5-year PFS Research Articles

Patterns of Care in Craniopharyngioma: Clinical Outcomes After Surgery and Radiation Therapy in a Real-World Setting

Craniopharyngioma (CP) is a benign neuroepithelial tumor generally treated with maximal safe resection and radiation therapy (RT) in incompletely resected CP or in recurrent tumors to achieve long-term control. We analyzed the clinical outcomes of patients with CPs treated with a multimodality approach. A retrospective clinical audit of histologically proven CPs registered between 2008 and 2019 at a specialized neuro-oncology center in India was performed. Time-to-event outcomes (overall survival [OS] and progression-free survival [PFS]) were analyzed. One hundred and twenty-two patients with CP were analyzed. The median age of the population was 14 years (interquartile range [IQR], 8-26) with a significant male preponderance. Gross total resection was achieved in only 25% of patients. At a median follow-up of 57.1 months (IQR, 27.8-87.8), 5-year estimates of PFS and OS were 52% (95% confidence interval, 46%-63.4%) and 85.8% (95% confidence interval, 78.6%-93%), respectively. Recurrence or progression was observed in 48 of 122 patients (39.3%) at a median time of 84.4 months (IQR, 24.7-174.8). On multivariate analysis, the absence of residual disease (P= 0.004), near-total resection (P= 0.035), and use of up-front adjuvant RT (P < 0.001) significantly improved the 5-year PFS, whereas the absence of extracavernous extension (P= 0.058) and any use of postoperative RT (P= 0.026) significantly improved the 5-year OS. This study represents one of the largest single-institutional series of CPs, showing improved PFS with up-front adjuvant RT in most cases of CP. Deferring adjuvant RT should be considered only in patients with no evidence of residual disease (as shown on dedicated sellar imaging) after primary surgery.

Identifying the Optimal Conditioning Intensity of Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia in Complete Remission

Background Allogeneic hematopoietic stem cell transplantation (HSCT) as consolidation therapy is considered a curative option for acute myeloid leukemia (AML) in complete remission (CR) to prevent relapse. Many studies have investigated the optimal conditioning intensity, comparing reduced-intensity conditioning regimen (RIC) and myeloablative conditioning regimen (MAC) for patients with AML in CR. However, inconsistent results have been observed, possibly due to selection biases and significant heterogeneous treatment effects when focusing on average treatment effect. Some studies have attempted to assess treatment effects in specific subgroups, highlighting the heterogeneity conditioning intensity's impact. However, these analyses typically examined one factor at a time, overlooking potential multiple-factor combinations that might contribute to such heterogeneity.To address these limitations and surpass conventional comparison studies and subgroup analyses, machine-learning methods for group identification have been developed. In this study, we aimed to identify patient groups in which MAC or RIC had a superior PFS in patients with AML in CR using a machine-learning approach. Methods Our study included 3273 patients aged 40-69 years with AML in CR from the TRUMP2. These patients were divided into training (N=2020) and validation cohorts (N=1253). In the training cohort, we employed a group identification model to identify patient subsets. Preprocessing of variables was performed to ensure the ease of use in clinical practice. We modeled the magnitude of interaction between treatment and covariates without the main effect of covariates, thus leading to the construction of a scoring system that measures the individualized-treatment effect. The objective variable was set as 1-year PFS, and the interaction effects between treatment and covariates were estimated using a regression model with propensity score weight and LASSO regularization. The sum of the interaction term between treatment and covariates was defined as the “Conditioning Intensity Score”. Patients were categorized into high-score and low-score groups using a cut-off level of median in patients who received RIC. Subsequently, in the validation cohort, we estimated the average treatment effect of RIC compared to MAC for each group with hazard ratios (HR) using inverse treatment probability weight analysis. Results In the training cohort, the median age was 55 years (IQR, 48-61 years), with 1110 (55%) male patients. Among them, 666 (33%) received RIC, while the others underwent MAC. Conditioning Intensity Model was developed and consistent with followings; age over 49 (1.4 points), age over 49 and male (0.8 points), age over 49 and poor karyotype (0.5 point), age over 49 and cord blood transplantation (0.9 points), poor karyotype (-1.6 points), poor karyotype and primary induction failure (8.0 points), poor karyotype and bone marrow transplantation (-5.3 points), cord blood transplantation and hematopoietic cell transplant comorbidity index over 2 (2.1 points) and cord blood transplantation and extra bone marrow involvement (-8.6 points). The cut-off level was set as 2.2. The weighted HR of RIC on 1-year PFS was 0.56 (95%CI; 0.40-0.79, p &amp;lt; 0.001) in the high-score group and 1.23 (95%CI: 0.97- 1.57, p=0.094) in the low-score group. In the entire validation cohort, there were no significant differences in PFS between the RIC and MAC (67.7% [95% CI: 62.1-70.3%] in the RIC group vs. 70.3% [95% CI: 67.2-73.1%] in the MAC group, P=0.318). Patients were divided into two groups based on Conditioning Intensity Score. In the high-score group, the 1-year PFS was 73.9% (95% CI: 65.0-80.9%) in the RIC group vs. 66.2% (95% CI: 58.3-73.0%) in the MAC group ( P=0.181), with a weighted HR of 0.69 (95% CI: 0.43-1.11) for PFS in the RIC group compared to that the MAC group ( P=0.125) (Figure left). Conversely, in the low-score group, the 1-year PFS was 63.7% (95% CI: 56.3-70.2%) in the RIC group vs. 71.2% (95% CI: 67.8-74.2%) in the MAC group ( P=0.031), with a weighted HR of 1.35 (95% CI: 0.96-1.89) in the RIC group compared to the MAC group (log-rank P=0.086) (Figure right). Conclusion In conclusion, we have demonstrated the feasibility of utilizing a machine learning method for subgroup identification of conditioning regimens in patients with AML in CR. This established model holds promise for designing patient-specific regimens.

Brentuximab Vedotin-Based Regimens for Older Patients with Newly Diagnosed Classical Hodgkin Lymphoma -Real World Experience

Introduction: Despite excellent outcomes for young patients with cHL, older patients (pts) age≥ 60 years have less favorable outcomes with a 5-year PFS of about 60% (Cheng, et al. Blood Advances 2022). This disparity is attributed to disease biology, comorbidities, treatment toxicity, dose reductions, and interruptions. Brentuximab vedotin (BV) is increasingly being used in the front-line setting for older pts. The aim of this study was to assess real-word outcomes with BV-based regimens in newly diagnosed older pts with cHL. Methods: We retrospectively reviewed older pts age ≥60 consecutively diagnosed with cHL between 03/2018-01/2023. Data on demographics, medical comorbidities, AEs, PFS and OS were extracted from electronic medical records and were evaluated. For a historical cohort, we reviewed older pts consecutively diagnosed with cHL between 01/2014-03/2018, representing the pre-brentuximab era. Matching 1:1 (the BV cohort to the historical cohort) by age, sex and ECOG was performed. Results: Forty-two patients were treated with BV-based regimens. Patient characteristics included median age of 72 years (range 60-88.5), 71% male, a median Cumulative Illness Rating Scale-Geriatric comorbidity score of 4 (range 0-10), 71% stage IV disease, 61% B symptoms, 49% EBV positive and had 54% had a non-nodular sclerosis histology, table. Twenty-seven (64%) patients received sequential BV-AVD; the rest either received co-current BV-AVD (9,21%) or other BV-palliative combinations (6,15%). The most common adverse events were peripheral neuropathy (35%), infections (16%), and deconditioning (12%), leading to a 33% reduction in treatment, primarily brentuximab vedotin. Twelve patients (28%) did not complete planned treatment, five of them due to AEs, four due to disease progression and three due to other co-morbidities. At median follow up of 2.4 years (95%CI 2.2-2.5), 2-year PFS and OS were 74% and 81%, respectively. After excluding patients treated with palliative regiments (n=36), 2-year PFS and OS were 76% and 93%, respectively. Seven patients died: four from other comorbidities, two from disease progression and one from AEs. Numerical difference in 2-year PFS favoring sequential vs. concurrent BV-AVD was observed, not significant possibly due to low number of pts receiving BV-AVD. When compared to the historical cohort of 43 older patients treated with AVD-based regimens, pts treated with non-palliative BV-based regimens had significantly improved PFS (2-year PFS 65% vs 80%, p=0.035) ,figure. However, there was no statistical significance difference in OS (2-year OS 93% vs 94%, p=0.46). In the BV-based group, all relapsed pts were treated with anti-PD-1-based therapies. In contrast, among the AVD-based group, salvage treatment involved BV-based therapy for 74% of patients, PD-1 therapy for 39%, and chemotherapy with subsequent ASCT for 13%. Conclusions: In this real-world series, sequential BV-AVD regimen was well-tolerated and safe with outcomes that are favorable and comparable to results from the phase II study by Evens et al (JCO 2018). Pts treated with BV-based regimens had significantly better PFS compared to the historical cohort, supporting the use of BV combinations for this elderly population. The lack of statistical significance in OS may be related to death from other comorbidities, limited sample size and the nature of a retrospective data. Additionally, the number of lymphoma-related deaths was low indicating that a significant number of patients can be successfully salvaged, thus also impacting OS observation. Ongoing multicenter data collection efforts are in progress to address the impact of novel agents on treatment of older adults with HL.

