of CLL therapy, between patients diagnosed with CLL in the pre-novel agent era versus the novel agent era. RESULTS Between 1/2000 and 4/2023, 3347 patients were seen at Mayo Clinic. The median age at diagnosis was 65 years (range 21-97 years), and 66% patients were male. Baseline characteristics of patients at the time of CLL and RT diagnoses between the two treatment eras were similar, including distance in miles of primary residence from Mayo Clinic ( Table 1). The median follow-up for the entire cohort was 5.6 years (9.5 years for the pre-novel agent era cohort and 3.2 years for the novel agent era cohort). A total of 82 patients were diagnosed with RT (69 in the pre-novel agent era and 13 in the novel agent era). Overall, the 1-, 5- and 10-year cumulative incidence rates for RT from the time of CLL/SLL diagnosis were 0.6% (95% CI: 0.4-0.9%), 1.8% (95% CI: 1.3-2.3%), and 3.0% (95% CI: 2.4-3.8%), respectively. Among the patients who received CLL/SLL therapy (n=1382), the 1-, 5-, and 10-year incidence rates for RT from the time of treatment start were 0.3% (95% CI: 0.1-0.8%), 3.3% (95% CI: 2.4-4.5%), and 4.9% (95% CI: 3.7-6.5%), respectively. Among 1981 patients diagnosed with CLL/SLL in the pre-novel agent era, the 1- and 5-year incidence rates for RT from the time of diagnosis were 0.6% (95% CI: 0.4-1.1%) and 2.1% (95% CI: 1.5-2.8%), respectively. Among 1366 patients diagnosed with CLL/SLL in the novel agent era, the 1- and 5-year incidence rates following CLL/SLL diagnosis were 0.5% (95% CI: 0.2-1.1%) and 1.1% (95% CI: 0.6-2.2%), respectively. The RT incidence from time of CLL/SLL diagnosis was not significantly different between the pre-novel agent and novel agent era patients (hazard ratio [HR] 1.6, 95%CI 0.9-3.0, p=0.13). Patients who received CLL/SLL treatment in the pre-novel agent era (n=926) and novel agent era (n=456) had subsequent 1-year incidence rates of RT of 0.3% (95% CI: 0.1-1.0%) and 0.2% (95% CI: 0.0-1.8%), respectively. The 5-year incidence rates for these groups were 3.7% (95% CI: 2.6-5.2%) and 1.9% (95% CI: 0.7-5.0%), respectively. Although an increased risk of RT after CLL/SLL directed therapy was observed in the pre-novel agent era compared to the novel agent era (HR 2.4, 95%CI: 0.9-6.1, p=0.07; Figure 1), this did not cross the threshold of statistial significance. Among patients diagnosed in the pre-novel agent era who developed RT (n=69), CLL treatment prior to RT included: none, n=19 (28%); chemoimmunotherapy only, n=36 (52%); and novel agent, n=14 (20%; includes 11 treated with prior chemoimmunotherapy also). In contrast, among patients diagnosed in the novel agent era who developed RT (n=13), CLL treatment prior to RT included: none, n=8 (62%); and novel agent, n=5 (38%). CONCLUSIONS Patients who received CLL/SLL directed treatment appear to have a lower risk of RT in the novel agent era. This may be driven by the fact that none of the patients who developed RT in the novel agent era received chemoimmunotherapy. Whether novel agent use for CLL/SLL suppresses the development of RT or avoids the risk associated with cytotoxic chemotherapy-induced clonal evolution requires further study. Although limited by length of follow-up, our findings challenge the notion that RT incidence will increase in parallel with CLL patients living longer with novel agent treatments.

