Spurgeon, Stephen E.

Introduction: Richter transformation is the development of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma, in patients (pts) with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Transformation into Hodgkin lymphoma (HT) is a rare event and outcomes in pts with this complication in the current CLL/SLL therapeutic era of small molecule inhibitors (SMI; e.g., Bruton tyrosine kinase inhibitors [BTKi] and BCL2 inhibitors [BCL2i]) are unknown. Methods: We conducted a retrospective study of pts from 12 academic centers. Pts with HT who had not previously received chemotherapy for CLL/SLL-directed treatment (tx) were included. Pt, disease, and tx characteristics were collected. HT was categorized into 3 groups: “Concurrent HT,” defined as HT and CLL/SLL diagnosed simultaneously (within 3 months); “HT without prior CLL/SLL tx,” defined as HT and CLL/SLL diagnosed >3 months apart with the CLL/SLL never treated; and “HT with prior non-chemotherapy tx for CLL/SLL” defined as having received non-chemotherapy CLL/SLL-directed tx prior to the diagnosis (dx) of HT. Overall survival (OS) was measured from HT dx and estimated using the Kaplan-Meier method. Cox regression model was used to identify prognostic factors associated with OS. Results: Within a total cohort of 402 pts with Richter transformation (all histologies) without prior chemotherapy, 41 pts with HT (10%) were identified: 12 with concurrent HT, 10 with HT without prior CLL/SLL tx, and 19 with HT with prior non-chemotherapy tx for CLL/SLL. The median age at CLL/SLL dx was 62 years (range 31-96 years) and 73% were male. At CLL/SLL dx, 67% (14/21 evaluated) had unmutated IGHV, and 24% (8/34 evaluated) had TP53 disruption (del(17p) and/or TP53 mutation). The median age at HT dx was 65 years (range 31-96 years) among all pts. At HT dx, there was no significant difference in highest SUV on PET (median 12.3, range 3-31.1), lactate dehydrogenase (LDH) level (median 242 U/L, range 112-859 U/L), or lymph node longest diameter (median 4.6 cm, range 1.6-25 cm) among the 3 subgroups. The median time from CLL/SLL dx to HT dx was 5.4 years (range 0.3-16.5 years) in pts with HT without prior CLL/SLL tx and 4.2 years (range 0.5-17.3 years) in pts with HT with prior non-chemotherapy tx for CLL/SLL. The median number of prior non-chemotherapy CLL/SLL-directed tx was 1 (range 1-6) and included BTKi only (n=17) and BTKi and BCL2i sequentially (n=2); no patient had received only prior BCL2i. Among the 19 pts with HT with prior non-chemotherapy tx for CLL/SLL, 18 pts were on active tx at time of dx (17 BTKi, 1 BCL2i). Initial HT management included: doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD; n=16), brentuximab vedotin (BV)-AVD (n=10), radiation only (n=2), other systemic tx (n=11), and supportive cares / hospice (n=2). All but 1 of the 11 other systemic tx were various HL tx regimens. Across all pts with available data (n=32), the overall response rate to 1st line HT tx was 78% (69% complete response rate); 13% had progressive disease and 9% (n=3; all with concurrent HT) died within 6 months without formal response assessment. A total of 11 pts received at least 1 additional line of therapy for HT, which included BV (n=4), an immune checkpoint inhibitor (n=1), or both (n=6) at any point beyond 1st line HT tx. Median follow-up from HT dx was 32.8 months (range 2.4-253.8 months). The 36-month OS for the entire cohort was 75% (95% CI: 55-87%). The 36-month OS estimates by subgroups were: 62% (95% CI: 26-84%) in pts with concurrent HT, 100% in pts with HT without prior CLL/SLL tx (no events by 36 months), and 67% (95% CI: 33-87%) in pts with HT with prior non-chemotherapy tx for CLL/SLL. Exploratory univariable analysis identified TP53 disruption at CLL dx (HR 12.36; 95% CI: 2.55-59.84) and lymph node longest diameter (HR 1.32 per 1 cm increase; 95% CI: 1.12-1.55) and LDH 2-fold increase (HR 3.97; 95% CI 1.24-12.68) at HT dx as prognostic for worse OS. HT subgroup was not prognostic. Conclusions: This is the largest report of outcomes in pts with CLL/SLL who develop HT following SMI tx without any prior chemotherapy, representing a contemporary cohort. Prior CLL/SLL tx status was not associated with OS; however, cautious interpretation is required given the sample size. Our findings support the use of appropriate HL-directed treatment in the setting of HT; however, OS estimates remain worse than would be expected in an older adult de novo HL cohort (Cheng Blood Adv 2022).