Phase Ib/II Study of Multi-Targeted Therapy with Venetoclax, Ibrutinib, Prednisone, Obinutuzumab, and Lenalidomide (ViPOR) in Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL)

Background: Foundational studies have revealed essential oncogenic pathways in DLBCL, triggering the development of drugs targeting distinct survival pathways in this malignancy. While many of these agents are active in DLBCL as monotherapy, they rarely induce deep responses or cure. Based on our identification of drug synergy in DLBCL models, we hypothesized that targeting multiple survival pathways concurrently could be curative in DLBCL. We developed a 5-drug combination regimen (ViPOR) that targets DLBCL survival sustained by constitutive B-cell receptor (BCR) signaling (ibrutinib, lenalidomide, prednisone) and by BCL2 (venetoclax), and also enlists the innate immune system using obinutuzumab. To maximize drug exposure and minimize toxicity, we administered all agents in non-continuous cycles for fixed duration in R/R DLBCL. Methods: R/R DLBCL pts with adequate organ function were eligible. In Ph I, pts were treated at 4 doses of venetoclax (200-800 mg) PO D2-14 to identify the MTD. An initial 12d venetoclax ramp-up was given in combination with fixed-dose ibrutinib 560 mg PO D1-14, prednisone 100 mg PO D1-7, obinutuzumab 1000 mg IV D1-2, and lenalidomide 15 mg PO D1-14. Ph II expansion cohorts of R/R GCB and non-GCB DLBCL were included at the MTD. Max 6C of ViPOR q21d were given without maintenance. TLS, G-CSF, and PCP prophylaxis were given to all pts. Baseline CT, PET, BM, and tumor biopsies were performed with CT after C1, 2, 4, and 6 and PET after C6. CT was then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y. Tumor genomics and ctDNA (clonoSEQ) were studied. Results: 50 DLBCL pts were enrolled (25 DLBCL NOS, 17 HGBCL-DH-BCL2, 3 HGBCL-DH-BCL6, and 5 THRLBCL). 52% and 48% were GCB and non-GCB subtype by IHC, respectively, with transformed lymphoma in 34%. Median age was 61y (range 29-77), with stage 3-4 disease in 92%, elevated LDH in 86%, &amp;gt;2 extranodal sites in 56%, and IPI &amp;gt;3 in 68% of pts. Median prior txs were 3 (range 1-9), with 40% post-CAR-T pts and 58% refractory. A single DLT of G3 intracranial hemorrhage occurred, and venetoclax 800 mg was identified as the MTD. Heme AEs were most common, with G3-4 neutropenia in 24%, thrombocytopenia in 23%, and anemia in 7% of cycles. Febrile neutropenia occurred in 3 (1%) cycles. The only G3-4 non-heme AE in &amp;gt;10% pts was hypokalemia (28%). G3 A.fib occurred in 3 pts, and G4 TLS occurred in 1 pt, which resolved. Other common any grade non-heme AEs (% pts) included diarrhea (68%), hypokalemia (67%), nausea (45%), rash (35%), and fatigue (33%). Dose reductions occurred in 17% of pts, and 8% discontinued tx due to AE. Of 48 evaluable pts (2 came off tx prior to restaging), ORR was 54% (26/48), and CR was 38% (18/48). Responses were observed across all molecular DLBCL subtypes, including a CR rate of 62% (8/13) in non-GCB DLBCL, 53% (8/15) in HGBCL-DH-BCL2, 25% (2/8) in other DLBCL, and a PR rate of 33% (4/12) in GCB DLBCL (non-DH) (Fig. 1A). CR rate was 20% (4/20) and 19% (5/27) in post-CAR-T and refractory pts, respectively. With a median FU of 40m, 72% of CRs are ongoing, with a 2-year PFS and OS of 34% and 36%, respectively. By histology, 2-year PFS was 47%, 38%, 38%, and 8% in HGBCL-DH-BCL2, non-GCB DLBCL, other DLBCL, and GCB DLBCL (non-DH), respectively (Fig. 1B). 2-year PFS was 30% and 21% in post-CAR-T and refractory pts, respectively. MRD was undetectable in 38% (16/42) of pts at end of therapy (EoT), and in 93% (14/15) of pts in PET CR at EoT. Elevated baseline ctDNA or detectable ctDNA during or at EoT were associated with significantly inferior PFS and OS, as were quantitative PET parameters (elevated baseline TMTV and TLG). Two genetic subtypes known to rely on BCR-dependent NF-kB signaling - MCD and N1 - had a significantly higher CR rate (5/6, 83%) than all other genetic subtypes (4/22, 18%; p=0.0066). Conclusions: This is the first study to show the feasibility and curative potential of multi-targeted therapy in R/R DLBCL. ViPOR was well tolerated across all ages in R/R DLBCL with rare febrile neutropenia. ViPOR was most effective in non-GCB DLBCL, as expected from its reliance on BCR signaling and BCL2. ViPOR was also highly active in HGBCL-DH-BCL2, possibly due to inhibition of MYC-driven apoptosis by BCL2 in this subtype. Durable remissions and likely cure were observed in non-GCB DLBCL (38%) and HGBCL-DH-BCL2 (47%), including pts relapsed after or refractory to CAR-T (30%). Multicenter Ph II testing is in development to confirm the activity of ViPOR in R/R non-GCB DLBCL and HGBCL-DH-BCL2.

Durable Remissions in Advanced Stage and Molecularly High Risk Untreated Classic Hodgkin Lymphoma with Pembrolizumab + AVD

Introduction We previously reported results of a frontline study of pembrolizumab + AVD (Lynch et al Blood 2023) in any stage classic Hodgkin lymphoma (CHL). Despite finding surprisingly high rates of positive interim and EOT PET/CT compared to historical data, this study revealed a 2-year PFS of 97%. Separately, recent data (Alig et al. ICML 2023) suggest that CHL is characterized by two dominant genetic subtypes (H1 vs. H2). H2 tumors harbor higher levels of genomic instability, are enriched for somatic mutations in TP53, KMT2D, and BCL2, and have increased risk of upfront treatment failure with conventional regimens. To better evaluate our findings in higher risk patients, we expanded the study to include 20 additional patients with advanced stage disease. Herein we present updated clinical data for our full 50-patient cohort, and report genotype associations including novel genetic subtypes of cHL. Methods We performed a single arm study (NCT03331341) combining concurrent pembrolizumab with AVD in untreated CHL of any stage. Pembrolizumab 200 mg IV was administered every 21 days concurrently with AVD chemotherapy. AVD was administered at the standard dosing and schedule. With the cohort expansion, total planned accrual was 50 patients. The objective of the expanded study was to evaluate longer term efficacy based on concerns with the utility of PET/CT. We defined success as a 1-year PFS in advanced stage patients of at least 85%. Samples were analyzed for ctDNA at baseline, post cycle 1 (if available), post cycle 2, and end of treatment. ctDNA levels were quantified as haploid genome equivalents/mL plasma using CAPP-Seq (Newman et al Nat Biotech 2016) and PhasED-Seq (Kurtz et al. Nat Biotech 2021). Using baseline CAPP-Seq genotypes from plasma ctDNA, patients were classified as H1 vs H2 cHL by a previously validated probabilistic Latent Dirichlet Allocation (LDA) algorithm (Alig et al, 2023, in review). Results 50 patients, enrolled between Feb 1, 2019, and Apr 13, 2023, were evaluable for updated safety, response and/or exploratory analyses (one patient withdrew from study treatment prior to any response assessment). With a median follow up of 2.3 years, 2-year PFS and OS were 98% and 100%, respectively. Among advanced stage patients (n=38), 2-year PFS and OS were 97% and 100% respectively. PET2 was performed in 49 patients, with a CR rate of 73% in the early stage patients, and 58% in those with advanced stage. EOT PET was evaluable in 41 patients, with a CR rate of 91% in early stage, and 73% in those with advanced stage. To date, only one patient with a positive EOT PET has developed biopsy-proven recurrence. Four EOT PET+ patients are now &amp;gt; 3 years post treatment without relapse. Four additional EOT PET+ patients are less than 1 year post therapy, and one has resolved FDG uptake on repeat scan with the others undergoing surveillance. Eight (16%) patients experienced SAEs, including sepsis (one each G3 and G4), G3 Guillain Barre syndrome that resolved after permanent pembrolizumab discontinuation, and five (10%) G3 febrile neutropenia. Non-invasive genotyping using ctDNA was available in 25 patients. Among 6 patients with H2 genotypes (24%), all had advanced stage, and this group included the only patient experiencing disease recurrence. The remaining patients including all early-stage patients were classified as H1 (76%). All patients will have completed treatment and safety evaluations by October 2023, and updated safety, efficacy, and exploratory data including ctDNA will be presented at the meeting. Conclusion With longer follow up, including patients who started therapy over 4 years ago, concurrent pembrolizumab + AVD represents a highly effective frontline therapy for CHL, including for advanced stage patients and those with high risk H2 genotypes. PET2 demonstrated limited clinical utility, and no late relapses have been seen to date.

Minimal Residual Disease (MRD) Status Predicts Outcomes in Patients with Follicular Lymphoma (FL) Treated with Chemo-Immunotherapy on SWOG S0016