Introduction: Splenic marginal zone lymphoma (SMZL) is a rare, indolent disease. There is no universally accepted standard therapy and long-term outcome data are limited. Rituximab monotherapy is increasingly used over splenectomy in the first-line setting despite a paucity of comparative studies. In the absence of randomized trials, large-scale international real-world data studies are critical to evaluate outcomes of different treatment interventions and to understand the natural history of SMZL in the rituximab-era. Methods: Adult patients with SMZL diagnosed between Jan 1 st 2000 and Dec 31 st 2018 were identified using regional/nationwide population-based registries or hospital registries in Europe, the UK, North America, and Australia. Medical records and pathology reports from eligible patients were reviewed locally by clinicians with specialty experience in hemato-oncology. SMZL cases were required to meet the diagnostic criteria by Matutes et al. Detailed data on clinico-pathological features, comorbidities, treatments (including treatment intention), treatment responses and survival outcomes were entered in a central study database. Overall survival (OS) was defined as time from diagnosis until death from any cause or censoring at last follow-up unless stated otherwise. Event-free survival (EFS) was defined as the time from diagnosis until histological transformation, initiation of new chemotherapy or death from any cause. Survival probabilities were estimated using the Kaplan-Meier estimator. Cumulative risk of transformation was estimated with death as a competing risk. Primary endpoints were 10-year OS and 5-year EFS respectivly. Results: A total of 934 patients from 25 sites were included. Median age at diagnosis was 68 years (IQR 60-76) and 54% were female. Bone marrow involvement was present in 96% (564/590) of those assessed, anemia (Hb <12g/dL for women or <13g/dL for men) in 58%, LDH >UNL in 46%, lymphocytosis (>5 x10 9/L) in 34%, and B-symptoms in 34%. Treatment data were available for 97% of patients. Median follow-up was 9.1 years (range 0-23). Watch and wait was the initial strategy in 28% and 88% of patients received at least one line of treatment during follow-up with the most common being splenectomy (45%), immuno-chemotherapy (19%) or rituximab monotherapy (8%). Fifteen percent received “other” treatments (i.e., combinations of listed therapies and/or radiation). The overall response rate to first-line treatment was 88% (95%CI: 85-90%) with 61% (95%CI: 57-64%) achieving CR. Second line (2L) therapy was needed in 34% during follow-up, 3L in 20% and 4L+ in 9%. The 5-year EFS and OS for all patients were 61% (95%CI: 57-65%) and 77% (95%CI: 74-80%) respectively. The 10-year OS and lymphoma-specific mortality (with non-SMZL deaths as competing risk) estimates were 60% (95%CI: 57-64%) and 11% (95%CI: 9-14%) respectively. The 5-year OS after 2L and 3L were 61% (95%CI: 55-68%) and 51% (95%CI: 42-61%) respectively (figure 1). The 10-year cumulative risk of histological transformation was 17% (95%CI: 13-21%), with 5-year post-transformation OS of 42% (32-54%). At the time of transformation, 60% were chemo-naive and 52% had never been treated for SMZL. The 5-year OS for chemo-naive patients with transformation was 54% (95%CI: 41-71%) versus 24% (95% CI: 13-44%) for transformations after (immuno)chemotherapy (p = 0.01). When comparing patients intended for treatment in first line with splenectomy (n=312) versus rituximab (n=70), patients treated with splenectomy more frequently presented with extra-hilar lymphadenopathy (35% vs 18%), splenomegaly (92% vs 87%) and anemia (64% vs 48%). OS was similar for the two groups (Figure 2, p = 0.53). The 5-year EFS were 63% (95%CI: 57-68%) and 64% (95%CI: 54-77%), respectively (p = 0.31). Conclusions: To date, this is the largest real-world study of SMZL with detailed treatment and outcome data. The study shows that histological transformation was not uncommon with 10-year risk of 17%. However, outcomes for the entire cohort were excellent irrespective of initial treatment and both OS and EFS were similar after first line rituximab versus splenectomy. Long-term survival remained relatively high even following multiple lines of therapy.

