Subset Of Pts Research Articles

Mutations Associated with Progression in Follicular Lymphoma Predict Inferior Outcomes in Newly Diagnosed Patients (Alliance 151303)

Follicular lymphoma (FL) is a clinically heterogeneous B cell non-Hodgkin lymphoma (B-NHL) subtype. While some patients (pts) tolerate watch-and-wait for years, others require prompt treatment. Further, a subset of pts suffers progression of disease within 24 months (mo) of treatment initiation (POD24) and/or aggressive histologic transformation (tFL). No predictive model guides FL treatment, but the FLIPI stratifies pt outcomes using clinical parameters. The m7-FLIPI integrates FLIPI, performance status (PS), and mutations in EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, and CARD11; however, it is not routinely used to guide treatment due to unproven generalizability and actionability to date. We conducted a clinicogenomic analysis of 343 pts with FL or tFL [enrolled on CALGB/Alliance trials 50402, 50701, or 50803 (n = 58); or real-world cohorts from WUSTL (n = 191), Cleveland Clinic (n = 77), and U Miami (n = 17)], applying a custom 2,611-gene sequencing panel to B-NHL specimens. We explored patterns of mutated genes in newly diagnosed FL (n = 231), relapsed (rel) FL (n = 65), and tFL (n = 47). We also asked whether specific genomic features were associated with clinical parameters and assessed the association of different mutations with pt outcomes. Median age was 60 years (range: 22-89); stage distribution was 23% early vs 77% advanced; FLIPI distribution was 34% low vs 34% intermediate vs 32% high. Progression-free and overall survival (PFS/OS) of pts in our cohort exhibited anticipated relationships with key parameters (e.g., histology: 48-mo OS 96% vs 69% for FL vs tFL). We applied the m7-FLIPI to our 231 newly diagnosed FL samples, observing weak prognostic impact [low vs high risk; HR for PFS 1.37 (95% CI 0.43-1.23), p = 0.2]. Given heterogeneous treatment histories of our pts compared to uniform pt treatment in the initial m7-FLIPI cohort, we tested for an interaction between m7-FLIPI and frontline treatment. We observed a strong interaction between m7-FLIPI risk stratification and receipt of cytotoxic chemotherapy (p < 0.01; Fig 1A). 48-mo PFS was 80% for pts with low risk m7-FLIPI receiving chemo-based frontline treatment, vs 50-55% for all three other pt subsets (high risk m7-FLIPI pts irrespective of chemo-status, and low risk m7-FLIPI pts receiving chemo-free treatment). This suggests that the prognostic value of the m7-FLIPI mutational pattern is impacted by pt treatment. To probe the links between the B-NHL genomic landscape and pathologic or clinical features, we compared the mutation burden (median number of mutations) across a range of B-NHL subsets. FL cohorts based on grade 1-2 vs 3A, early vs advanced stage, FLIPI, initial treatment vs observation, and POD24 vs no POD24 did not differ by mutation burden. However, mutation burden was significantly higher (p < 0.01) in tFL than rel FL, and in rel FL than newly diagnosed FL. Using a Cox proportional hazard penalized splines model, we did not find a significant relationship between mutation burden at FL diagnosis and PFS. CREBBP was the only gene in which mutations were significantly more common in FL than tFL (BH FDR q < 0.1), yet mutated CREBBP was associated with shorter frontline PFS in pts with FL (p < 0.05). Conversely, mutations in 23 other genes were more common in either rel FL or tFL compared to newly diagnosed FL (BH FDR q < 0.1), including 6 significantly mutated genes (SMGs; by MutSigCV): STAT6, TP53, IGLL5, B2M, SOCS1, and MYD88. We hypothesized that pts with newly diagnosed FL may be at high risk of poor outcomes if their pre-treatment tumors harbor mutations more common in progressive/transformed disease. We defined a 'mutations associated with progression' (MAP) signature as 2 or more mutations in these 7 genes (6 SMGs enriched in progressive/transformed disease and CREBBP). Applying univariate and multivariate Cox proportional hazard modeling (adjusting for FLIPI and PS), pts with newly diagnosed FL possessing a MAP signature had significantly shorter frontline PFS [multivariate HR for PFS 1.9 (95% CI 1.12-3.2), p < 0.05; median PFS 39 vs 89 mo, p < 0.05; Fig 1B]. In summary, our analyses highlight a set of MAPs that may offer unique insight into progression risk in FL, which may be more generalizable than the m7-FLIPI. Future studies are warranted to validate the poor prognosis associated with the presence of MAPs in pts with untreated FL, which could facilitate prospective studies of novel therapies in this subset of high risk pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

KarMMa-2 Cohort 2a: Efficacy and Safety of Idecabtagene Vicleucel in Clinical High-Risk Multiple Myeloma Patients with Early Relapse after Frontline Autologous Stem Cell Transplantation