Background. FL is associated with a heterogeneous clinical course, and currently available prognostic indicators are unable to reliably separate patients who exhibit early therapy resistance (POD24, defined as progression within 24 months from diagnosis) from those who achieve “functional cure” following initial therapy. NGS methods developed in recent years enabled quantification of MRD. The ClonoSeq assay (Adaptive Biotechnology, Inc.) has been FDA-cleared to track MRD in several hematologic malignancies. Here we demonstrate that MRD analysis by ClonoSeq assay predicts outcomes in a prospective cohort of patients with advanced stage FL enrolled on SWOG S0016 clinical trial. Methods. SWOG S0016 was a phase III randomized study that compared the safety and efficacy of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) with CHOP-RIT (CHOP + I 133-tositumomab) in patients with FL. Between 2001 and 2008, 531 patients with previously untreated advanced-stage FL (bulky stage II, III-IV) of any pathologic grade were randomly assigned to receive 6 cycles of R-CHOP or CHOP-RIT. We used high-throughput sequencing (HTS) of the IGH and IGK/L loci (ClonoSeq assay) from tumor biopsy specimenstaken prior to treatment to define CDR3 rearrangements that tag the tumor. Subsequently, 1-year bone marrow specimens were screened for residual disease. The baseline dominant clone was defined as ≥10 estimated number of genomes (ENG) and comprised ≥5% of the library. MRD-positive state (MRDp) was defined as a minimum Hamming distance (HD) ≤6 in a patient's post-library (in any clone also detected in a pre-library) and conserved pre-existing SHM (if HD&amp;gt;0). Undetectable MRD (MRDu, at &amp;lt;10 -4) was defined as CRD3 HD&amp;gt;6 in a post-library with a depth &amp;gt;10,000 ENG. Five-year progression-free survival was the primary endpoint (PFS; defined as the time from registration to the first observation of progression or death due to any cause). Landmark analysis was defined at 1 year after registration and used for imputing the 5-year PFS and OS. Overall survival (OS) was defined as the time from registration to date of death due to any cause or last follow-up. PFS and OS estimates and 95% confidence interval were calculated using the Kaplan-Meier method and compared for MRDp and MRDu disease using two-sided log-rank test. HR and 95% CI were calculated using Cox regression model. Results. Tumor biopsy tissue was available for 189 patients. Of these, 24 patients were not evaluable (16 did not consent for banking, 6 were ineligible and 4 had an early event). In 36 patients, pre-libraries did not yield a trackable clone. In total, MRD status could not be ascertained in 47 patients due to absence of a clear trackable clone in either pre- or post-library, contributing to a 28.8% failure rate. Of 116 patients which yielded a trackable clone in both libraries, 83 were MRDu and 33 were MRDp. Baseline characteristics (age, sex, race, β2M, B symptoms, bulky disease, grade 3, stage, and FLIPI risk) were similar between MRDp and MRDu patients; however, MRDp patients were more likely to exhibit morphologic baseline bone marrow involvement by FL (82% vs. 55%, p=0.01). The estimated 5-year PFS was 72% in MRDu patients and 30% in MRD+ patients (Figure); 10-year PFS was 56% and 17%, correspondingly. Meanwhile, 5-year OS was not different (96% for MRDu, 81% for MRD+, p=0.91). Patients with MRDu had a significantly higher best overall response rate than MRDp patients (96% vs 79%, p=0.005), but complete response (CR) rates were similar (41% vs. 30.3%). Patients who received CHOP-RIT had better PFS regardless of MRD status (HR=0.48, p=0.01 for MRDu; HR=0.38, p=0.02 for MRDp), while OS was not statistically different. Five-year PFS was superior in patients who achieved MRDu (75% for CR and 70% for PR) compared with MRDp patients, regardless of response (34%). Patients who had MRDp status had a significantly increased risk of experiencing POD24 relative to MRDu patients (RR=6.5, 95% CI 3.0-14.0; p&amp;lt;0.0001). Conclusion. Here we for the first time demonstrate that MRDu status, as assessed by Clonoseq, predicts improved 5- and 10-year PFS in patients with FL initially treated with chemoimmunotherapy. MRD+ status in the bone marrow at a 1-year timepoint was associated with POD24. Despite a relatively high failure rate to detect trackable sequences using current technology (~29%), MRD assessment by NGS is a promising prognostic tool in FL. *co-senior authors

Lenalidomide Maintenance in Multiple Myeloma: A Retrospective, Nationwide, Real-World Study

Introduction: Lenalidomide maintenance (LM) has shown progression-free (PFS) and overall survival (OS) benefit in clinical trials and is the recommended standard of care in patients with newly diagnosed multiple myeloma (MM) after high-dose melphalan and autologous stem cell transplantation (HDM-ASCT). In Denmark, LM has been approved for all patients treated with HDM-ASCT since June 2019 and is publicly funded. That LM was made available nationwide simultaneous across all regions creates a unique opportunity to study the real-world use pattern, efficacy, and adverse effects of LM in an unselected, population-based cohort without referral bias. Methods: Patients with newly diagnosed MM treated with their first HDM-ASCT between June 2019 and March 2022 were included and followed until data cut-off in June 2023. To compare outcomes, a historical pre-LM cohort from the Danish MM Registry, consisting of MM patients treated with HDM-ASCT between June 2015 and June 2019, was used. Baseline clinical characteristics were acquired from the Danish MM Registry. To avoid the risk of guarantee-time bias, several strategies were applied. Early discontinuation of LM was studied using landmark analysis at 6 months after initiation of LM. For comparison with the pre-LM cohort, survival time was calculated from date of ASCT to progression or death for PFS and death of any cause for OS. Cox proportional hazards regression was used to calculate hazard ratios. Multivariate adjustment was made for age and sex as well as known risk factors for worse outcome: ISS and high-risk cytogenetics. Results: Lenalidomide maintenance cohort: Among 364 patients treated with HDM-ASCT after June 2019, 22.3% received consolidation therapy, and 3.7% underwent tandem HDM-ASCT. During follow-up, 297 patients (81.6%) initiated maintenance therapy, with 277 (76.1%) receiving LM. Overall, 145 patients (52.3%) discontinued LM most commonly due to toxicity 75 (51.7%), with fatigue (30.7%), cytopenia (25.3%), and neuropathy (17.3%) being the main reasons. During follow up, 119 (32.7%) patients had an event of progressive disease or death and 38 died. Only 1 death was related to Covid-19. To study the impact of early discontinuation of LM on clinical outcomes a 6-month landmark analysis was conducted. Early discontinuation did not negatively impact PFS, HR 0.92 (95% CI: 0.50, 1.70) or OS, HR 1.12 (0.25, 5.12). Results were similar in a 12-month landmark analysis. Comparison to the pre-lenalidomide maintenance cohort: A cohort of 364 multiple myeloma patients treated before the introduction of lenalidomide maintenance was used as comparison (pre-LM cohort). In that we take advantage of the randomness in being treated for MM in the years before and after the approval of lenalidomide. As the inclusion to either cohort was solely defined by the date of HDM-ASCT baseline characteristics were well balanced as expected with a median age of 61.1 vs 61.8 in the LM cohort and pre-LM cohort, respectively. By chance the dates of inclusion resulted in equal numbers of participants in both cohorts. We confirmed that lenalidomide maintenance was not routinely used before the approval in June 2019 by reviewing the electronic records of all patients treated with HDM-ASCT between January and June 2019. Of these, only 3 (7%) received LM, and in each case, LM was initiated just prior to approval. The LM cohort had similar PFS, HR 0.82 (0.65, 1.04), and OS HR 1.22 (0.78, 1.89) compared to the pre-LM cohort in unadjusted analysis, Figure 1. Results were similar after multivariate adjustment. The 3-year PFS and OS rates in the LM cohort were 61% (95 CI: 55%, 67%) and 86% (95 CI: 82%, 91%), respectively, while the pre-LM cohort had a 3-year PFS of 55% (50%, 60%) and a 3-year OS of 89% (86%, 93%). Conclusion: In this study encompassing all Danish patients with MM treated with HDM-ASCT since the introduction LM, we found that LM was initiated in approximately three out of four patients. One third of patients treated with LM discontinued this treatment within the first year, mainly due to toxicity. Early discontinuation of LM was not associated with worse clinical outcomes. When comparing post-transplantation PFS and OS in two cohorts of patients treated before and after the approval of LM, respectively, we found no differences.

Post-Hoc Analysis of the Final, Three-Year Follow-up Results of a Phase I/II Study on Tirabrutinib (ONO-4059) in Patients with Relapsed or Refractory Primary Central Nervous System Lymphoma

[Background] Tirabrutinib (TIR; ONO-4059) is a second-generation inhibitor of Bruton's tyrosine kinase with high kinase selectivity. Based on the results of study ONO-4059-02 in patients with relapsed or refractory (r/r) primary central nervous system lymphoma (PCNSL) (Phase I/II study, jRCT: 2080223590), TIR was approved in Japan, Korea, and Taiwan. We have reported the results of 3-year follow-up (median follow-up: 37.1 months) of study ONO-4059-02, in which the overall response rate (ORR), the primary endpoint, was 63.6% and median duration of response was 9.2 months. The 3-year PFS and OS rates were 13.9% and 56.7%, respectively (Asai et al. ASCO 2023, Abstract 7548). Several clinical questions still remained to be addressed, including the proportion of patients who received subsequent treatment after discontinuation of TIR, and their treatment types; the characteristics of patients with higher efficacy of TIR; and the impact of long-term TIR treatment on Karnofsky Performance Status (KPS) and the Quality of Life (QoL). Here, we report the results of post-hoc analyses of the 37-month follow-up data of study ONO-4059-02. [Methods] In study ONO-4059-02, 44 patients with r/r PCNSL, age ≥20, and KPS≥70 were treated with TIR once daily at doses of 320 mg (n=20), 480 mg (n=7), or 480 mg (n=17) under a fasted condition. TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. We assessed the number of patients who received subsequent treatment after discontinuation of TIR and their treatment types. ORR was assessed in patient subgroups according to their characteristics. In addition, patient characteristics associated with 12-month PFS rates were identified using univariate/multivariate logistic regression analysis. The time course of KPS and QoL during the TIR treatment was also assessed. QoL was evaluated using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-BN20, and EuroQol 5 dimensions. [Results] Of the 44 patients, 6 patients were treated for 3 years. At the time of last visit, 2 patients (4.5%) continued the TIR treatment, 10 (22.7%) discontinued the TIR treatment but had not received subsequent treatment, and 32 (72.7%) received subsequent treatment after discontinuation of TIR. The subsequent treatments included systemic therapy, radiotherapy, hematopoietic stem cell transplantation, and surgery. Major subsequent treatments were MTX-based therapy (n=18) and radiotherapy (n=10) with the 3-year OS rate of 61.1% and 40.0%, respectively. The subgroup analyses of ORR by patient characteristics showed that response to TIR was observed in all patient subgroups; ORR was low in those refractory to the treatment just before TIR (33.3%), those receiving ≥ 4 previous treatments (33.3%), those receiving hematopoietic stem cell transplantation (28.6%), those with high tumor burden (42.9%), and those having mutations in CD79B and MYD88 (40.0%). The univariate/multivariate analyses for the 12-month PFS rate identified that baseline KPS 90-100 was significantly associated with long-term response (odds ratio 5.99, P=0.0289). The median baseline KPS was 80.0 (range: 70~100) and was maintained during the TIR treatment (max: 49 cycles). QoL scores were generally maintained. [Conclusion] The majority of patients were able to receive subsequent treatment, including MTX, after TIR. TIR responses were observed in all patient subpopulations, and the baseline KPS was suggested to be associated with long-term response. KPS and QoL were generally maintained during the long-term observation period.