Background: Chimeric antigen receptor (CAR) T cells have repeatedly demonstrated capacity to induce high rates of response and durable remissions for B cell cancers. In contrast, CAR T cells for the treatment of acute myeloid leukemia (AML) have not yet achieved this impact. We previously demonstrated that CD123 is expressed on AML blasts at high frequency, thus making it an attractive target antigen for AML-directed CAR T cells. Methods and Results: We conducted a pilot study of CD123-directed CAR T cells (CART-123) in adults with relapsed or refractory AML. The primary objective was safety with a secondary objective of anti-leukemia efficacy. Twenty-two subjects were screened, and 20 were eligible for the trial. Fludarabine and cyclophosphamide were used for lymphodepletion (LD). Twelve subjects were infused with CART-123. There were two treatment-related deaths due to cytokine release syndrome (CRS) and infection. Four subjects (33%) achieved complete response with incomplete count recovery (CRi), three subjects had progressive disease, and five had stable disease. Of the four who achieved CRi, one subject remains alive in remission after a relapse and subsequent consolidative hematopoietic stem cell transplant (HSCT). One other subject is alive after HSCT following CART-123 failure. There was evidence of CAR T cell expansion and ten subjects (83%) experienced clinical CRS ranging from Grade I to Grade V. There was no neurotoxicity. To address the apparent paradox of high rates of CART-123 bioactivity (clinical CRS and in vivo expansion) co-occurring with low rates of response, we hypothesized that cytokines produced during CRS may undermine the anti-AML effect of CART cells. We obtained serum drawn from trial subjects at baseline (prior to LD chemotherapy) or during CRS. Serum drawn during CRS promotes primary AML survival in cell culture, while matched baseline serum from the same subjects does not. Individual cytokines secreted during CRS that signal through receptors expressed on myeloid progenitors (such as GM-CSF and Flt3 ligand) reproduced this survival advantage in primary AML blasts when tested at physiologically relevant levels. In contrast, these cytokines did not produce a pro-survival effect in primary patient B-ALL blasts. Crucially, candidate myeloid-acting cytokines, as well as serum drawn during the peak of clinical CRS, promoted resistance of AML to killing by CART-123 in vitro. Using scRNAseq of bone marrow aspirates from subjects on this clinical trial, we found that GM-CSF and FLT3L were most frequently expressed by CD4+ T cells. Exposure of primary AML samples to CRS cytokines led to upregulation of signaling (e.g. JAK/STAT5) and pro-survival pathways. In previous work in B-ALL, we showed that relative resistance to killing can translate to a functional deficit in CART-19 due to development of exhaustion in the CART cells. We similarly find that that exposure to GM-CSF reduces AML blast sensitivity to CART-123, and that the persistence of antigen leads to exhaustion in CART cells (Figure 1). Specifically, co-incubation of CART-123 cells and cytokine-exposed primary AML blasts leads to increased populations of PD-1+/CD39+/CTLA4+/LAG3+ CAR T cells, consistent with an exhaustion phenotype. Finally, we found that anti-apoptotic effects of cytokines can be prevented, and CART-123 killing of AML can be restored, via ruxolitinib blockade of JAK/STAT signaling in both in vitro and in vivo settings. Significance: Our work reveals CRS as active in undermining CART-123 lethality first by promoting survival of AML, and subsequently by exhausting CAR T cells. This is in stark contrast to its role in lymphoid malignancies and underscores biological differences in myeloid versus lymphoid neoplasms. These results highlight a need to tailor therapy to limit cytokine effects on AML blasts to improve outcomes with AML-directed CAR T cell therapy.