**Co-lead author Introduction Patients with multiple myeloma (MM) who relapse early after frontline therapy with autologous stem cell transplant (ASCT) have a poor prognosis. Novel therapies are needed to improve outcomes (Paiva Blood 2012; Bygrave Br J Haematol 2020). In the pivotal phase 2 KarMMa study (NCT03361748), treatment with the B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell therapy idecabtagene vicleucel (ide-cel) resulted in frequent, deep, and durable responses in pts with relapsed and refractory MM (RRMM) who were triple-class exposed and refractory to last treatment (Munshi N Engl J Med 2021). KarMMa-2 is a multicohort, phase 2, multicenter trial (NCT03601078) of ide-cel in RRMM and in clinical high-risk MM, defined as early relapse after frontline therapy (cohorts 2a, 2b) or inadequate response after frontline ASCT (2c). The efficacy and safety of ide-cel in cohort 2a are presented. Methods Eligible pts in cohort 2a had early relapse after frontline therapy, defined as progressive disease (PD) <18 mo from starting treatment containing induction, ASCT (single or tandem), and lenalidomide-containing maintenance. After lymphodepletion (cyclophosphamide 300 mg/m2 + fludarabine 30 mg/m2 × 3), pts received a single infusion of ide-cel at 150-450 × 106 CAR+ T cells. The primary efficacy endpoint was complete response (CR) rate (CRR; CR and stringent CR) by investigator per IMWG criteria. Secondary endpoints included overall response rate (ORR; ≥ partial response), time to response (TTR), duration of response (DOR), PFS, OS, safety, and pharmacokinetics (PK). Exploratory endpoints included assessment of soluble BCMA (sBCMA) level and minimal residual disease negativity (MRD-) by next-generation sequencing (<10-5 nucleated cells). Efficacy and safety were analyzed in all pts who received ide-cel; PK and sBCMA were analyzed in evaluable pts. MRD- is reported for evaluable pts with ≥CR. Results Ide-cel was successfully manufactured and infused in 37/39 pts. Median age was 57 y; median time since diagnosis was 1.6 y. A total of 62.2% pts had ECOG PS 0, and 70.3% received bridging therapies (corticosteroids, alkylating agents, immunomodulatory agents, proteasome inhibitors [PI], and/or anti-CD38 antibodies) for MM. At study entry, 13.5%/51.4%/5.4% pts had R-ISS stage I/II/III disease, 32.4% had high-risk cytogenetics, 18.9% had bone marrow biopsy-determined high tumor burden (≥50% bone marrow CD138+ plasma cells), and 8.1% had extramedullary disease. Most pts had disease refractory to an immunomodulatory agent (86.5%) or PI (89.2%); 86.5% had double refractory disease. At data cut-off (14 Mar 2022), median follow-up was 21.5 mo (range 2-31). CRR was 45.9% (95% CI 29.5-63.1), and ORR was 83.8% (95% CI 68.0-93.8) (Table 1). At 6 mo post-ide-cel, MRD− was observed in 11/13 (85%; 95% CI 57.8-95.7) pts. At 12 mo, MRD− was observed in 7/10 (70%; 95% CI 39.7-89.2) pts; of the 7 pts, 1 had PD at 20.8 mo, 5 sustained MRD− at ≥18 mo, and >12 mo data was unavailable for 1 pt. Median TTR was 1 mo (range 0.9-2.9). Median DOR was 15.7 mo (95% CI 7.62-19.81). Median PFS was 11.4 mo (95% CI 5.55-19.58); median OS was not reached. Time to event endpoint results for DOR, PFS, and OS are shown in Table 1. Grade (Gr) 3-4 AEs on or after ide-cel infusion occurred in all pts, most commonly neutropenia in 35 (94.6%) pts, anemia in 17 (45.9%), and thrombocytopenia in 14 (37.8%). Two pts died due to pneumonia and pseudomonal sepsis. Gr 1/2 cytokine release syndrome (CRS) occurred in 30 (81.1%) pts; 1 (2.7%) pt had a Gr 3 event (Table 1). Gr 1/2 investigator-identified neurotoxicity (NT) occurred in 8 (21.6%) pts; no pts had ≥Gr 3 NT. Robust cell expansion was seen in 36 evaluable pts (Table 2). Ide-cel cellular expansion levels were higher in pts who had ≥CR vs those who had <CR with ide-cel (Table 2). sBCMA (range 15.0-737.0 ng/mL at infusion, n = 36) was cleared within 2 mo post-ide-cel infusion in 25/37 (67.6%) pts, including all pts who had ≥CR. Conclusions Ide-cel treatment demonstrated frequent, deep responses in pts who experienced an early relapse after frontline therapy with ASCT. MRD− was sustained in a subset of pts >18 mo. The incidence of CRS and NT were similar in these pts vs those treated with ide-cel in later lines. These results support a favorable clinical benefit-risk profile of ide-cel and its potential use in earlier lines of treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Geotrichum Capitatum Infections in the Hematologic Setting

Introduction: Geotrichum capitatum is a ubiquitous fungus in nature and can be responsible for invasive fungal infections (IFI) in immunocompromised patients (pts) in the hematologic setting, most often within the context of a diagnosis of acute leukemia. Approximately 85% of cases of G. capitatum IFI have been reported in Europe (with approximately 85% of which in Italy and Spain), and it has been suggested that the mediterranean climate could be a contributing factor to its epidemiology; considering the limited geographic distribution of reported cases, the largest published multicentric clinical series comprises just 35 pts. The narrow clinical experience with this IFI thus hinders the development of treatment guidelines, and therefore larger series are needed to address these limitations. Methods: We reviewed all fungal infections in our mediterranean Hematology Department in adult pts (18 years and over) over a 10.5 year period from October 2011 to April 2022, selecting cases with positive fungal identifications of G. capitatum by mycologic methods. The date of "Diagnosis” (Dx) was considered to be the moment of collection of the positive sample. Results: We identified 39 patients with G. capitatum isolates. The average number of cases per year was 3.7 (range: 0-6), with a peak of infections in 2014-2015 temporally coinciding with construction work in the main hospital building, in proximity to the Hematology ward. The mean age at IFI-Dx was 59.0 years (range: 23.2-83.2; median: 64.5) and 61.5% of pts were male. The majority of pts had a Dx of acute leukemia - 61.5% (n=24) myeloid (AML) and 7.7% (n=3) lymphoblastic (ALL) -, with a further 5.1% (n=2) with myelodysplastic syndromes (MDS) with excess blasts; 5.1% (n=2) had Burkitt's lymphoma, 12.8% (n=5) had other chronic lymphoproliferative diseases, 5.1% (n=2) had multiple myeloma (MM), and one pt (2.5%) had aplastic anemia. Two-thirds of pts (66.7%, n=26) presented with fungemia in cultures of peripheral blood (PB) or central venous access (CVA) blood (with 38.5%, n=15, in both); 28.2% (n=11) had positive cultures in either sputum or bronchial aspirate (n=1 in both); 7.7% had urinary isolates and one pt each had positive cultures in a wound exudate and in abscess material. The median OS after IFI-Dx was 17 days (range: 0 days-8.5 years); 31% of pts (n=12) died within a week of Dx, half of whom within the first 3 days, often before fungal identification was established; these pts (none of whom were autopsied) were considered a posteriori to have a G. capitatum IFI as their cause of death. A further 33% of pts (n=13) died from a week to a month after Dx; the direct cause of death in this group of pts could not be established in the absence of autopsy, and both the infection and the underlying hematologic disease were considered equally likely causes. A final 21% of pts (n=8) died between one month and one year after IFI-Dx, and the likeliest cause of death was considered to be progressive disease. Five pts (13%), treated with voriconazole+liposomal amphotericin B, are still alive, with no evidence of recurring IFI, and in complete remission (CR) of the underlying hemato-oncology disease: one with ALL at 8.3 months post-IFI-Dx, one with diffuse large B-cell lymphoma at 11.2 months post-IFI-Dx, one with MM at 4.1 years, and two cases of AML, at 7.2 and 8.5 years post-IFI-Dx, respectively. While the ALL pt had fungemia (in both PB and CVA cultures), the other four surviving pts had no evidence of fungemia and had positive cultures in sputum (n=3) and abscess fluid (n=1). Discussion: We present a very large unicentric clinical series, overtaking the largest published multicentric series reported in the literature. In our cohort, the acute leukemias together with high risk MDS account for three quarters of cases. Approximately one third of patients died of active infection in the acute phase of IFI, while one fifth died of progressive hemato-oncologic disease; in one third of patients, who were not autopsied, the cause of death (IFI vs progressive disease) was not established. Only one-eighth of the cohort currently survives in CR; this subset of pts is relevant for the relative absence of fungemia - present in only 20% of pts, vs 66.7% of the full cohort. Our retrospective series of a rare infection, although underpowered to allow statistical analysis (as has been the case with previously published data) relevantly expands the current knowledge base on G. capitatum IFI in the hematologic patient.