Introduction: Mantle cell lymphoma (MCL) is an uncommon B-cell non-Hodgkin lymphoma (NHL) Prognosis is highly variable due to underlying biological and molecular heterogeneity. The first-line (1L) treatment paradigm for MCL continues to evolve with increasing use of bruton tyrosine kinase inhibitors (BTKi) and decreasing use of autologous stem cell transplant (ASCT). TP53 alterations are associated with inferior outcomes in MCL. The aim of this retrospective study is to determine treatment strategies and clinical outcomes in MCL patients based on TP53 gene mutation status. Methods: Retrospective data were collected from 19 institutions in the United States from 1/1993 to 1/2024. We examined treatment patterns and outcomes among MCL patients >18 years of age with known TP53 mutation status by sequencing. Patients who did not receive treatment were excluded. The analysis was stratified based on presence of TP53 mutations. Systemic therapies were categorized as chemo-immunotherapy (CIT), non-chemotherapy (including monoclonal antibodies, lenalidomide, venetoclax, and novel agents on clinical trial), and regimens containing BTKi. The primary outcome was overall survival (OS) and secondary outcomes were progression free survival (PFS) and time to next treatment (TTNT). OS and PFS were estimated with the Kaplan-Meier method and log-rank tests were used to compare groups. Results: 645 patients were included in the study, with 468 men (72.6%) and median age was 64 years (range 30-89). 230/645 patients (35.7%) had a TP53 mutation, of which 182 (79%) were identified prior to 1L. While the male/female distribution was the same between the mutated and unmutated groups, median age at diagnosis and MIPI risk score was higher in the TP53 mutated group (age 65.9 vs 63.1 yrs, p= 0.015; MIPI 6.4 vs 6.1, p<0.001). TP53 unmutated patients had a median of 1 line of therapy vs. 2 for the mutated group (p<0.001, range 1-8). Blastoid histology and higher ki67 were also associated with the TP53 mutated group (p=0.045, 0.01 respectively) The median OS was 14.2 years for TP53 unmutated and 8.3 years for TP53 mutated patients (p<0.0001). PFS in 1L was 0.95 years in TP53 mutated compared to 2.02 years in TP53 unmutated group (p<0.0001). Selection of 1L therapeutic strategy was not associated with presence of TP53 mutation (Χ2 p= 0.21) although more patients in the TP53 unmutated group underwent ASCT (119/415 vs 38/230; Χ2 p=0.0006) TP53 mutation was associated with inferior survival compared to TP53 unmutated patients for CIT in 1L but the difference did not reach statistical significance when non-chemotherapy regimens and regimens containing BTKi were used. For CIT in 1L, 5 year OS was 78% [71-84%] for unmutated compared to 58% [48-67%] for the mutated group (p=0.0001 ). For non-chemotherapy regimens, 5 year OS for unmutated patients was 73% [52- 86%] compared to 52% [25-73%] for the mutated group (p=0.09). For regimens containing BTKi, 5 year OS for unmutated was 93% [81-97%] compared to 57% [28-78%] for mutated (p=0.07). Within the TP53 mutated group, there were no differences in any clinical outcomes between those receiving CIT, non-chemotherapy, or BTKi in 1L. While median OS appeared numerically longer in the BTKi group (14.4 yrs vs 8.8 yrs for CIT and 6.8 yrs for non-chemotherapy), the difference did not reach statistical significance (p=0.58). In contrast,TP53 unmutated patients who received CIT in 1L had better TTNT (p=0.0039) compared to those in non-chemotherapy and BTKi groups. There was no improvement in PFS (p=0.79) or OS (p=0.47). Conclusions To our knowledge this is the largest retrospective real world dataset of MCL treatment outcomes stratified by TP53 mutation. As in prior studies, TP53 mutation portends a worse prognosis in MCL compared to TP53 unmutated patients, but outcomes are better than historically reported. CIT in 1L was not associated with improved OS in either group. Irrespective of TP53 mutation status, incorporation of BTKi in first line was not associated with improved clinical outcomes. The gap in OS between TP53 mutated and unmutated MCL may be narrowing as treatment paradigms shift away from intensive induction chemotherapy and ASCT, and due to an increasing number of effective therapies for relapsed patients. Clinical trials of novel agents are needed to further improve the OS of TP53 mutated MCL patients.