Treosulfan Compared to Busulfan in Allogeneic Haematopoietic Stem Cell Transplantation for Myelofibrosis: A Registry-Based Study from the Chronic Malignancies Working Party of the EBMT

Background The optimal conditioning prior to allogeneic stem cell transplantation (HSCT) for myelofibrosis (MF) remains an ongoing matter of debate. There is a paucity of randomized trials robustly showing superiority of one over another. Registry studies comparing reduced intensity conditioning (RIC) versus myeloablative conditioning (MAC) regimens did not show significant differences in overall survival (OS). Recently, a multi-center phase 3 trial in MDS-AML reported an advantage of fludarabine-treosulfan (TREO) over fludarabine-busuflan (BU) RIC (Lancet Haematol Beelen et al 2020). The role of this large EBMT registry study was to compare outcomes of MF HSCT following TREO and BU based MAC or RIC regimens. Methods Patients with MF transplanted from a T-cell replete graft between 2010-2018 following BUMAC, BURIC or TREO were identified in the EBMT registry. Patients who were transformed into AML were excluded. Centers were contacted to participate in additional data collection. 63 centers included a total of 536 patients of whom 6 patients were excluded due to missing data for major endpoints (relapse or regimen). The role of TREO was tested in multi-variable models adjusted on major prognostic factors especially those who were not well balanced between groups and using multiple imputation for missing values. Results Most TREO (n=73) patients received it in combination with FLUDARABINE (95%) and most BU (n=457) received FLUDARABINE +/- other (93%). Median total dose received of TREO was 42 g/m2 and median dose of BU was 8mg/kg. Main differences between the 3 groups were: 1) Recipient age; patients were the oldest in the RIC group (median age 61 years, (IQR: 55-65), the youngest in BUMAC (56 years, (IQR: 51-62)), and intermediate in the TREO group (59 years, (IQR: 54-64); 2) Performance status; Karnofsky score was &amp;lt; 80 in 20%, 30%, 42% in the TREO, BUMAC and BURIC groups, respectively; 3) Comorbidity score (HCT-CI) was lowest in the MAC group (HCT-CT ‘low’ in 56%, 45% and 37% of BUMAC, BURIC and TREO groups); 4) Disease status; patients in the TREO group were more often transplanted with progressive disease (58% vs 30% in BUMAC and 34% in BURIC); 5) JAK inhibitor prior to HSCT; a higher proportion of patients in the TREO group were treated with a JAK inhibitor before HSCT (61% vs 50% in BUMAC and 42% in BURIC); 6) Cytomegalovirus (CMV) donor/ recipient status; CMV combinations were more frequently donor recipient -/- in the TREO cohort (41% vs 28% in MAC and 36% in RIC); 7) an HLA matched sibling donor was less frequently used in TREO group (18% vs. 28% in BURIC and 36% in BUMAC). The 3 groups were well balanced regarding period of transplantation, MF classification (primary versus secondary), splenomegaly at time of transplantation, chromosome abnormalities, MF related symptoms, DIPSS score, GVHD prophylaxis and use of ATG. Median time to neutrophil recovery was 17 days (range: 6-54), with no differences between the 3 groups. Cumulative incidence of engraftment at day 30 was 91.5% (95%CI: 89.1-93.9), with no differences between the 3 groups. Cumulative incidence of grade 2-4 acute GVHD at 120 days for the entire cohort was 23% (95%CI: 19-26%); similar in the 3 groups. Three-year OS was 62% (95% CI 58 -66), 3-year PFS was 49% (45-53). At 3 years, cumulative incidence of relapse was 26% (22-29) and NRM was 25% (21-29). Figure 1 shows OS, PFS, NRM and cumulative incidence of relapse (CIR) according to regimen. Multiple variables Cox models after selection are shown in Table 1. TREO group had a significantly better OS than BUMAC (HR: 0.61, 95%CI: 0.39-0.93), BURIC had similar OS to BUMAC (HR: 0.92, 95%CI: 0.68-1.26) and there was a trend for a better OS with TREO over BURIC (HR: 0.66, 95%CI: 0.41-1.05). The same trend was also observed for PFS with a significant advantage of TREO over BUMAC (HR: 0.57, 95%CI: 0.38-0.84) and BURIC (HR: 0.60, 95%CI: 0.39-0.91) while BURIC had a similar risk to BUMAC (HR: 1.05, 95%CI: 0.80-1.39). The improvement of OS and PFS was related to a lower NRM (HR: 0.44, 95%CI: 0.24-0.80 TREO vs BUMAC; HR: 0.54, 95%CI: 0.28-1.04 TREO vs BURIC) and same relapse risk with TREO over BU (TREO vs BUMAC, HR: 0.71, 95%CI: 0.42-1.20; TREO vs BURIC, HR: 0.63, 95%CI: 0.36-1.11). Conclusion TREO based regimens compared to BU based shows better PFS in MF HSCT. This advantage was also confirmed for OS and NRM when compared to BUMAC. More specific prospective studies are needed to confirm findings from this registry based study.

The Impact of Anti-T-Lymphocyte-Globulin Dosing on Gvhd in Matched Sibling Allogeneic Stemcell Transplantation

Introduction: Due to the graft versus tumor effect allogeneic stem cell transplantation (allo-SCT) is a curative strategy for hematological malignancies. However, its benefits are offset by non-related mortality (NRM) primarily from graft-versus-host-disease (GVHD). In vivo T-cell depletion (TCD) with Anti-T-Lymphocyte globulin (ATLG) can reduce GVHD. Although lower ATLG doses may compromise the immunosuppression effects, higher ATLG doses may offset its benefit by decreasing antiviral and graft-versus-malignancy effect by depletion of donor effector T cells. Even though the use of ATLG in allo-SCT is well established, however, data on optimal ATLG dosing in the setting of matched sibling donor (MSD) -allo-SCT is scarce. Methods: In this retrospective study conducted at the Department of stem cell transplantation, University Medical Center Hamburg Eppendorf (UKE) we aim to compare the transplant outcomes between recipients of 15 mg/Kg vs 30 mg/Kg ATLG as T-cell depletion in Patients undergoing allo-SCT from MRD. Results: In the study, 109 sequential patients (ATLG 15, n=72; ATLG 30, n=37) underwent allo-SCT between the years 2018 and 2022 from MSD for hematological conditions. PBSC was the primary stem cell source in both cohorts (ATLG-15, 99%; ATLG-30, 92%; p=0.08). In the ATLG-15 group, 13% received TBI versus none in the ATLG-30 group (p=0.025). The MAC regimen was utilized in 65% of ATLG-15 patients, compared to 27% in ATLG-30 (p&amp;lt;0.001). The most prevalent disease was AML in ATLG-15 (54%) and PMF in ATLG-30 (54%, p&amp;lt;0.001). More ATLG-15 patients were transplanted in CR (43%) than in ATLG-30 (16%, p=0.02). All ATLG-15 patients had ECOG0-1 status, against 90% in ATLG-30 (p=0.007). The median age at transplant was similar, 58 and 56 years in ATLG-15 and ATLG-30, respectively (p=0.99). All other Patients donor and transplant characteristics were comparable between the two groups. One patient died prior to engraftment and three patients had primary graft failure in the ATLG-15 group, all remaining patients successfully engrafted. The ATLG-15 cohort showed an earlier leukocyte engraftment (median 11 days, range 9-19, p=0.001) and a tendency towards quicker platelet engraftment (median 12 days, range 8-107, p=0.06) compared to the other group's medians of 13 days (range 8-16) and 17 days (range 3-130), respectively. Grade II-IV aGVHD at day 100 was 36% in the ATLG-15 group compared to 23% in the ATLG-30 group (p=0.45). A trend towards lower 2-year moderate/severe cGVHD was observed in the ATLG-15 group (48% vs 36%, p=0.08). The ATLG-15 group showed a trend towards higher 2-year OS (84% vs 72%, p=0.06), however this trend disappeared on multivariate analysis (MVA) (HR 0.853 [95%CI 0.319, 2.283]; p=0.75) no other factor affected OS on MVA. The 2-year PFS was similar across both groups (ATLG-15, 63%; ATLG-30, 60%; p=0.5). On MVA only TBI had a significant effect on PFS (HR 0.310 [95%CI, 0.101, 0.957], p=0.04), none of the other factors significantly affected PFS. There was a trend for Lower NRM in the ATLG-30 group (at 1 Yr, 0% vs 11%, p=0.09), while the two-year relapse incidences were comparable (ATLG-15, 7%; ATLG-30, 14%; p=0.2). Conclusion: Acknowledging the retrospective nature of our study, however our results show that a higher ATLG dose may reduce incidence of chronic GVHD in Patients undergoing allo-SCT from MSD, however our findings should be confirmed in larger prospective studies.