SF3B1, RUNX1 and TP53 Mutations Significantly Impact the Outcome of Patients with Lower-Risk Myelodysplastic Syndrome

Introduction: Prognosis of patients (pts) with myelodysplastic syndrome (MDS), particularly the group with lower-risk disease (LR-MDS) is very heterogeneous. In the last decade, different studies have reported the role of recurrent somatic mutations involved in multiple cellular pathways and incorporated them into clinical practice and current prognostic models, including all risk categories. Recently, the incorporation of genomic data to clinical parameters defined the new Molecular International Prognostic Scoring System (IPSS-M). Materials and Methods: A retrospective study evaluating the impact of molecular profile in a series of 181 pts with LR-MDS and non-proliferative chronic myelomonocytic leukemia (CMML) focused on survival estimates and the probability of leukemic progression. Genomic DNA was isolated from bone marrow mononuclear cells at diagnosis using DNA kit from Qiagen according to the manufacturer´s instructions. A PCR-based targeted was performed sequencing of 40 genes involved in myeloid neoplasms (Oncomine Myeloid Research panel, including hotspots of ABL, BRAF, CBL, CSF3R, DNMT3A, FLT3, GATA2, HRAS, IDH1, IDH2, JAK2, KIT, KRAS, MPL, MYD88, NPM1, NRAS, PTPN11, SETBP1, SF3B1, SRSF2, U2AF1, WT1 and entire coding regions of ASXL1, BCOR, CALR, CEBPA, ETEV6, EZH2, IKZF1, NF1, PHF6, PRPF8, RB1, RUNX1, SH2B3, STAG2, TET2, TP53, ZRSR2). Sequencing was performed using the Ion Torrent S5 sequencing platform from Life Technologies. Survival (OS) was analyzed from diagnosis until death as a result of any cause or the last follow-up and calculated by the Kaplan-Meier method and log rank test. A Cox proportional hazard regression model was performed to analyze OS as endpoint. Analysis was performed by the IBMÒ SPSSÒ version 26.0.0. The probability of leukemic progression was analyzed using the Gray test in the framework of competing risk and considering death not attributable to AML as a competing event. This study was conducted at Hospital Universitario Virgen del Rocío, approved by the local ethics committee and was performed in accordance with the Declaration of Helsinki. Results: In total, 392 mutations were detected in the 181 pts analyzed with a median of 2 mutations per sample (range: 0-8). Sixty-seven pts (37%) harbored ³3 mutations. Table shows baseline characteristics of pts. Most frequent mutated genes were TET2, SF3B1, RUNX1, ASXL1, TP53, and SRSF2 (all of them present in >10% of pts). Epigenetic regulation was the most recurrently mutated pathway, followed by mutations in splicing factors. After a median follow-up of 47 months (95% CI, 37-56 months), 93 out of 191 pts had died (48%). Median OS for the whole cohort was 41 months (95% CI, 28-53 months). TP53 mutations were detected in 22 pts, with equal distribution of mono-allelic or multi-hit TP53 state. As no significant differences in median OS was observed between groups [23 months (95% CI, 12-53 months) in mono-allelic TP53 state vs. 17 months (95% CI, 11-22 months) in multi-hit cases ( P = 0.1)], TP53 mutation was analyzed as a single parameter. Mutations in SF3B1 were detected in 34 pts and the majority of them (31 out of 34; 91%) were classified as SF3B1a according to the recent segregation of SF3B1-mutated cases by the IPSS-M. In univariate analysis, RUNX1 or TP53mutations correlated with lower median OS (Table 2). In contrast, SF3B1 mutation was associated with prolonged median OS [95 months (95% IC, 32-157) vs. 33 months (95% CI, 19-46) in unmutated pts (P < 0.01)]. In a multivariate Cox regression model, RUNX1 mutations independently associated with shorter OS, while SF3B1 mutation retained its favorable impact on outcome (HR: 0.24, 95% CI, 0.1-0.5; P = 0.001). At last follow-up, 49 patients (25%) progressed to AML. Median time to progression was 16.2 months (range: 2-105 months). Subdistribution hazard ratios (sHRs) for leukemic progression were estimated to identify predictive covariates for progression. TP53 mutation (sHR, 6.3; 95% CI, 3-14); P < 0.001) and RUNX1 mutation (sHR, 6.9; 95% CI, 3.3-14; P < 0.001) were predictive for the probability of leukemic progression (Table 2). Conclusion: Incorporation of molecular testing in LR-MDS identified a subset of pts with expected poorer outcome, either due to lower survival or probability of leukemic progression. Results herein reported may help prognosis stratification in this set of pts with low-risk disease and support the recommendation of molecular testing in pts with MDS. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Outcomes of Patients with Breast Implant- Associated Anaplastic Large- Cell Lymphoma (BIA-ALCL) Treated with Chemotherapy and Brentuximab Vedotin