Introduction: The optimal induction for younger fit patients (pts) with mantle cell lymphoma (MCL) is unknown; though intensive chemoimmunotherapy (CIT) containing high dose cytarabine has been shown to prolong remission. Achieving molecular remission is an independent predictor of outcomes post induction therapy in patients with MCL. Incorporating undetectable measurable residual disease (uMRD) status into the primary endpoint may be preferable to progression-free survival (PFS), particularly when approaches following induction are varied (e.g., ASCT, maintenance treatment, observation). Induction with 3 cycles of bendamustine and rituximab followed by 3 cycles of cytarabine and rituximab (BR/CR) is associated with high complete metabolic response (CMR) and uMRD rates (Armand et al., BJH 2016; Merryman et al., Blood Adv 2020). Bruton's tyrosine kinase inhibitors (BTKi) including ibrutinib and acalabrutinib (A) in combination with CIT are highly effective in MCL (Wang et al., EHA 2024, LBA 3439). In 2019, the US Intergroup activated EA4181 to explore the efficacy with the addition of fixed duration BTKi, to BR or BR/CR for patients with MCL ≤ 70 years old. Patients and methods: Patients were randomized 1:1:1 (stratified by MIPI risk status) to 6 cycles of BR/CR (control arm), BR/CR-A, or BR-A. Cytarabine was dosed at 2 g/m2 Q12 hours x 4, with dose reductions based on age and creatinine clearance. Acalabrutinib was dosed at 100 mg BID continuously on BR cycles with the BR/CR-A and BR-A arms and at 100 mg BID on days 1-7 and 22-28 with CR cycles on the BR/CR-A arm to mitigate hematologic toxicity. Consolidation approaches following induction were at the discretion of the treating physician. The primary endpoint was a composite of PET/CT CMR and peripheral blood uMRD rate (< 1 in 105). ClonoSEQ (Adaptive Biotechnologies) was performed at baseline and MRD testing was obtained at the end of induction. Secondary clinical objectives included PFS and overall survival (OS) at 36 months (mo), objective response rates (ORR), and toxicity rates. With 108 patients per arm expected, there was 86% power to detect an increase in PET/CT CMR/uMRD rate from 60% in the control arm to 75% in either BR/CR-A or BR-A arms using a Z-test with a 10% alpha (1-sided). Results: Between October 2019 and March 2023, 359 participants were randomized to BR/CR (n = 128), BR/CR-A (n = 129), and BR-A (n = 102). BR-A was closed to further accrual by the DSMC based on interim futility analysis for superiority in Fall 2022. The median (range) age was 61 (25, 70), 30% were ≥ 65 years, 77% were male, 89% were white, 89% were non-Hispanic, 18%/43%/39% were low/intermediate/high risk MIPI. Baseline clonal sequence was identified in 308/326 (95%) among samples received. 281/308 were eligible and treated and 260/281 had an end of treatment MRD test result (BR/CR = 85, BR/CR-A = 98, BR-A = 77). This subset (n = 260) is the focus of the primary analysis; sensitivity analysis included 281 eligible and treated pts with trackable clonal marker. In the primary analysis subset, 94%, 91%, and 90% in BR/CR, BR/CR-A, and BR-A arms, respectively, completed 6 cycles of protocol therapy. The PET/CT CMR/uMRD rates were 82% (BR/CR), 82% (BR/CR-A; p = 0.55 vs BR/CR), and 78% (BR-A; p = 0.76 vs BR/CR). In the sensitivity analysis set, PET/CT CMR/uMRD rates were 74% with BR/CR (n = 94), 76% (p = 0.44) with BR/CR-A (n = 106), and 74% (p = 0.52) with BR-A (n = 81). ORR (CMR) rates were 94% (91%), 99% (90%), and 94% (91%) with BR/CR, BR/CR-A, and BR-A, respectively. At a median follow-up of 27.9 mo, estimated 12-mo PFS/OS were 86%/94% (BR/CR), 89%/98% (BR/CR-A) and 87%/95% (BR-A). The proportion of treatment-related grade 3 or higher adverse events (AE) was 78%/88%/73%, with neutropenia in 52%/58%/27%, anemia in 23%/32%/3%, thrombocytopenia in 55%/66%/6%, and febrile neutropenia in 11%/12%/4%; treatment discontinuation due to AE occurred in 5%/7%/8% in BR/CR, BR/CR-A, and BR-A arms, respectively. Conclusion: High PET/CT CMR uMRD rates were seen in all 3 arms. BR/CR can be considered as a standard induction in pts ≤ 70. Addition of acalabrutinib to the standard arm added toxicity without improvement in efficacy, suggesting acalabrutinib should be avoided during Ara-C cycles. BR-A was found not superior and closed early by the DSMC; however, it is the least toxic arm with similar efficacy, and represents an appealing option to avoid high dose cytarabine.

Abstract Although Bruton tyrosine kinase inhibitors (BTKis) are generally well tolerated and less toxic than chemotherapy alternatives used to treat lymphoid malignancies, BTKis like ibrutinib have the potential to cause new or worsening hypertension (HTN). Little is known about the optimal treatment of BTKi-associated HTN. Randomly selected patients with lymphoid malignancies on a BTKi and antihypertensive drug(s) and with at least 3 months of follow-up data were sorted into 2 groups: those diagnosed with HTN before BTKi initiation (prior-HTN), and those diagnosed with HTN after BTKi initiation (de novo HTN). Generalized estimating equations assessed associations between time varying mean arterial pressures (MAPs) and individual anti-HTN drug categories. Of 196 patients included in the study, 118 had prior-HTN, and 78 developed de novo HTN. Statistically significant mean MAP reductions were observed in patients with prior-HTN who took β blockers (BBs) with hydrochlorothiazide (HCTZ), (−5.05 mmHg; 95% confidence interval [CI], 10.0 to −0.0596; P = .047), and patients diagnosed with de novo HTN who took either an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) with HCTZ (−5.47 mmHg; 95% CI, 10.9 to −0.001; P = .05). These regimens also correlated with the greatest percentages of normotensive MAPs. Treatment of HTN in patients taking a BTKi is challenging and may require multiple antihypertensives. Patients with prior-HTN appear to benefit from combination regimens with BBs and HCTZ, whereas patients with de novo HTN appear to benefit from ACEi/ARBs with HCTZ. These results should be confirmed in prospective studies.

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.