Low Levels of Circulating Tumor Cells Correlate with Favorable Clinical Outcome and Unique Biological Features in Newly Diagnosed Multiple Myeloma Patients

Introduction Circulating tumor cells (CTCs) have been proposed as a prognostic biomarker in newly-diagnosed MM (NDMM) but their low frequency questions their use in clinical practice. Lower CTC levels (cut-off &amp;lt;0.01-0.07%) correlate with a favorable prognostic outcomes in transplant-eligible (TE) patients (pts); however, several issues remain to be addressed. On clinical grounds, it remains unclear whether there is a similar prognostic cut-off value for transplant-ineligible (TI) pts. Furthermore, it is not clear whether the CTCs mimic the characteristics of a single (main)-site bone marrow (ΒΜ) myeloma cells or if they represent the total disease burden, i.e. in cases with extramedullary or macrofocal disease. Moreover, there is limited information of the biological factors that may lead myeloma cells to egress their primary BM site. Methods BM and matched peripheral blood (PB) samples from 550 NDMM pts (210 TE, 340 TI) were evaluated with NGF (median LOD 2.1x10 -6) for the presence of myeloma cells. Various multivariable regression models including CTCs, R-ISS, cytogenetic status and LDH were assessed to define the optimal clinical CTC cut-off. The BM niche profiling was examined with mass cytometry (CyTOF, n=15 pts, 8 with no CTCs, 7 with CTCs higher than the cut-off) and various multicolor flow cytometry panels (n=199 pts including 56 pts with no CTCs) that allowed the detection of 32 distinct immune populations. Results The median value of CTCs was 0.01% of total PB cells (range: 0.0002%-63%) and in 57/550 (10.4%) pts CTCs could not be detected. Increased levels of CTCs correlated with ISS III stage (median: 0.037%, 0.007% and 0.002% for pts with ISS-3, ISS-2 and ISS-1, respectively; p&amp;lt;0.0001), high risk cytogenetics (median: 0.038% vs. 0.006% in standard risk, p&amp;lt;0.0001), and higher levels of b2-microglobulin and BM infiltration. Median follow-up was 41 months (range: 5-66 months). PFS and OS were gradually worsened towards a CTCs log increment, independently of ISS, cytogenetic status and LDH. Hence, pts with undetectable CTCs had the most favorable prognosis with a 5-year PFS and OS of 83% and 97% respectively. The optimal clinical CTCs cut-off that stratified pts into two distinct prognostic groups was defined at the level of 0.02%, which was common for both TE (median PFS: NR in both high and low CTC subsets; p&amp;lt;0.01) and TI subgroups (median PFS: 47 for low vs. 23 months for high CTCs subset, p&amp;lt;0.0001). Importantly, this cut-off, together with the phenotypic classification of pts (MGUS-like, MM-like etc.) could be incorporated in the established R-ISS system, providing an improved ptnts' stratification. The 2-year achievement of MRD negativity was 45%, 67% and 73% for pts with high, low and undetectable CTCs and median time for MRD negativity was 34, 17 and 12 months, respectively (p&amp;lt;0.001). Of note, pts with high CTCs who achieved MRD negativity, modulated their unfavorable risk status and showed similar PFS with those who had low CTCs. In 73/493 (14.8%) pts with detectable CTCs, there was an obvious phenotypic inconsistency between BM myeloma cells and CTCs, either in regard to the relative ratio of the detected (sub)clones, or the appearance of ≥1 phenotypically distinct clonal populations, which were present only in BM or PB. Pts with phenotypic inconsistencies had higher CTC levels and more often diffuse MRI patterns than those with a phenotypic agreement (frequency: 40% vs. 10%; p&amp;lt;0.01). To better understand the heterogeneous dissemination of myeloma cells to PB, we compared the BM niche profiles of pts with high CTC levels (&amp;gt;10 -3) and those with no CTCs. The analyses highlighted clear differences in the BM composition of the two groups with the BM of pts with no CTCs showing significantly lower levels of T cells, NK cells, TAMs and an increased naïve/memory B cell ratio. Of note, no differences were observed in the prevalence of immunosuppressive cell subsets (Tregs, MDSCs) between the two groups. Discussion The presence of CTCs at levels &amp;gt;0.02% confers an adverse prognostic factor for NDMM pts, irrespective of their transplant status. On the contrary, pts with no CTCs have the more favorable outcome and share unique microenvironmental features, which may eliminate CTCs dissemination. Since the liquid biopsy seems to be a better representative of the entire tumor load than a single tissue biopsy, the CTC analysis serves as the new hallmark for the real-time evaluation of a patient's disease and immune status.

A Single Center, 10-Year Experience of CALGB-10403 Regimen in AYA Population with Philadelphia-Chromosome Negative Acute Lymphoblastic Leukemia

INTRODUCTION: The use of pediatric-inspired regimens for the treatment of acute lymphoblastic leukemia (ALL) has now become the standard of care in adolescents and adults (AYA). One such regimen, CALGB 10403, had higher rates of event free survival (EFS) and overall survival (OS) compared with historical controls using adult ALL regimens. It was shown to be feasible and efficacious in fit patients up to the age of 40 (Wendy Stock et al., Blood 2019). In 2012, based on emerging data on the improved efficacy of pediatric-inspired regimens in AYA patients, CALGB 10403 was adopted as the standard-of-care regimen in this population at Karmanos Cancer Institute (KCI), an adult cancer treatment center. Here we report our single center, real world experience of using this regimen in a Philadelphia chromosome negative (Ph-) AYA population, approximately 10 years after its adoption. METHODS: We conducted a retrospective chart review of consecutive AYA (ages 18-39) patients with Ph- ALL treated with CALGB 10403 regimen between January 2012 and June 2023 at KCI. Patients who received alternative regimens due to distance from KCI were excluded. Baseline demographic, clinical and molecular characteristics were noted. High-risk cytogenetics were defined as KMT2A rearrangements, hypodiploidy with a chromosome number ≤43, and complex karyotype. Testing for Ph-like ALL was not available in most patients. Beginning in 2019, clonoSEQ assay was used to test for minimal residual disease (MRD), with MRD negativity defined at a threshold of less than 10 -4. Incidence of adverse effects and treatment related mortality were reported to describe safety. Complete response (CR) rate, OS and PFS were used as efficacy outcomes. Kaplan-Meier curves were used to estimate OS and PFS. RESULTS: A total of 17 Ph- AYA patients were treated at KCI with a median age at diagnosis of 25 years (range 18-34). Males and females had a near equal representation (47% and 53%). The patients were predominantly White (64%). The majority of patients had a good ECOG performance status of 0 or 1 (88%). The diagnosis was B-ALL in 9 (53%) and T-ALL in 8 (47%) patients. High risk cytogenetics were present in 3 (80%) of the evaluable patients. None of the patients had CNS involvement at diagnosis. Baseline laboratory parameters expressed as medians were bone marrow blast percentage 80%, WBC count 9.2 x1000/mm 3, hemoglobin 8.4 g/dL, platelets 109 x1000/mm 3, and LDH 480. The median duration of follow-up was 54 months. 15 (88%) patients had CR with induction, and MRD was negative in 4 (57%) of the 7 evaluable patients. 2 (12%) patients had primary refractory disease. One of the patients with refractory disease underwent further therapy with blinatumomab, inotuzumab, CAR-T and allogeneic stem cell transplantation and is alive at 16 months from diagnosis. Another underwent salvage with hyper-CVAD and allogeneic stem cell transplant, and is currently alive at 88 months from diagnosis. Two additional patients were MRD positive after induction (course I) but subsequently attained MRD negativity. One of these eventually relapsed 7.5 months from diagnosis with a mixed phenotypic (T/myeloid) leukemia and died at 10 months, while the other is currently under treatment. An additional patient with CR1 and unknown MRD status had CNS relapse at 35 months, underwent successful hyper-CVAD, reintroduction of intrathecal chemotherapy and allo-HSCT salvage and is alive at 122 months. The 5-year PFS and OS were 74.5% and 94% respectively and the medians were not reached for both. Noteworthy adverse effects include neutropenic fever (65%), liver function tests (LFT) abnormalities (70%), and neuropathy from vincristine (70%). Peg-asparaginase administration was associated with pancreatitis in 12%, thromboembolism in 30% and hypersensitivity reactions in 24% requiring switching to alternative forms of asparaginase products (erwinia and Rylaze). These toxicities were manageable and there were no treatment-related deaths in our cohort. CONCLUSIONS: The pediatric-inspired regimen CALGB 10403 was safe and efficacious in our AYA Ph- ALL population with no deaths due to treatment and a 5-year overall survival of 94%. Toxicities, especially from peg-asparaginase, should be closely monitored. While most patients will attain durable remission/cure, the minority with refractory or relapsed disease can still be successfully salvaged to achieve long term survival.

Prescription Patterns of Initial Therapy and Outcomes of Elderly Hodgkin Lymphoma Patients. Toxicity and Efficacy Balance of Attenuated Initial Therapy

Introduction Patients (pts) older than 60 years of age diagnosed with classic Hodgkin lymphoma (cHL) have worse prognosis than younger pts, including complete remission rates (CR) as well as lower progression free (PFS) and overall survival (OS). Age over 70 years, along with comorbidities, has been identified as a factor conferring additional worse prognosis. We sought to evaluate the prescription patterns and outcomes of pts ≥70y in comparison with “younger” elderly cHL pts diagnosed 60-69y. Methods We conducted a retrospective review of newly diagnosed cHL patients treated at our academic medical center between 2012-2022. Baseline and treatment characteristics, including planned and unplanned dose reduction events were collected from electronic medical records. Outcomes included disease response to initial therapy, PFS, OS and non - relapse mortality (NRM). All analyses were done using R and its packages. Differences between age groups were evaluated using Fisher and Wilcoxon rank-sum tests. PFS and OS were calculated using the Kaplan Meier method, comparisons done using log-rank. The cumulative incidence of NRM was calculated considering relapse as a competing risk, comparisons evaluated with Gray's test. Results We identified 81 pts ≥60 years (y) diagnosed with cHL, 37 of whom were ≥70y. Among baseline characteristics, more pts ≥70y had ECOG performance status ≥2 (30 vs. 9%, p = 0.05), and all had at least one comorbidity, compared with 77% in pts 60-69y (p = 0.002); other baseline characteristics were comparable, and the numerical difference in the rates of individual comorbidities did not reach statistical significance (table 1). A statistically significant higher proportion of pts ≥70y had planned de-intensification of their treatment (46% vs. 16%, p = 0.007), most commonly this corresponded by prescription of the doxorubicin, vinblastine and dacarbazine (AVD) as initial therapy, use of brentuximab vedotin alone or in combination with non-anthracycline containing regimens. One pt in the younger cohort did not receive therapy and died within two weeks of diagnosis. Subsequent dose reductions occurred in both age groups and pts ≥70y had a higher proportion of pts with overall reduced treatment intensity (i.e., planned + unplanned) (n = 22, 59% vs. n = 14, 33%, p = 0.024). Among pts treated with systemic therapy (n = 80), overall response rates were 73% and 85% for ≥70y and younger pts, respectively (p = 0.42). Complete response (CR) rates were 70% and 81% (p = 0.23). For pts treated with an anthracycline containing regimen, CR rates were 78% for pts ≥70y and 83% for pts 60 - 69y (p = 0.77). After a median follow up of 53 months (IQR 32-71), 18 (23%) pts had progression of their disease after initial therapy and 18 (23%) pts had died. Median progression free survival had not been reached for both groups, and four-year estimates were 65% for pts ≥70y (95% CI 51-85%) and 83% for pts 60 - 69y (95% CI 73-95%), this difference did not reach statistical significance (p = 0.08). Similar results were observed for PFS when the analysis was limited to pts treated with anthracycline-containing regimens (4-year PFS: ≥70y = 68% vs. 60-69y = 85%, p = 0.06). Median OS was not reached for both groups, four-year estimates were 75% for pts ≥70y (95% CI 61-92%) and 90% for pts 60-69y (95% CI 81-100%) (p =0.007), with comparable results when pts treated with anthracycline were studied (4-year OS: ≥70y = 75% vs. 60-69y = 92%, p = 0.003). Analysis of the cumulative incidence of NRM (with relapse as competing risk) showed there were no significant differences among pts ≥70y (1-year 5.8% [95% CI 1-17%]) vs. 60-69y (4.7% [95% CI 1-14%]) (p = 0.2) (figure 1). Conclusions Patients diagnosed with cHL at ages ≥70 years have more comorbidities and more often have worse performance status than pts 60-69y. Older pts more often are treated with attenuated regimens and/or require dose reductions/discontinuation after starting therapy. While the dose reductions and modifications limit NRM to rates comparable to those of younger pts, PFS and OS remain lower for pts ≥70y, suggesting long - term disease control is inferior in this patient subgroup. Systematic prospective studies of attenuated but more effective regimens are needed in cHL pts diagnosed at advanced age.