Background BIA-ALCL is a rare form of CD30-positive, ALK-negative ALCL associated with textured breast implants. Patients with stage I BIA-ALCL have disease limited to the capsule which can be completely resected to achieve cure. Advanced stages of disease with capsular invasion, lymph node involvement and/or distant spread require more therapeutic interventions, including radiation (XRT), chemotherapy (CTX), or immunotherapy (ADC). Chemotherapy treatments are similar to those for systemic ALCL and often include anti-CD30 ADC brentuximab vedotin (BV). This study aims to compare outcomes between patients (pts) with advanced BIA-ALCL treated with adjuvant CTX and BV versus those without treatment (Tx). Methods This study is a single institution, IRB approved retrospective chart review, wherein we examined newly diagnosed pts with BIA-ALCL and review of literature between 2008 and 2022. Variables collected included age, radiologic imaging, stage, surgical procedure, pathology review, and laboratory data. Data on treatment and progression, including response to frontline CTX and BV-based therapy, was also analyzed. Overall survival (OS) was the primary endpoint of the study. R studio version 4.2.1 was used for statistical analysis. Results In a cohort of 130 pts (71 MDACC pts and 59 literature review pts) with BIA-ALCL, the median age was 53 years (range, 29-77). The indication for implants were as follows: 69 (53%) for cosmetic purpose, 45 (35%) for breast reconstruction following breast cancer, and 1 due to fibrocystic changes. Twenty-five pts with a history of breast cancer had a recorded history of Tx including CTX, radiation, and hormonal therapy. There were 61 pts (47%) with silicone implants, 30 (23%) with saline, and 3 (2%) had both silicone and saline; implant filling was not available for 36 pts (28%). In terms of types of implants: 61 (47%) had Allergan/McGhan/Inamed (A/M/I), 3 (2%) had A/M/I and implants from other companies, 1 had A/M/I and Mentor (1%), 5 (4%) had Mentor, 2 (2%) had Mentor and other companies, and 7 (5%) had implants from other companies; data was not available for 51 (39%) pts. All 82 pts for whom data was available had textured implants. The average time between implant placement and diagnosis was 12.8 years. On initial clinical presentation, 97 (75%, n=130) pts had swelling, 95 (73%, n= 130) had effusions, 22 (17%, n=130) had lymphadenopathy (LAD), and 7 (5%, n=130) had other clinical presentations such as contractures and rash. Stage included: I- 42%, II- 12%, III-7%, and IV-4%. Overall, 54 (52%) pts did not receive Tx (CTX and BV) and 50 (48%) pts did. Among pts that received no treatment (n=54), 96% had effusions and among pts who had Tx (n= 50), 74% had effusions (p=0.003). Fewer pts on the Tx arm underwent capsulectomy versus those who did not receive Tx: 17 (37.6%) vs 25 (56.8%), p= 0.001). For CTX pts 86% (n=43) pts received CHOP or CHOP-like regimens. Seven (14%) received BV only while 6 (12%) had CTX + BV. A median of 5.1 months passed between diagnosis of BIA-ALCL and starting CTX. Eighty-eight (68%) pts achieved complete remission, 6 (5%) pts were alive with disease, 7 (5%) pts died from disease and 3 (2%) pts died from unrelated diseases. Endpoint response was not available for 26 pts. Most pts who did not receive CTX had Stage I and were treated with complete capsulectomy. We compared the overall survival amongst pts with no Tx, CTX, CTX + BV, and BV. The survival probability of pts receiving CTX and CTX + BV was lower (0.9 and 0.63, respectively) as the disease was similar to systemic ALCL. Overall, there was no significant difference in OS rate (p=0.054) among all four groups of pts. Conclusion Complete surgical excision continues to play a central role in the management of pts with BIA-ALCL. Although most pts with BI-ALCL have excellent outcomes, a subset of pts with advanced stage disease has a more aggressive course and need CTX or BV. Given the smaller numbers of pts with various CTX combinations, prospective studies are required to evaluate the beneficial role of BV in pts with advanced BIA-ALCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

High Response and Prolonged Treatment-Free Remission after a Short-Course of Modified Intensive Chemotherapy and Venetoclax in Elderly AML: An Updated Analysis of the Caveat Trial

Background Venetoclax (VEN) plus azacitidine has an established role in the management of older patients (pts) with AML (DiNardo, NEJM 2020). To explore the feasibility of intensive chemotherapy combined with VEN in older pts with newly diagnosed AML, we conducted the CAVEAT trial (Chua et al, JCO 2020). We now present an updated analysis of this trial (with >3 years median follow-up), reporting on the optimal dose of VEN with chemotherapy, with and without posaconazole (POSA), the deliverability of consolidation therapy, characteristics of treatment failure and observation of substantial treatment-free remission in subsets of pts using this time-limited, short-course regimen. Methods The CAVEAT study enrolled pts aged ≥65 years with de novo or secondary/therapy-related AML (sAML) considered suitable for intensive chemotherapy. Five VEN dose escalation cohorts (50-100-200-400-600 mg) were explored initially. Two additional cohorts examined the safety of adjusted dosing of VEN (50 or 100 mg) during anti-fungal prophylaxis with the strong CYP3A4 inhibitor POSA. For induction, VEN was administered over 14 days, commencing with a 7-day pre-chemo dose ramp-up, followed by a 7-day overlap with 5+2 chemotherapy (cytarabine 100mg/m2/d IVI d1-5 and idarubicin 12mg/m2 IV d2-3). Consolidation (CONS) with 2+1 chemotherapy (below), followed by up to 7 cycles of VEN monotherapy maintenance was planned. Results Data cut-off: 31MAR2022. A total of 69 pts are included in this analysis (first pt 17JUL2016, last pt 15MAY2020). Median age was 71 years (range 63-80). Poor risk features included sAML (42%), adverse karyotype (28%) and prior HMA (23%). From the dose escalation phase, the VEN 600 mg cohort was well tolerated (30-day mortality 6%). Induction with VEN-POSA (n=18) was also well tolerated (30-day mortality 0%) with 3 DLTs observed: 2 hematologic (1 in each cohort) and 1 due to pulmonary infiltrates occurring on d2 induction (suspected to be allopurinol hypersensitivity). No clinical TLS was observed. Although hematologic recovery was satisfactory after VEN-POSA induction, recovery was considerably longer in the VEN (100mg)-POSA cohort after CONS1 compared to VEN (50mg)-POSA for both neutrophils (median 64 vs 44d to 0.5 x109/L) and platelets (median not reached vs 26d to 50 x109/L). Therefore, if POSA is used concurrently, VEN 50 mg is recommended. Alternatively, if VEN 600 mg is used, POSA should commence only after completion of VEN. In the VEN 600 mg cohort, significant delays in hematological recovery were also observed after multiple rounds of attenuated CONS (VEN d1-14, bolus doses of cytarabine 100 mg/m2 d1-2, idarubicin 12 mg/m2 on d1), limiting deliverability (median CONS cycles 1; range 1-3). By intention-to-treat, the overall response (CR/CRi) rate was 73%. CR/CRi was 90% in de novo AML (vs 51% in sAML), 84% in intermediate karyotype (vs 69% in adverse), 76% and 83% in NPM1 and IDH2 mutant AML, respectively. With a median follow-up of 37 months (m), the median overall survival (OS) was 15.4m. Median OS was 31.3m in de novo AML (40% alive at 36m) and 30.3m in intermediate karyotype AML (38% alive at 36m). In the VEN 600 mg cohort, median OS was 24.1m (36% alive at 36m). As CAVEAT delivered just one intensive cycle of therapy, followed by limited post remission therapy (median time on therapy 7.7m), we next assessed the duration of treatment-free remission (TFR) among responders. Among pts achieving CR/CRi, 20/51 (39%) experienced TFR (Fig 1). The median TFR was 22.1m (range 4.6-48.3m). At data cut-off, 12 (24%) have ongoing TFR. Notably, 15/20 (75%) with TFR had an NPM1 or IDH2 mutation at diagnosis. 11 out of 14 evaluable pts with NPM1 mutation had mutation clearance by RT-qPCR, including 3 with NPM1 negative disease at time of failure (1 refractory, 2 relapse). Two pts with persistently mutated NPM1 at relapse had a concomitant FLT3-ITD or KIT mutation. The mutation landscape at relapse is shown (Fig 1) Conclusion VEN combined with modified intensive chemotherapy achieved high response rates in older pts with newly diagnosed AML. With long-term follow-up, the time-limited CAVEAT schedule enabled pts, especially with mutated NPM1 or IDH2, to experience a durable treatment-free remission. Cumulative hematological toxicity is limiting, prompting us to now explore non-anthracycline CONS (low dose cytarabine 20mg/m2 SC d1-10 + VEN 400mg d1-7, for up to 4 cycles), followed by VEN monotherapy (400mg D1-14 q28d cycle x7). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Patterns of Disease Progression in Patients with Systemic Mastocytosis: A US Population-Level Analysis Using Health Claims-Based Dataset