Background The therapeutic landscape of mantle cell lymphoma (MCL) has evolved significantly since the early 2000s. We previously reported that a shift in frontline immunochemotherapy choices from 2002−2009 to 2010−2015 was associated with improved event-free survival and overall survival (OS) in both younger (age ≤65) and older (age >65) patients in a prospective Mayo Clinic/University of Iowa cohort (Castellino, Blood Advances, 2022). In addition, we recently reported that changes in treatment for relapsed/refractory (R/R) disease over the last two decades were associated with steady improvements in OS for R/R MCL (Tawfiq, ASH, 2022). In this study, we utilized data from the National Cancer Database (NCDB) to investigate the impact of therapy in the modern era on survival outcomes of patients with MCL in the US since 2004. Methods The NCDB is an outcomes database of more than 1,500 hospital-based cancer registries covering approximately 70% of newly diagnosed cancers in the US. The latest version of NCDB was used to identify patients with newly diagnosed MCL from 2004 to 2020. Three treatment eras were defined as Era 1 (2004−2009), Era 2 (2010−2014), and Era 3 (2015−2020), based on immunochemotherapy changes (from Era 1 to Era 2) and increased access to novel agents such as Bruton's tyrosine kinase (BTK) inhibitors (from Era 2 to Era 3). Overall survival between different eras was stratified and analyzed based on 3 age groups: <65, 65−79, and ≥80 years. Survival analysis was performed using the Kaplan-Meier method and all Cox proportional hazards models were adjusted for age and sex. Results A total of 32,746 patients with newly diagnosed MCL was identified, 12,847 (39.2%) patients were age <65, 14,297 (43.7%) age 65−79, and 5,602 (17.1%) age ≥80. For every age group, the distributions in sex, stage, Charlson-Deyo score, and treatment facility type (academic vs non-academic) were largely similar between eras. As expected, the median OS was significantly worse for patients age ≥80 years (19.8 months) compared to patients age 65-79 years (60.9 months) and patients age <65 years (143.9 months; p <0.001). In patients age <65 years, OS in Era 2 was improved when compared to Era 1, with a 5-year OS rate of 72.1% vs 67.6% (logrank p<0.001) (Figure 1) and an age- and sex-adjusted hazard ratio (HR) of 0.83 (95% CI 0.78−0.89, p<0.001). OS in Era 3 was similar to that in Era 2, with a 5-year OS rate of 72.2% vs 72.1% (logrank p=0.61) and an age- and sex-adjusted HR of 0.97 (95% CI 0.89−1.06, p=0.51). In patients age 65-79 years, similar trends in OS changes between eras were observed. The 5-year OS rate in Era 1, Era 2, and Era 3 was 43.3%, 52.8%, and 54.9%, respectively (p<0.001 comparing Era 2 vs Era 1, and p=0.05 comparing Era 3 vs Era 2). Age- and sex-adjusted HR was 0.83 (95% CI 0.78−0.87, p<0.001) comparing Era 2 vs Era 1 and 0.95 (95% CI 0.89−1.01, p=0.07) comparing Era 3 vs Era 2. In patients age ≥80 years, the improvement in OS from Era 1 to Era 2 was less prominent than other age groups. The 5-year OS rate was 22.9% vs 19.5% (p=0.03), and age- and sex-adjusted HR was 0.88 (95% CI 0.81−0.94, p<0.001). OS in Era 3 vs Era 2 was similar, with a 5-year OS rate of 23.1% vs 22.9% (logrank p=0.79) and an age- and sex-adjusted HR of 0.98 (95% CI 0.91−1.06, p=0.67). Conclusions This large NCDB study demonstrated that survival of patients with newly diagnosed MCL has improved over the last two decades. The results are consistent with our Mayo Clinic/University of Iowa prospective cohort study and confirm an improved OS after 2010, which was most likely driven by both frontline immunochemotherapy changes and better access to novel agents for R/R disease. The 5-year OS in patients diagnosed in 2015−2020 did not appear to be superior to those in 2010−2014, despite presumably having better access to novel agents such as BTK inhibitors in the R/R setting. This lack of a difference in OS may be partially due to short follow-up, but may also suggest that further improvement in frontline therapies by incorporating novel agents may be required to improve OS. The OS of patients age ≥80 years is limited and has only minimally improved after 2010, highlighting a significant unmet need for therapies with improved tolerability and efficacy in this age group.