Post Allogeneic Stem Cell Transplant Outcomes Following Response to Hypomethylating Agent Therapy in Myelodysplastic Syndromes Are Predicted By Persistent International Prognostic Scoring System-Molecular Risk

Introduction: The International Prognostic Scoring System-Molecular (IPSS-M) ( Bernard NEJM Evidence 2022) and the 2023 International Working Group (IWG) response criteria for myelodysplastic syndrome (MDS) ( Zeidan Blood 2023) are used to more accurately assess prognosis and therapeutic response in MDS. However, it is unknown if these tools can be used to predict outcomes post-allogeneic hematopoietic stem cell transplant (HCT). We sought to understand the impact of pre-HCT IPSS-M on post-HCT outcomes in patients (pts) with MDS who responded to hypomethylating agent (HMA) therapy. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT post-HMA at Dana-Farber Cancer Institute from January 2014 to December 2020 were included. Response to HMA was assessed by 2023 IWG response criteria and was defined as complete remission (CR) + CR with bi-lineage blood count recovery (CRbi) + CR with uni-lineage blood count recovery (Cruni) + CR with partial hematological recovery (CRh). Combined clinical and molecular risk was assessed by IPSS-M at times of diagnosis and of HCT, the latter using the bone marrow biopsy and sequencing data collected closest to HCT. High risk was defined as IPSS-M moderately high, high, and very high, whereas low risk was defined as IPSS-M very low, low, and moderately low. Results: A total of 148 pts with MDS who received HMA and underwent subsequent HCT were included. Median age was 64 years (range 26-79) and 61.5% were men. Pts were diagnosed with MDS-EB1 (26.4%), MDS-EB2 (45.3%), and other MDS subtypes (28.3%). IPSS-M at time of diagnosis was very low (2%), low (10.1%), moderate low (6.1%), moderate high (8.8%), high (31.8%), and very high (22.3%). IPSS-M pre-HCT was very low (12.8%), low (8.8%), moderate low (10.8%), moderate high (12.8%), high (20.3%), and very high (10.8%). IPSS-M at diagnosis and pre-HCT could not be calculated because of missing molecular data in 18.9% and 23.6% of pts, respectively. Pts received a median of 4 HMA cycles (range 1-20) and were treated with azacitidine for 7 days (54.1%), decitabine for 5 days (39.2%), and other schedules (6.7%). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), partial remission (PR: 1.4%), hematological improvement (HI: 9.5%), and no response (38.5%). Most pts received HCT from either a matched unrelated (60.8%) or matched related donor (18.2%) with reduced intensity conditioning (74.3%). Pts received graft versus host disease prophylaxis with tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), post-transplant cyclophosphamide/mycophenolate mofetil/tac (15.5%), tac/sirolimus (8.1%), other (2%). Median HCT-comorbidity index (CI) was 2 (range 0-13) and 48.6% pts had HCT-CI ≥ 3. For the entire cohort, the median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). Among pts who responded to HMA per IWG 2023 criteria (CR/CRbi/CRuni/CRh), those who had high risk by IPSS-M prior to HCT had significantly shorter median overall survival (OS) (27 months; 95% CI 7.5-51) compared to pts with a low risk by IPSS-M (not reached; p=0.016) ( Figure A). Cumulative incidence of relapse (CIR) at 4 years was 66% for pts with high risk and 31% for low risk (p=0.034) ( Figure B). Pts with response to HMA with high risk by IPSS-M had lower OS (4-year OS: 27% versus 53%; p=0.016) and progression-free survival (4-year PFS: 19% versus 50%; p=0.018) but similar non-relapse mortality (NRM) (4-year NRM: 16% vs. 19%; p=0.66) post-HCT compared to pts with low risk at time of HCT. Conclusion: For pts with MDS who achieve a response to HMA prior to HCT, combined clinical/molecular risk, as assessed by IPSS-M, has an important prognostic impact on post-HCT outcomes. Pre-HCT risk should be evaluated for prognostication and to guide patient care, including future prospective studies evaluating novel agents for post-HCT therapy.

Easix Indices Predict CRS and Overall Survival in Adult CAR-T Cell Recipients

Background: Immunotherapy with Chimeric Antigen Receptor T cells (CAR-Τ) is worldwide commercially available for refractory B cell malignancies, with continuously expanding indications.Given that cytokine release syndrome (CRS) and neurotoxicity (ICANS) are encountered in many CAR-T recipients both in trials and real-world setting, novel predictive and prognostic markers are highly needed. Aim: To this end, we hypothesized that EASIX (Endothelial Activation and Stress Index) and the most recently described modified EASIX (mEASIX) would be associated with severe CRS, ICANS and/or Overall Survival (OS) in the real-world setting. Methods: We collected data from consecutive adult patients (pts) from six transplant centers in Greece. Tisagenlecleucel and axicabtagene ciloleucel were administered since 2020, and brexucabtagene autoleucel since 2022. All pts received lymphodepleting therapy before CAR-T cell infusion with combination of cyclophosphamide and fludarabine. For patient monitoring as well as for prophylaxis and treatment of side effects, the EBMT and MD Anderson guidelines were adopted. EASIX (lactate dehydrogenase [LDH; U/L] x creatinine [mg/dL]/platelet [PLT] count; 10 9/L]) and mEASIX (which replaces creatinine with CRP [mg/dL]) were calculated before lymphodepletion (baseline), at day of infusion (0), and day 14 (14). The following variables were analyzed: age, gender, disease type and phase, product type, time from collection to product arrival and to infusion, progression-free (PFS) and overall survival (OS), laboratory markers at pre-specified time-points (LDH, creatinine, platelets, ferritin, CRP). Data cut-off date was end of June 2023, with at least 1 month of follow-up post infusion. Multivariate models were not performed due to multicollinearity issues. Results: Ninety pts, aged 49 (18-75) years, received commercial CAR-T cell products (33 tisagenlecleucel, 37 axicabtagene ciloleucel, 11 brexucabtagene autoleucel) for refractory/relapsed DLBCL (56), PMBCL (5), TFL (8), B-ALL (10), or MCL (11) after a median of 3 (1-9) previous lines of treatment including autologous (n=13) or allogeneic (n=7) transplantation. Severe (grade 3-4) CRS and ICANS were noted in 21% and 39%, respectively. Severe CRS was associated with mEASIXbaseline (p=0.025), and CRPbaseline (p=0.001), EASIX14 and m-EASIX14 (p&amp;lt;0.001). Both mEASIXbaseline and m-EASIX14 were able to predict severe CRS in ROC curve (AUC=0.768, p=0.032 and AUC=0.712, p=0.027). Severe ICANS did not correlate with EASIX indices, except for a trend towards statistically significant association with EASIX14 (p=0.054). On the other hand, severe ICANS was associated with increased LDH at baseline (p=0.001). With a median follow-up of 6.6 (1-42) months, 1-year PFS and OS were 33.2% and 62.5% respectively. Baseline values of ferritin and LDH, CRP values at all time-points, EASIX14 and mEASIX14 were associated with OS. Both EASIX indices predicted death in ROC curves. Similarly, EASIX14 was associated with PFS. Conclusions: This multicenter study, based on real-world experience with CAR-T cell therapy, confirms the predictive value of EASIX and mEASIX not only for life-threatening complications but also for survival outcomes. The implementation of EASIX may therefore aid in the selection of patients who are candidates for interventions to mitigate untoward sequelae of CAR-T therapy.