Background Systemic mastocytosis (SM) is a rare clonal mast cell neoplasm driven by the KIT D816V mutation in ~95% of patients (pts). SM includes AdvSM (aggressive SM, SM with associated hematological neoplasm, and mast cell leukemia) and non-advanced SM (indolent & smoldering SM), which accounts for ~95% of cases. The uncontrolled proliferation and activation of mast cells can cause severe & unpredictable symptoms resulting in debilitation, reduced QOL, and organ infiltration and damage with reduced survival in AdvSM. While WHO criteria differentiate between subtypes of mastocytosis, there remains a lack of understanding of patterns of disease progression between SM subtypes. In this analysis we developed a novel claims-based algorithm to identify SM cases and assess disease progression. Methods Using a large, nationally representative claims database, we identified a cohort of SM pts with observed claims activity in each of the year 2019-2022. We developed a novel claims-based algorithm based on WHO diagnostic criteria (2016), including codes for laboratory tests, procedures, and treatments typically used for management of SM. Pts were included if they fulfilled 1 of the following criteria: had ≥2 diagnoses with an SM-specific ICD-10 code (D47.02, C96.21, C94.3X) at least 30 days apart in any setting of care; bone marrow biopsy followed by 1 SM diagnosis (dx) claim code in any setting of care; or 1 SM dx code in any setting of care & at least 1 prescription claim for an SM-specific treatment (avapritinib, midostaurin, imatinib, cladribine, interferons, brentuximab, omalizumab, montelukast, or cromolyn sodium). Pts were then categorized as either AdvSM, higher symptom ISM (ISM-higher), or lower symptom ISM (ISM-lower) based on additional disease-specific codes (Table 1) accumulated over the pt's total observable claims history, from 2015 to the date of evaluation. For pts who met these criteria, SM subtyping was evaluated as of Dec 31, 2019, Dec 31, 2020, and Dec 31, 2021. Treatment rates of select SM-directed therapies were also evaluated over the 12- month period from Jan-Dec, 2021. Results Of 10,939 pts with SM, 80% (8,707 pts) with claims in each of the years 2019, 2020, 2021 and 2022 were included. The first analysis looked at pts’ disease category as of Dec 2021 and assessed utilization of several SM-directed Rx therapies. This included 1,587 AdvSM, 2,705 ISM-higher, and 4,415 ISM-lower pts. Among pts across all cohorts, the most frequently observed therapies were anti-mediator therapies (AdvSM 20%, ISM-higher 37%, ISM-lower 20%) and cromolyn sodium (AdvSM 10%, ISM-higher 19%, ISM-lower 12%). When evaluating disease category evolution, 11.3% and 18.8% of pts with ISM-low migrated to ISM-higher or AdvSM over a 12-month (Dec 2020 - Dec 2021), or 24-month (Dec 2019 - Dec 2021) interval respectively. Across all ISM types, 2.2% of pts progressed to AdvSM in a 12-month interval, and 3.9% progressed to AdvSM over a 24-month interval. Among those pts who emerged with AdvSM in a 12-month interval ending Dec 2021 (N=392), 33% progressed from ISM-Lower or ISM-higher while 67% appeared as de novo diagnoses. Conclusions This study used a large claims dataset to identify pts with SM, classified them with a novel algorithm, and describe patterns of disease progression over a 12-month or 24-month interval. Of note, while this algorithm has been developed with expert clinical input, inherent limitations of claims and a single ICD-10 code for SM leave some ambiguity around the true clinical dx of these pts. Despite this, these analyses reflect the accumulation of severe symptoms over time by a meaningful subset of pts. Approximately 35% of pts with an SM dx did not have a SM dx 2 years prior, possibly due in part to the recency of the SM ICD-10 codes and also raising concerns regarding timely dx. Further, not all ISM pts demonstrated truly indolent disease behavior, illustrated by the 30% of ISM pts categorized as ISM-high requiring greater use of symptom-directed and disease-specific therapies. Finally, the proportion of AdvSM pts on FDA-approved TKI-directed therapies remain low, highlighting large unmet treatment need. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Combined Ibrutinib and Venetoclax for First-Line Treatment of Patients with Chronic Lymphocytic Leukemia (CLL): 4-Year Follow-up Data