Background Limited stage (stage I−II) disease is an uncommon presentation of mantle cell lymphoma (MCL), and its optimal management remains controversial. A British Columbia study (Leitch, Ann Oncol, 2003) and a Surveillance, Epidemiology and End Results (SEER) study (Murthy, Clin Lymphoma Myeloma Leuk, 2014) suggested the importance of radiotherapy (RT). A National Cancer Database (NCDB) study in the pre-BTK inhibitor (BTKi) era showed that chemotherapy (Chemo) plus RT (Chemo+RT) improved overall survival (OS) compared to Chemo or RT alone (Gill, Int J Radiat Oncol Biol Phys, 2015). However, a retrospective International Lymphoma Radiation Oncology Group study (Dabaja, Ann Oncol, 2017) reported comparable OS with Chemo+RT vs Chemo or RT alone. The potential differences in OS with different frontline therapy modalities may be modified by subsequent therapies for relapsed or refractory (R/R) disease. In this study, we used the NCDB data to analyze frontline treatment patterns and outcomes of limited stage MCL in the pre-BTKi vs BTKi eras. Methods The NCDB was queried to identify patients with stage I−II MCL diagnosed in 2004−2020. Because the first BTKi ibrutinib was approved by the FDA for R/R MCL in November 2013, we defined 2004−2013 as pre-BTKi era and 2014−2020 as BTKi era. Frontline treatment modalities were categorized to RT alone, Chemo alone, or Chemo+RT. Survival analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model. Results Among 32,746 patients with newly diagnosed MCL in 2004−2020, 3,836 (11.7%) presented with stage I−II disease, with 2,428 having treatment information available. For patients diagnosed in the pre-BTKi era (n = 2005), 195 (9.7%) received RT alone, 1472 (73.4%) received Chemo alone, and 338 (16.9%) received Chemo+RT. For patients diagnosed in the BTKi era (n = 423), 45 (10.6%) received RT alone, 320 (75.7%) received Chemo alone, and 58 (13.7%) received Chemo+RT. Patients in the RT alone group were older (P <0.001) and had more females (P <0.001), but there were no statistically significant differences in Charlson-Deyo score, international prognostic index, or treating facility type (academic vs non-academic). For patients with stage I disease, in the pre-BTKi era, patients treated with Chemo+RT (n = 182) had improved OS compared to those treated with RT alone (n = 141) or Chemo alone (n = 647), with a 5-year OS of 75.4% vs 71.8% vs 61.4% (P <0.001). Similar results were observed in the BTKi-era, with a 5-year OS of 83.6% vs 69.5% vs 62.9% (P <0.001) for patients treated with Chemo+RT (n = 31), RT alone (n = 30), or Chemo alone (n = 130), respectively. After adjusting for age and sex, Chemo+RT was associated with improved OS compared to Chemo alone (pre-BTKi era, HR = 0.59, 95% CI = 0.46−0.75, P <0.001; BTKi era, HR = 0.34, 95% CI = 0.14−0.79, P = 0.013), but not compared to RT alone (pre-BTKi era, HR = 0.62, 95% CI = 0.23−1.68, P = 0.343; BTKi era, HR = 0.77, 95% CI = 0.56−1.05, P = 0.10) (Figure 1A). For patients with stage II disease, in the pre-BTKi era, patients treated with Chemo+RT (n = 156) had improved OS compared to those treated with RT alone (n = 54) or Chemo alone (n = 825), with a 5-year OS of 70.0% vs 47.3% vs 58.4% (P <0.001). In the BTKi-era, patients treated with Chemo+RT (n = 27) or RT alone (n = 15) both had improved OS compared to those treated with Chemo alone (n = 190), with a 5-year OS of 77.2% vs 78.8% vs 61.9% (P = 0.004) . After adjusting for age and sex, Chemo+RT was associated with improved OS compared to Chemo alone in BTKi era only (pre-BTKi era, HR = 0.85, 95% CI = 0.67−1.07, P = 0.165; BTKi era, HR = 0.49, 95% CI = 0.25−0.95, P = 0.034), but not compared to RT alone (pre-BTKi era, HR = 0.78, 95% CI = 0.53−1.13, P = 0.185; BTKi era, HR = 0.97, 95% CI = 0.35−2.67, P = 0.952) (Figure 1B). Conclusions Treatment pattern for limited stage MCL has not changed significantly from the pre-BTKi era to the BTKi era, with approximately 15% of patients receiving Chemo+RT, 10% RT alone and 75% Chemo alone. In the BTKi era, Chemo+RT appeared to be associated with better OS compared to Chemo alone but not compared to RT alone. Interpretation of the results requires caution because (1) patient numbers are small in Chemo+RT and RT alone groups, (2) longer follow-up may be needed, and (3) selection of therapy was not random, eg, patients receiving Chemo alone may have had higher disease burden such as bulky disease and/or non-contiguous stage II involvement but these details are not available in NCDB.