CD19/CD22 CAR T-Cell Therapy Following Autologous Transplantation Is an Optimizing Strategy in Relapsed/Refractory Central Nervous System Lymphoma

Background and Objectives: Relapsed/refractory (R/R) primary and secondary central nervous system lymphomas (PCNSL, SCNSL) are associated with short survival and represent an unmet need, requiring novel effective strategies. Methods: We retrospectively compared the safety and efficacy of CD19/22 CAR T-cell therapy combined with HDT-ASCT (ASCT+CAR-T group), CD19/22 CAR T-cell cocktail therapy (CAR-T group) and targeted drugs combined with chemotherapy (Targeted drugs group) in treating R/R CNSL patients. Results: The median age of the Targeted drugs group is older than that of the other two groups, 73.3%, 100% and 41.2% patients were secondary CNS lymphoma in ASCT+CAR-T group, CAR-T group and Targeted drugs group, respectively. The incidence of Grade 3/4 hematological toxicities in ASCT+CAR-T and CAR-T group was more than Targeted drugs group. Patients in two CAR-T therapy group exhibited comparable incidence and severity of CRS and ICANS. The ORR was 83.3% in ASCT+CAR-T group, 64.3% in CAR-T group and 58.8% in Targeted drugs group respectively (Figure 1). As of December 31, 2022, the median follow-up time after therapy was 15.53 months (range, 0.53-50.53 months). The median duration of OS and PFS was not reached in the ASCT+CAR-T group. The median PFS and OS in the CAR-T group were 3.07 months and 9.67 months, respectively. In the Targeted drugs group, the median PFS and OS were 6.63 months and 12.30 months, respectively. The 1-year PFS and OS rate of the patients in the ASCT+CAR-T group (66.67% and 76.52%) was significantly higher than that of the patients in the CAR-T group (18.75% and 50%) ( P=0.0006 and P=0.0253) and targeted drugs group (17.65% and 52.94%) ( P=0.0004 and P=0.0358) (Figure 1). In both univariable and multivariate analysis, PD before treatment was indicated worser PFS (HR: 3.134, 95% CI, 1.144 to 8.587, P=0.026), rather than OS, both in ASCT+CAR-T and CAR-T group and compared with CAR-T group, patients received ASCT+CAR-T treatment had better PFS (HR: 0.279, 95% CI, 0.120 to 0.651, P=0.003), rather than OS. PFS and OS of patients with PD before treatment, patients with ECOG ≥2, with high risk factors, and with＞3 prior lines of therapy in the ASCT+CAR-T group were superior to CAR-T group (Supplementary Figure 1). In the ASCT+CAR-T group, PFS, rather than OS, of patients without systemic disease in the ASCT+CAR-T group was superior to those with systemic disease ( P=0.0335). Discussion: Our results support the development of CAR T -cells in R/R CNSL. With the durability of remission and low toxicity, ASCT combined with CART therapy appears to be a more effective and safe treatment option for primary and secondary relapsed/refractory CNS lymphoma.

Allogeneic Hematopoietic Cell Transplantation with Sequential-Based Conditioning in Refractory / Relapsed Acute Myeloid Leukemia: Experience from a Single Institution

INTRODUCTION: Despite improvements in the treatment and outcomes of patients with acute myeloid leukemia (AML), in nearly 10-20% of the cases, a morphological remission (CR) after administrating induction regimens is not achieved. In other cases, and despite initial CR, early disease relapse may occur, with only a minority of patients durably benefiting from salvage regimens. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative strategy for patients with relapsed / refractory (R/R) AML. However, the prognostic of these patients after allo-HCT remains dismal, with reported survival rates ranging from 20% to 35% in different publications. Allo-HCT using peripheral blood and sequential-based conditioning regimens has been the transplant platform used at our institution for R/R AML during the last decade. During the study period the use of post-transplant cyclophosphamide (PTCY) combined with tacrolimus (TK) has been implemented on this allo-HCT setting. This study evaluates the results obtained from a single institution obtained from using sequential allo-HCT for patients with R/R AML, and the effectiveness of having implemented the use of PTCY in this type of transplant. Very few studies have evaluated the safety of including PTCY-based in sequential-based conditioning allo-HCTs. METHODS: This study includes the 21 patients with R/R AML who underwent allo-HCT with sequential-based conditioning regimens at our institution between 2011 and 2022. Retrospective data were collected during June 2023. Sequential regimens combined fludarabine (150 mg/m2), cytarabine (2 g/m2 x 5 days), and idarubicin (12 mg/m2 x 3 days) chemotherapy with low doses of Bu (n=3), melphalan (n=17), or treosulfan (n=1). Six adults transplanted after November 2016 received PTCY (50mg/kg/24h) on day +3 and +4 followed by TK from day +5 to day +90 for GvHD prevention. RESULTS: The main baseline characteristics of the study cohort and according to the GVHD prophylaxis are shown in Table 1 . The median age was 53 years (range 31-68), 11 (52%) patients were males, and all patients had R/R AML after having received at least one line of induction chemotherapy with curative intent. Fourteen (66.7%) patients received grafts from HLA-matched donors, and 7 (33.3%) from 9/10 HLA mismatched unrelated donors (MMUD). Baseline characteristics between patients who received PTCY and those who did not were balanced, except for the proportion of allo-HCT performed from MMUD which was higher in the PTCY group (66.7% vs. 20.0% p=0.03). Post-transplant results are shown in Table 2. All patients engrafted (100%). Patients who received PTCY experienced similar median of days to neutrophil engraftment (18 vs. 15 days, P=0.103) and a longer median of time to platelet engraftment (25 vs. 13 days, P=0.046). The day +100 cumulative incidences (CI) of grade II-IV and III-IV aGVHD, and 2-year CI of moderate/severe cGVHD were 33.3%, 0% and 0% for patients who received PTCY-TK, and 40% (p=0.823), 33% (p=0.118), and 40.4% (p=0.099) for those who did not. During the first 2-years after allo-HCT, 8 (38%) out of 21 patients died and 7 (21%) relapsed. The main causes of death were relapse (n=4, 19%) and infection (n=2, 9.5%), and the 2-year OS, PFS, NRM and CIR were 61.5%, 51.9%, 14.3%, and 33.3%. As shown in Table 2 patients who received PTCY had comparable rates of OS (2-y: 50.0% vs. 66.7%, p=0.903) and RFS (2-y: 50.0% vs. 53.3%, p=0.873) and those who did not. In addition, and although no patient who received PTCY died secondary to transplant-related toxicity (2-y 0 vs. 20%, p=0.254), a non-significant trend to higher cumulative incidence of relapse (2-y: 50.0% vs. 26.7%, p=0.282) was observed in this group of patients. Lastly, a non-significant trend to higher GRFS was documented in patients who received PTCY (2-y: 50.0% and 25.0%, p=0.266). CONCLUSIONS: At our institution, 50% of the patients with R/R AML going thought allo-HCT performed using sequential-based conditioning regimens survived after two years. The implementation of PTCY as part of the GVHD prophylaxis results decreased rates clinically relevant GVHD and NRM, resulting on a trend to better GRFS. Although the results provided by this analysis suggest that using PTCY in this allo-HCT is safe and effective, caution is still recommended considering the trend to higher relapse rates observed among these patients and the limited sample size.

A Novel Composite Endpoint of Toxicity-Free, Progression-Free Survival (TPFS) after CD19-Directed Chimeric Antigen Receptor T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma

Background: CD19-directed chimeric antigen receptor T-cell (CAR T) therapy with axicabtagene ciloleucel (axi-cel), tisagenlecleucel (tisa-cel), or lisocabtagene maraleucel (liso-cel) are FDA-approved for relapsed and/or refractory (r/r) large B-cell lymphoma (LBCL) after ≥2 prior lines of systemic therapy (all 3) or earlier after 1 line (axi-cel and liso-cel) based on durable remissions of 30-40%. Pivotal trials and real-world data demonstrated notable heterogeneity in toxicity and efficacy between CAR T products. To account for such differences, we have established a novel composite endpoint of toxicity-free, progression-free survival within 6 months (TPFS6) after CAR T-cell therapy. We also studied factors associated with TPFS6 across CAR T-cell products and its impact on long-term success of CAR T-cell therapy. Methods: This retrospective cohort analysis included 282 consecutive adult patients with r/r LBCL and its variants who received axi-cel (n=228), tisa-cel (n=47), or liso-cel (n=7) at Moffitt Cancer Center (05/2015-01/2022). TPFS6 was defined as absence of severe (≥Grade 3) cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), progressive disease (PD)/stable disease (SD) and non-relapse mortality (NRM) within 6 months of CAR T-cell infusion. CRS and ICANS were graded according to CTCAE or ASTCT Consensus grading. Factors associated with TPFS6 were assessed via logistic regression multivariate analysis (MVA). Landmark analysis at the 6-month point examined the impact of TPFS on overall survival (OS). All analyses were performed utilizing SAS and R. Results: For the entire cohort (median age=64 years [range, 19-86]; 60.3% males), the TPFS6 was 37% (95% confidence interval [CI] 31-43, Figure 1A) with no difference between the recipients of axi-cel, tisa-cel, or liso-cel ( p=0.97). Individual components of TPFS6 such as severe CRS/ICANS, NRM, and PD/SD accounted for 6.8%/30.3%, 1.7%, and 61.2%, respectively. Patients with TPFS6 differed from their counterparts by gender (males, 51% vs 65.7%, p =0.014), presence of bulky (8.7% vs 17.4%, p =0.045) or extra nodal (≥2 sites, 30.8% vs 46.6%, p=0.009) disease, ECOG performance (≥2, 7.7% vs 20.8%, p=0.004), prior autologous transplant (25% vs 13.5%, p=0.015), C-reactive protein (CRP) (&amp;gt;4 mg/dL, 10.6% vs 35.4%, p&amp;lt;0.001), ferritin (≥400 ng/mL, 37.5% vs 62.4%, p&amp;lt;0.001), lactate dehydrogenase (LDH) (≥225 U/L, 51% vs 76.4%, p&amp;lt;0.001) at lymphodepletion (LD). TPFS6 patients were comparable to those experiencing at least one of the TPFS6 endpoints according to age, race, number of prior lines or use of bridging therapy, LBCL variants, Ann Arbor staging, double/triple hit status, prior CNS involvement, and vein-to-vein time (all p&amp;gt;0.1). In logistic regression MVA, lower levels of baseline LDH (odds ratio [OR]=0.44, p=0.004), CRP (OR=0.33, p=0.004), ECOG&amp;lt;2 (OR=0.43; p=0.05) and female gender (OR=0.5; p=0.01) were associated with TPFS6. In the landmark Cox MVA of OS, TPFS6 was strongly associated with 5.2-fold survival difference ( p&amp;lt;0.001, Figure 1B) after adjustment for age (hazard ratio [HR]=1.24 per 10-year increment, p=0.077) male gender (HR=1.92, p=0.013), ECOG≥2 (HR=2.34, p=0.004), high LDH at LD (HR=2.63, p&amp;lt;0.001), and CAR T product (HR=1.67 for tisa-cel vs axi-cel, p=0.079). At 6 months, overall response and complete response rates were 48% and 45%, respectively. With median follow up of 15.4 months for surviving patients, the estimated 2-year OS and PFS were 54.5% and 39.3%, respectively. Conclusions: Only 37% of patients were alive at 6 months without experiencing a TPFS-defining event. TPFS6 was associated with known clinical risk factors such as CRP, LDH, ECOG and gender but not the type of CAR T product. TPFS6 encompasses clinically meaningful components associated with OS and it therefore represents an ideal recovery outcome by measuring initial treatment success without progression, major morbidity, and mortality. Thus, TPFS6 needs to be further explored as a uniform endpoint for evaluating CAR T-cell safety and efficacy in future clinical trials of r/r LBCL.