Background: Ibrutinib (IBR) and venetoclax (VEN) combination is an effective therapy for patients (pts) with CLL. We previously reported results of the first-line cohort of a phase II trial of combined IBR and VEN for high-risk pts with CLL (Jain, NEJM 2019, JAMA Oncology 2021). Here we report updated data for 120 pts (80 pts in the original published cohort and 40 pts in an expansion cohort) with a median follow-up of 4 years. Methods: Pts with previously untreated CLL meeting IWCLL treatment criteria were enrolled. All pts had at least one high-risk feature: del(17p), mutated TP53, del(11q), unmutated IGHV, or age ≥65 years. Pts received IBR 420 mg daily for 3 cycles followed by addition of VEN (weekly dose-escalation to 400mg daily). Combined therapy was given for 24 cycles (28 days/cycle). Pts with bone marrow (BM) undetectable MRD (U-MRD) (flow cytometry; sensitivity 10-4) at 24 cycles of combined therapy discontinued both VEN and IBR; MRD+ pts continued IBR. A trial amendment allowed an additional 12 cycles of combined VEN and IBR for pts who remained BM MRD+ after Cycle 24. Response assessments included BM and CT studies (2008 IWCLL criteria). U-MRD was defined as <0.01%; low MRD+ 0.01% to <1%; high MRD+ ≥1%. Progression-free survival (PFS) was assessed as the time from the start of study drug to CLL progression, Richter transformation, or death from any cause. Blood MRD was monitored every 6 months after active therapy. Results: Between August 2016 and February 2019, a total of 120 pts were enrolled. Baseline characteristics are shown in Table 1. The median follow-up is 48.8 months. Six pts came off study during 1st 3 cycles of IBR monotherapy; 114 pts initiated VEN. After 12 cycles of the combination, 62/120 (52%) achieved BM U-MRD remission; 43/120 (36%) were BM MRD-positive (low MRD+, n=35; high MRD+, n=8). After 24 cycles of the combination, 77/120 (64%) achieved BM U-MRD remission; 24/120 (20%) were BM MRD+ (low MRD+, n=23; high MRD+, n=1). Overall, 86/120 (72%) achieved BM U-MRD as the best response. We evaluated baseline pt and disease characteristics (age, gender, IGHV mutation status, CLL FISH panel, complex karyotype, TP53 mutation, del(17p)/TP53 mutation) and rate of bone marrow U-MRD at 6 months, 12 months and at any time during the combined IBR+VEN treatment. At 6 months of combined therapy, presence of TP53 mutation was associated with a lower rate of bone marrow U-MRD (p=0.03); however, none of the aforementioned characteristics, including TP53 mutation were associated with marrow U-MRD responses at 12 months or with best MRD response at any time during the combined therapy. There was a trend towards lower U-MRD rate among pts with mutated IGHV vs. unmutated IGHV at 12 month (p=0.09) and as best response (p=0.09). The 4-year PFS is 94.5% (95% CI, 90.3%-98.9%) and 4-year OS is 96.6% (95% CI, 93.3%-99.9%). The 4-year PFS by TP53 aberrant status is shown in Figure 1. The 4-year PFS for pts with del(17p)/TP53 mutation (n=27) is 90.9% and for pts without del(17p)/TP53 mutation (n=93) is 95.5%. None of the aforementioned pt/disease characteristics were associated with PFS. Of the 77 pts who were BM U-MRD at the end of cycle 24 of the combination, 73 discontinued all therapy, 4 pts continued IBR per treating physician discretion. Among these 77 pts, with a median time of 23.9 months post Cycle 24, 11 pts had recurrence of blood MRD (defined as MRD ≥0.01% in 2 consecutive visits). Of the 11 pts with MRD recurrence, 10 are being monitored without any active therapy for CLL and without clinical disease progression; 1 pt had disease progression after 22 months of treatment-free interval and is currently receiving acalabrutinib. There were 24 pts who were BM MRD+ at the end of cycle 24 of the combination (low MRD+, n=23; high MRD+, n=1). The only pt with high-MRD+ at end of cycle 24 was noted to have Richter transformation at that time. The remaining 23 pts (all low MRD+ in BM, range 0.01-0.95%) continued IBR monotherapy. With a recent trial amendment, MRD+ pts after Cycle 24 could get 12 additional cycles of VEN; 18/23 pts have resumed VEN. 11/18 (61%) pts achieved U-MRD remission during the third year of combined therapy. Conclusions: We report long term follow-up of combined IBR and VEN in first-line CLL (n=120) with a 4-year PFS of 94.5%. MRD responses and PFS were independent of baseline pt/disease characteristics. Continuation of combined therapy among marrow MRD+ pts during the second and the third year led to achievement of U-MRD in a subset of pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Transfusion Patterns during Early Follow-up Predict Overall Survival Independently of IPSS-M in Patients with Myelodysplastic Syndromes

Background: The cumulative red blood cells (RBC) transfusion burden is known to impact outcomes in myelodysplastic syndromes (MDS) but doesn't accurately predict prognosis during the early disease phase. Here we aimed to assess the prognostic value of early changes in transfusion patterns in addition to the recent IPSS-M scoring system. Methods: We gathered diagnostic biobank samples from adult patients (pts) with MDS and registered in the Karolinska Institute's biobank (KI) and the National Swedish MDS Biobank (NB) between 2003-2017 and 2013-2017, respectively. DNA targeted sequencing (152 genes) was performed (Bernard et al., NEJM Evid, 2022). Clinical data was retrieved through pts’ charts (KI) and the Swedish cancer registry (NB). Pts were treated according to Nordic/EU guidelines and most common therapies for lower-risk MDS and higher-risk MDS were erythropoietin and azacytidine, respectively. Transfusion data was obtained from the SCANDAT registry. Pts were followed with regards to RBC transfusion until censored due to death, transformation to acute myeloid leukemia (AML-t), allogenic stem cell transplantation (allo-SCT), or end of follow-up on the 31st of August 2018, whichever occurred first. As per the IWG hematological response criteria for MDS (Platzbecker et al., Blood 2019), transfusion states (TS) were categorized every 4 months (m) as transfusion dependent (TD) or transfusion free (TF) during the past 4 m period. Lower-risk MDS (LR) was defined as IPSS-M very low, low and moderate low, and higher-risk MDS (HR) as IPSS-M very high, high and moderate high at diagnosis (Bernard et al., NEJM Evid, 2022). Landmark analyses of overall survival (OS) were performed with the Kaplan-Meier method for estimating probabilities of OS over time. Multivariable analyses were conducted using Cox proportional hazards model. Results: We gathered a cohort of 688 pts with MDS from KI (n=424) and 33 other clinics in Sweden (NB, n=264). Median age at diagnosis was 74 years (y) old (range 19-93). The male:female ratio in the cohort was 1.4. At diagnosis, 63% of the pts were TF. Out of 646 pts evaluable by the IPSS-M score at diagnosis 54% had LR. Most frequently mutated genes in the cohort were TET2, SF3B1, ASXL1, DNMT3A, RUNX1, TET2, TP53 (66% TP53 multihit), U2AF1, STAG2, ZRSR2. Changes between TS (transitions) preferentially occurred within a year after diagnosis (panel A) with a median time for occurrence of transfusion-related transitions of 1.0 y (range 0.33-8.37). Based on this finding, we assessed whether TS at 8 m landmark impacted prognosis. We observed that there was a significant difference in OS since landmark between TF pts compared with TD pts at landmark 8 m and across IPSS-M categories (panel B). LR pts who were TD at 8 m, had a median OS of 3.2 y (95% CI: 2.2-4.0) versus 6.9 y (95% CI: 5.6-8.9) for LR pts who were TF (P<0.0001). Similarly, median OS was 0.8 y (95% CI: 0.6-1.1) in HR and TD pts while it was 2.4 y (95% CI: 2.1-3.1) in HR and TF pts at landmark 8 m (P<0.0001). Interestingly, OS for LR pts who were TD didn't significantly differ from HR pts who were TF at 8 m. Overall, pts TD at 8 m had more gene mutations compared to TF pts (median 5 [1;13] and 4 [1;16], respectively, P=0.0084). Moreover, studying specific genetic subgroups of MDS, TS at 8 m distinguished subsets of pts with adverse or favorable outcomes within SF3B1-mutated LR pts. In this population, the median OS in pts TF at 8 m was 8.4 y (95% CI: 6.5-13.1) compared to 3.2 y (95% CI: 1.7-4.1) for TD pts (P<0.0001). Next, in multivariable analysis, we found that TD at 8 m significantly impacted OS (HR=2.4 [95% CI: 1.9-3.1]), independently of diagnostic IPSS-M score, age, gender and type of MDS (de novo or therapy-related). Conclusion: TS at landmark 8 m, usually after outcome of first-line treatment was evaluated, appears to be a strong and independent predictor of OS in MDS. These findings are of particular importance for the LR group in which it could discriminate subsets with favorable outcomes from those with adverse prognosis. In addition to the IPSS-M calculation at diagnosis, transfusion dependency could be easily used for prognostic reassessment during follow-up. More generally, these results highlight the need of dynamic outcomes prediction tools and/or validation of current prognostic scores in dynamic settings. Finally, multistate modeling of the dataset is being completed and aims to assess how changes of transfusion patterns over time impact prognosis. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Efficacy and Safety of Add-on Parsaclisib to Ruxolitinib Therapy in Myelofibrosis Patients With Suboptimal Response to Ruxolitinib: Final Results From a Phase 2 Study