Background: Richter Transformation (RT) refers to the development of an aggressive lymphoma in the setting of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Small molecule inhibitors (SMI), such as the Bruton tyrosine kinase inhibitors (BTKi) and BCL2 inhibitors (BCL2i), have revolutionized the treatment of CLL/SLL. Prior studies evaluated outcomes of patients (pts) with RT in an era where chemoimmunotherapy (CIT) was typically used to treat CLL/SLL. Now that SMI are standard of care, fewer pts with CLL/SLL receive CIT, therefore we sought to determine which variables predict survival in pts who developed RT without prior CIT exposure for CLL/SLL. Methods: We conducted an international multicenter retrospective study of pts from 11 academic centers. Pts with RT occurring as large B-cell lymphoma who did not previously receive CIT (e.g., fludarabine, cyclophosphamide, bendamustine, chlorambucil) for their CLL/SLL were included. We collected pt, disease, and treatment (tx) characteristics. RT was categorized into 3 groups: “Concurrent RT,” defined as RT and CLL/SLL diagnosed simultaneously (within 3 months [mos]); “RT w/o prior CLL/SLL tx,” defined as RT and CLL/SLL diagnosed >3 mos apart with the CLL/SLL never treated; and “RT with prior non-CIT tx for CLL/SLL” defined as having received prior CLL/SLL tx. Overall survival (OS) was measured from RT diagnosis (Dx) and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: 242 pts were identified. At CLL/SLL Dx, 66% of pts had unmutated IGHV, 37% had del17p/ TP53 disruption, and 20% had trisomy 12. At RT Dx, 56% of the RT with prior non-CIT tx for CLL/SLL group had a del17p/ TP53 disruption versus 27% for the concurrent RT group and 18% for the RT w/o prior CLL/SLL tx groups. Median time from CLL/SLL Dx to RT Dx was 47 mos (range 3-394) for RT w/o prior CLL/SLL tx and 46 mos (range 4-218) for RT with prior non-CIT tx for CLL/SLL. Pts with prior non-CIT tx for CLL/SLL received a median of 1 (range 1-5) prior tx. 86% of pts previously received a BTKi or a BCL2i for tx of CLL/SLL (54% BTKi only, 5% BCL2i only, 27% both). The remaining 14% had been treated with an anti-CD20 monoclonal antibody (MoAb), steroids, lenalidomide, radiation, or alemtuzumab. 85% of pts developed RT while on active tx with SMI. Median age at RT Dx was 69 years (range 37-92). At RT Dx, 38% and 21% of pts had del17p/ TP53 disruption, and trisomy 12 in CLL/SLL tissue, respectively. At RT Dx, there was no difference in highest SUV on PET (median 16, range 2.9-65.6), LDH (median 325, range 103-8162, ULN range 180-271), largest lymph node in diameter (median 4.9 cm, range 0-17.1), Ki-67 (median 80%, range 5%-100%), rate of GCB subtype (27%), presence of MYC translocation (20%), or CLL/SLL and RT clonal relationship (81%) for those pts tested amongst the 3 groups ( Table). The most common 1 st line tx for RT was CIT with or w/o radiation and/or steroids (76%), followed by CIT plus SMI (13%), SMI single agent or combination (7%), and other (4%, which includes anti-CD20 MoAb). Median follow-up from RT Dx was 42.3 mos; the median OS for the entire cohort was 25.8 mos (95% CI: 16.8-49.1). Pts with RT after non-CIT tx for CLL/SLL had a significantly worse OS (median 8.2 mos [95% CI: 5.6-14.3]) than pts with concurrent RT (median 46.3 mos [95% CI: 23.8-96.9]) and RT w/o prior CLL/SLL tx (median 63.5 mos [95% CI: 28.3-70.3]) ( Figure). From an exploratory univariable analysis, we found RT after non-CIT tx for CLL/SLL compared to concurrent RT (HR 2.32 [95% CI: 1.55-3.46]), RT Dx age (HR for 5-year increase 1.14 [95% CI: 1.05-1.23]), del17p/ TP53 disruption (HR 2.27 [95% CI: 1.45-3.56]), and LDH (HR for 2-fold increase 1.37 [95% CI: 1.20-1.58]) were prognostic for worse OS. Conclusions: This is the largest cohort of pts who developed RT having received only SMI with no CIT for their CLL reported, thus reflecting the current treatment landscape. Despite being CIT-naïve, pts in our series who received tx for their CLL/SLL and then developed RT had a short OS, underscoring the need to develop better therapies for these pts. In contrast, as in other published analyses (Wang Haematologica 2020), pts w/o prior tx for CLL/SLL had more favorable outcomes, with a median OS of approximately 5 years. Further analysis to determine PFS and OS by tx for RT for pts who have been treated with SMI for their CLL/SLL is ongoing.