Graft Versus Host Disease Prophylaxis with Tacrolimus, Sirolimus and MMF in Patients Undergoing Reduced Intensity Conditioning Allogeneic Transplantation

I ntroduction GvHD remains the leading cause of toxic morbidity and mortality (NRM) after allo-HSCT. Different prophylaxis schemes have been developed in the context of reduced intensity conditioning (RIC). In 2019, the multicenter phase 3 trial NCT01231412 compared GvHD prophylaxis based on the calcineurin inhibitor (CNI) CSA plus MMF with (experimental arm) or without (control arm) sirolimus. The triple combination was associated with a lower risk of aGvHD and longer survival and, in the authors' opinion, could constitute a new standard (Sandmaier, Lancet Oncol 2019). We present the largest real-world experience to date with the triple prophylaxis scheme in the context of allo-HSCT with RIC from matched-related (MRD), matched-unrelated (MUD) and mismatched URD (mmURD). Material and Methods Prospective study of 159 consecutive patients receiving an allo-HSCT after RIC between 09/2019 and 12/2022 at two centers using the tacro/siro/MMF as GvHD prophylaxis. The primary endpoint was the cumulative incidence of aGvHD grades 2-4. As secondary variables: cGvHD at 1 and 3 years, NRM at +100, +1 year and overall NRM, OS at 1 and 3 years, PFS at 1 and 3 years and GRFS at 1 and 3 years. Results Baseline characteristics are shown in Table 1. Note the high percentage of patients with high/very high rDRI or HCT-CI of 3+. In 38.4% an URD was used as source of progenitor cells and in 20.8% it was a MMURD. The median follow-up was 20 months (3-40). There were 4 (2.5%) graft failures (2 of them secondary). Median neutrophil and platelet engraftment was 16 days (3-175) and 12 days (7-210). The risk of relapse was 31% and 35% at 1 and 3 years. NRM at day +100, + 1 year and overall NRM was 4.4%, 8.17% and 9.4%. The causes of NRM were GvHD +/- infection in 73%, with other causes being TMA (n=1) and SOS (n=1). The cumulative incidence (CI) of grades 2-4 aGvHD 2-4 at day +100 and +180 was 29.7% and 32.3%, including 40% of upper gastrointestinal tract involvement which resolved with topical treatment. The CI of grades 3-4 aGvHD at day +100 and +180 was 12.8% and 16% (3.14% grade 4). The CI of cGvHD at 1 and 3 years was 21.5% and 51.2% and for moderate/severe it was 13.9% and 36.6%. OS at 1 and 3 years was 70.3% and 61%. Median PFS was 35 months, with 1- and 3-year PFS of 60% and 49%. The GRFS at 1 and 3 years was 44% and 32%. The risk of grades 2-4 aGvHD was significantly higher among patients receiving allo-HSCT from MMURD (at d+100 and +180, 35.4% and 39.9%) vs matched donors (at d+100 and +180, 55.5% and 61%, p=0.04). The same variable also influenced on OS (at 1 and 3 years 73.3% vs 64.6% and 57.6% vs 37.8% for matched vs mismatched donors, respectively; p=0.013) (Figure 1). On the other hand, low and intermediate DRI patients had a significantly better OS as compared to high/very high rDRI patients (at 1 and 3 years 80.8% and 80.8% for low vs 86.7% and 78.3% for intermediate vs 56.9% and 55.1% for high and very high; p=0.013) (Figure 1). Conclusions Triple prophylaxis with Tacro-Siro-MMF shows excelent results in terms of NRM, GvHD and survival in a high-risk and elderly population in the context of allo-HSCT from matched-related (MRD) and matched-unrelated (MUD) donors. The subgroup of patients receiving allo-HSCT from MMURD showed a high incidence of overall and grade 3-4 aGvHD with impact on OS, being a group that will probably benefit from other prophylaxis strategies.

In-Class Transition ( iCT) from Parenteral Bortezomib (V) to Oral Ixazomib Therapy in Newly Diagnosed Multiple Myeloma (NDMM) Patients (Pts) in the Community-Based US MM-6 Study: Subanalysis of Randomized Controlled Trial (RCT)-Ineligible and RCT-Eligible Pts

Introduction Up to 72% of real-world multiple myeloma (MM) pts are considered ineligible for RCTs due to criteria such as old age, frailty, and comorbidities, limiting the generalizability of findings to the wider MM population. The US MM-6 study (NCT03173092) aimed to increase the duration of proteasome inhibitor (PI)-based therapy and improve outcomes with a tolerable safety profile in a patient (pt) cohort representative of that in routine clinical practice. Results for the fully accrued dataset have been reported previously (N=141; Yimer IMS 2022). Here we report the results of a US MM-6 subanalysis describing pt characteristics and key efficacy and safety outcomes of two groups: RCT-ineligible (RCT-i) and RCT-eligible (RCT-e). Methods Transplant-ineligible/delayed-transplant (≥24 months) NDMM pts with ≥stable disease after 3 cycles of parenteral V-based induction were enrolled at US community sites to receive all-oral ixazomib-lenalidomide-dexamethasone (IRd) for up to 39 cycles or until progression or toxicity (Manda CLML 2020). Pts were grouped based on whether any baseline characteristic met common RCT ineligibility criteria including but not limited to hematologic/organ dysfunction, ECOG PS &amp;gt;2, renal dysfunction, prior malignancies, cardiac dysfunction, and pulmonary disease. Two-year progression-free survival (PFS; primary endpoint), overall survival (OS), overall response rate (ORR), and safety were analyzed by RCT group. Results At final data cut-off (Oct 17, 2022) 140 pts were evaluable; 57 (40.7%) met ≥1 RCT ineligibility criteria and were included in the RCT-i group; 83 (59.3%) were included in the RCT-e group. The most common ineligibility criteria in the RCT-i group were cardiac arrhythmias (14.3%), chronic pulmonary disease (8.6%), and prior malignancy (7.9%) (Table). At enrollment, in the RCT-i vs RCT-e groups, median age was 73 years (range 48-90) vs 72 years (range 49-86), 54.4% vs 60.2% were male, 77.2% vs 69.9% were white. In RCT-i vs RCT-e, 24.6% vs 27.7%, 40.4% vs 42.2%, and 33.3% vs 30.1% had ISS stage I, II, and III, respectively. A total of 98.2% vs 90.4% of pts in the RCT-i vs RCT-e group had any comorbidity; 15.8% vs 10.8% had peripheral neuropathy (PN) as a comorbidity. At data cut-off, 84.2% of pts in the RCT-i group had discontinued treatment, commonly (&amp;gt;20% of pts) due to progressive disease (27.1%), adverse events (25.0%), and pt withdrawal (20.8%). In the RCT-e group, 75.9% had discontinued treatment, commonly due to pt withdrawal (25.4%) and adverse events (23.8%). In both RCT-i and RCT-e groups, pts received a median of 11 (range 1-39) IRd and ixazomib cycles; median duration of PI therapy was 13.6 months. After a median follow-up of 29.2 vs 24.6 months for RCT-i vs RCT-e groups, 2-year PFS rates were 68% (95% confidence interval [CI] 52-80) vs 73% (95% CI 60-82); 2-year OS rates were 90% (95% CI 78-96) vs 84% (95% CI 72-91). ORR increased from 61.4% vs 66.3% at the end of V-based induction to 80.7% vs 79.5% after iCT for RCT-i vs RCT-e groups. For the respective RCT-i and RCT-e groups, treatment-emergent adverse events (TEAEs) were observed in 98.2% and 97.6% of pts (treatment-related: 82.5% and 81.9%), and serious TEAEs in 43.9% and 44.6% (treatment-related: 12.3% and 13.3%) of pts; on-study deaths occurred in 3 pts and 1 pt. The most common any-grade TEAEs (&amp;gt;30% of pts in either arm) were diarrhea (RCT-i: 49.1%; RCT-e: 51.8%), fatigue (RCT-i: 38.6%; RCT-e: 30.1%), and PN (RCT-i: 31.6%; RCT-e: 25.3%). In the RCT-i and RCT-e groups, respectively, grade ≥3 TEAEs were observed in 73.7% and 65.1% of pts. The most common grade ≥3 TEAEs in RCT-i pts were pneumonia (8.8%), cellulitis, neutropenia, and hypokalemia (all 7.0%). Among RCT-e pts the most common grade ≥3 TEAEs were diarrhea (12.0%), pneumonia, anemia, and fatigue (all 4.8%). TEAEs led to dose modification/discontinuation of any of the three study drugs in the IRd regimen in 68.4%/21.1% of RCT-i pts and 65.1%/19.3% of RCT-e pts. Conclusions This subanalysis demonstrates the feasibility of utilizing iCT to obtain similar outcomes to RCTs in the community. Although 41% of US MM-6 pts would have been ineligible for RCTs, there were no notable differences in PFS, ORR, OS, and safety data between the two groups. These data show that iCT from V-based induction to IRd permits long-term, tolerable PI-based therapy translating into improved efficacy in community-treated pts with NDMM who are more representative of the wider MM population.