Background: Ruxolitinib (RUX) is a potent JAK1/JAK2 inhibitor and is effective in patients (pts) with myelofibrosis (MF). However, suboptimal or declining responses to RUX occur in a subset of pts, possibly due to persistent PI3K pathway activation with chronic JAK inhibitor therapy. Parsaclisib is a potent and highly selective next-generation PI3Kδ inhibitor. We conducted a phase 2 study (NCT02718300) evaluating add-on parsaclisib to stable doses of RUX, for pts with MF who experienced a suboptimal response to RUX (Yacoub A. HemaSphere 2021;5 Suppl 2:512). Here we report efficacy and safety results from the completed study. Methods: Eligible pts had primary or post-essential thrombocythemia/post-polycythemia vera MF with suboptimal response (palpable spleen >10 cm below left subcostal margin [LSM], or palpable splenomegaly 5-10 cm below LSM and presence of 1 symptom score ≥5 or 2 symptom scores ≥3 each using the Screening Symptom Form) after ≥6 months of RUX (5-25 mg twice daily; RUX stable dose, ≥8 wks). Pts remained on their stable RUX dose and were randomized to receive add-on parsaclisib 10 mg or 20 mg once daily (QD) for 8 wks and the same dose once weekly (QW) thereafter (QD/QW group), or parsaclisib 5 mg or 20 mg QD for 8 wks and 5 mg QD thereafter (all QD group) (Figure). Primary efficacy endpoint was change in spleen volume (SV) from baseline to wk 12 by MRI/CT scan. Key secondary endpoints included change in SV to wk 24, change in total symptom score (MFSAF-TSS, MPN-SAF-TSS), and safety. Results: Overall, 32 pts received parsaclisib QD/QW and 42 pts received parsaclisib all QD. Baseline median age was 68.0 (range 41.0-89.0) years and 47.3% of pts were male. The study has been completed. Median treatment duration was 336.5 days; median average daily dose was 5.0 mg/day for parsaclisib and 29.8 mg/day for RUX. Among all pts, 16 (21.6%) were rolled over to continue therapy in an open-label parsaclisib study after ending treatment in the present study. Other common reasons for pts discontinuing treatment were adverse events (13 [17.6%]) and progressive disease (10 [13.5%]); remainder discontinued for physician decision, pt decision, or "Other." Baseline median SV (cm3) was 2414.5 in QD/QW (n=29) and 1877.5 in QD (n=37); median MFSAF-TSS was 10.8 (n=28) and 16.3 (n=32) and median MPN-SAF-TSS was 25.5 (n=28) and 30.0 (n=37), respectively. Median percentage change in SV at wk 12 was −1.6 (n=28) in QD/QW and −15.4 (n=37) in QD, and at wk 24 was −2.5 (n=20) and −19.3 (n=29), respectively. Median percentage change in MFSAF-TSS at wk 12 was −14.0 (n=21) in QD/QW and −32.8 (n=24) in QD, and at wk 24 was −10.0 (n=16) and −44.4 (n=18), respectively. Median percentage change in MPN-SAF-TSS at wk 12 was −19.2 (n=20) in QD/QW and −39.8 (n=30) in QD, and at wk 24 was −43.3 (n=15) and −60.8 (n=26), respectively. Responder analysis for these 3 efficacy variables is shown in the Table. Nonhematologic treatment-emergent adverse events (TEAEs) were primarily grade 1/2. Grade 3/4 nonhematologic TEAEs occurring in >1 pt overall were pneumonia (n=5; 3 QD/QW, 2 QD), fatigue, hypoxia (each n=2; each 1 QD/QW, 1 QD), dyspnea (n=2, all QD), fall, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, hypocalcemia (each n=2; all QD/QW). New-onset grade 3 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 11/42 pts (26.2%) in QD; grade 4 thrombocytopenia was observed in 6/32 pts (18.8%) in QD/QW and 3/42 pts (7.1%) in QD. TEAEs of special interest included grade ≥3 ALT and AST (each n=2; all QD/QW), grade ≥2 diarrhea (n=4) and rash (n=1) (all QD/QW), and any-grade herpes simplex (n= 4; 1 QD/QW, 3 QD) and VZV infection (n= 3; 1 QD/QW, 2, QD). No colitis was reported. TEAEs led to parsaclisib interruption in 16/32 pts in QD/QW and 22/42 pts in QD, and RUX interruption in 5/32 and 8/42 pts, respectively. TEAEs led to parsaclisib discontinuation in 5/32 pts in QD/QW and 4/42 pts in QD, and RUX discontinuation in 2/32 and 2/42 pts, respectively. Conclusion: Final results from the phase 2 study demonstrate improvement in symptoms and SV with add-on parsaclisib in patients with MF having a suboptimal response to ruxolitinib. All daily dosing regimens were more efficacious than daily/weekly dosing. Combination therapy was associated with limited grade 3/4 AEs and TEAE-related discontinuations. Phase 3 studies using 5 mg QD parsaclisib together with ruxolitinib in naive MF patients and ruxolitinib-experienced patients are in progress. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Global Treatment Standard in Multiple Myeloma Remains Elusive: Updated Results from the INSIGHT MM Global, Prospective, Observational Study