Introduction: Chronic lymphoproliferative disorder of natural killer cells (CLPD-NK) is a rare form of large granular lymphocytic leukemia. The clinical characteristics and outcomes of patients (pts) with CLPD-NK in the literature are limited. We aim to describe the patient characteristics, laboratory features, and clinical outcomes of CLPD-NK by reporting on, to our knowledge, the largest single-center cohort of CLPD-NK in the United States. Methods: We retrospectively identified Mayo Clinic pts with CLPD-NK, defined per the WHO 5 th edition and 2022 International Consensus Classification. We conducted chart review to collect clinical and laboratory data. Overall survival (OS) was plotted using Kaplan-Meier. Time to first treatment (TTFT) was displayed using cumulative incidence methodology accounting for competing risk of death. Univariable Cox regression models investigated associations between patient characteristics and outcomes (OS and TTFT). Results: We identified 45 pts who were diagnosed with CLPD-NK between 1997 and 2022. The median age at diagnosis was 69 years (range: 25-90) and 32 pts (71%) were male. At the time of diagnosis, 10 pts (22%) had a concomitant autoimmune disorder and 9 (20%) had laboratory evidence of a serologic abnormality (monoclonal gammopathy, rheumatoid factor, etc.). In addition, 10 pts (22%) had a prior diagnosis of a hematologic malignancy and 12 (27%) had a prior diagnosis of a solid tumor. Clinically, 4 pts (9%) had B symptoms, 15 (33%) had splenomegaly, and 13 (29%) were transfusion dependent. At diagnosis, median hemoglobin (hgb) was 10.2 g/dL, with 25 pts (56%) showing a hgb <11g/dL and 8 (18%) demonstrating a hgb <8 g/dL. The median platelet count was 202x10^9/L, with 12 pts (27%) demonstrating a platelet count <150x10^9/L. The median white blood cell count was 5.8x10^9/L. The median absolute neutrophil count (ANC) was 1.2x10^9/L, with 29 pts (64%) demonstrating an ANC <1.5x10^9/L. The median absolute lymphocyte count (ALC) was 3.8x10^9/L, with 20 pts (44%) demonstrating an ALC >4x10^9/L. The median absolute abnormal NK cell count per flow cytometry was 2.2x10^9/L. Flow cytometry revealed killer cell immunoglobulin-like receptor (KIR) restriction in all pts, with 27 (61%) lacking KIR expression and 17 (39%) demonstrating KIR restriction in CD158a, CD158b, and/or CD158e. CD7 expression was present in 42 pts (93%; 31% dim/partial), CD8 expression was present in 22 (49%; 42% d/p), CD56 expression was present in 17 (39%; 23% d/p), CD57 expression was present in 26 (59%; 46% d/p), CD94 expression was present in 33 (77%; 7% d/p), and NKG2A expression was present in 21 (50%; 5% d/p). Bone marrow examination (n=30) revealed that the median number of NK infiltrate was 11% (range: 5-40%) of cellularity, with 20 demonstrating an intrasinusoidal infiltrative pattern. The median follow-up was 41 months (mo), and 23 pts required at least one line of treatment. Treatment indications included anemia (39%), neutropenia (4%), bi/pancytopenia (39%), lymphocytosis (4%), or other (13%). The median TTFT was 32 mo (95% CI 2-93 mo). Hgb <11g/dL was associated with a shorter TTFT (9.7 vs 187 mo); however, neutropenia and thrombocytopenia were not associated with TTFT. For first-line treatment, in addition to frequent steroid use, 16 pts (70%) received a methotrexate-based regimen, 6 (26%) received a cyclophosphamide-based regimen, and 1 (4%) received a cyclosporine-based regimen. The median TTFT was not reached. Of those who required systemic treatment, 9 pts required a second-line therapy. The median OS from diagnosis was 162 mo (95% CI: 84-not estimable, NE), with 33 pts alive at last follow-up (Figure 1a). Increasing age (HR 1.2, 95% CI 1.1-1.3, p=0.002) and lack of CD94 expression (HR 5.6, 95% 1.3-25.0, p=0.02) were associated with worse OS. In the 23 pts who required treatment, the median OS from treatment initiation was 84 mo (95% CI: 52-NE) (Figure 1b). Conclusions: In this large cohort of 45 pts, the majority had neutropenia and anemia, and approximately half required systemic treatment. Estimated median OS from diagnosis exceeded a decade for the entire cohort and was seven years after treatment initiation. Anemia was associated with a shorter TTFT, while increasing age and lack of CD94 expression were associated with worse OS. This rare disease warrants additional investigations to understand optimal management and improve outcomes, especially for those requiring treatment.