Introduction INSIGHT MM (NCT02761187) is the largest global, prospective, observational multiple myeloma (MM) study to date, with 4188 newly diagnosed MM (NDMM) or relapsed/refractory MM (RRMM) patients (pts) included in this cross-sectional analysis. The study aims to describe contemporary, real-world patterns of pt & disease characteristics, treatment patterns, & outcomes. An interim analysis of the first 1000 pts enrolled to INSIGHT MM suggested considerable regional variation in treatment patterns (Boccadoro et al, EHA 2018). The aim of the current analysis is to characterize treatment patterns by world regions & line of therapy (LOT) in the overall INSIGHT MM study population. Methods Pts were enrolled at academic & community treatment facilities in 15 countries between July 2016 & July 2021. Data on prior & current treatments were collected at baseline & every 3 months. Full study methods have been reported previously (Costello 2019). We report a cross-sectional analysis of treatment regimens used in NDMM & RRMM pts at a data cut-off of Sept 30, 2021. A subset of pts with no protocol deviations (pts meeting all inclusion criteria who started index regimen <90 days before enrollment & enrolled at centers where data quality checks could be conducted) were included in an analysis of treatment shift patterns from first to second & subsequent LOTs. Results Among the 4188 pts, there were 2338 (55.8%) NDMM & 1850 (44.2%) RRMM cases at enrollment. This includes 2046 pts from Europe (EUR; Belgium, France, Germany, Greece, Italy, Spain, Turkey, United Kingdom; also includes Israel); 1317 pts from the United States (US); 470 pts from Latin America (LA; Brazil, Columbia, Mexico); & 355 pts from Asia (China, Taiwan). Median follow-up was 27.9 months. In NDMM pts, triplet therapy was the most common frontline approach across all regions (71.1% of pts overall); only 12.0% of pts received frontline doublet therapy. Triplet therapy typically included a proteasome inhibitor (PI) & dexamethasone (d; 62.5%). The most commonly used regimen was bortezomib (V), lenalidomide (R), & d (VRd; 23.5%); V-based triplet therapy with d & an IMiD was prescribed to 34.7% of NDMM pts overall. V-based triplets were the most widely used regimens across all regions. The US was the only region where carfilzomib (K) was included in one of the three most frequently used regimens (KRd in 8.3% of pts). Choice of IMiD varied regionally: R was most commonly used in the US, & thalidomide in EUR, LA, & Asia. In EUR & LA, cyclophosphamide (alkylating agent) was more commonly used than IMiDs. Vd (4.1%) & Rd (4.0%) doublets were the fourth & fifth most common regimens overall. Among RRMM pts, 49.6% received triplets & 33.7% received doublets. Triplet therapy was the most common approach across all LOTs & all regions except Asia; in Asia, doublets were more widely used than triplets (48.9% vs 42.4%). Rd was the most common regimen overall (15.4% across all regions & LOTs), & ixazomib-Rd (IRd) was the most common triplet (7.9% in all regions & LOTs; KRd was the second most common triplet overall [5.2%]). Unlike NDMM pts, RRMM pts were more likely to receive alternative PIs to V in ≥2nd LOT (IRd 6.8%; KRd 6.7%; VRd 2.7%), & daratumumab (D) was used instead of or alongside PIs in some triplets (DRd 4.9%; VDd 4.5%). Overall, 20.8% of pts received D as part of single-agent, doublet, triplet, or >triplet therapy. D was more widely used in the US (33.5%) than other regions (14.4-16.2%). Treatment shift patterns were examined in 3263 pts for whom robust data were available (1236 who underwent stem cell transplantation [SCT] in first line of therapy & 2027 who did not [NSCT]). A shift from predominantly PI- or PI/IMiD-based frontline therapy in both SCT & NSCT pts to more varied second-line regimens, including monoclonal antibody (mAb) therapy, was observed (Figure). Treatment shift patterns in later LOTs & across regions will be presented. Conclusions V-based triplets were the most common frontline treatment in NDMM pts in all regions. Regimens used in later LOTs in RRMM pts were more varied across regions, & generally included greater use of doublets, PIs other than V, & mAbs such as D. Acknowledging that treatment use is dependent on approval status & availability, this analysis shows that, while global frontline standard of care (SOC) is broadly established, there remains no consistent SOC in later LOTs; adoption of newer therapies, such as mAbs, varies across regions worldwide. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The Areal Project: How Virtual Reality Application Could Enhance Patient's Quality Time during Transfusion Therapy in Adult Patients with Thalassemia and Sickle Cell Disease

Background Chronic red blood cell transfusion therapy (CTT) is an integral component of the management of Transfusion Dependent Thalassemia (TDT) and Sickle Cell Disease (SCD). CTT requires time and significantly impacts the quality of life of patients with TDT and SCD. In some cases, the environment in which transfusions are performed is uncomfortable and doesn't offer adequate spaces and facilities. And as a result, the patient experiences a condition of discomfort and tries with his own means to get distracted or "estranged". Hence, attention should be paid to psychological, emotional and social needs of patients on CTT in order to reduce the burden of the procedure with activities that are capable of engaging more the person. Aims From this need and the opportunities offered by the digital technologies available today, the AREAL project was designed by the Italian startup Softcare Studios in partnership with the pharma company Novartis and in collaboration with hemoglobinopathy specialized medical staff. Objectives of this pilot project were: i) collect feedback from patients with TDT and SCD and from healthcare professional workers regarding utility and feasibility of AREAL; ii) detect and evaluate changing in states of patient's anxiety and depression. Methods AREAL consists of three gaming activities enjoyed in virtual reality thanks to the use of suitable Virtual Reality (VR) viewers (Figure 1A) developed to immerse the patient in a sensorial stimulating scenario and designed to stimulate cognitive skills: activity 1 for short-term memory, activity 2 for task switching, activity 3 for problem solving. AREAL also integrates elements of patient education in therapy and recommended lifestyle habits to promote their well-being. Anxiety and depression were assessed by a self-assessment questionnaire, the Hospital Anxiety and Depression Scale (HADS), administered after each virtual session. Results The pilot group was composed by 70 subjects on CTT followed in 3 hospital centers in Italy (Genova, Napoli, Padova). The 57% were males, median age was 31 years (IQR: 21-40), 53 patients were affected by TDT and 6 by SCD. The total number of sessions collected is 129; 59 patients experienced two sessions and were included in the analysis for HADS. The average duration of game sessions lasted 17 minutes.Activity 1 was the most played and most rarely interrupted, followed by 2 and finally by 3, where 50% of sessions are been interrupted due to its difficulty. In Activity 1 patients recognized the goal of the game, which is to stimulate memory, and they liked its immediacy. Excessive facility, especially considering the repetition over time during the therapy, was emphasized by patients who suggested making the game more complicated. Compared to Activity 1, Activity 2 is more complicated and engaging, emerging as the overall favorite of the study patients. Undoubtedly, Activity 3 emerged as the most difficult one, both to play and to understand, also given its focus on problem solving. Based on the feedback from healthcare professionals learning to use the virtual application wasn't particularly difficult. The experience of the staff confirmed some of the critical issues also communicated by patients (such as the high difficulty of the third game activity and request for greater variability over time).Anxiety and depression were detected by HADS respectively in 13 and in 9 pts after first session, in 10 and in 4 pts after second session, suggesting a possible benefit of VR; the number of patients with borderline profile reduced from 8 to 3 both for anxiety and depression (Figure 1B). There were no significant differences of scores and/or percentages between sessions. Conclusions There is a significant need to iterate AREAL on the basis of different age groups, each with specific needs, preferences and level of confidence with technologies. From the collected feedback, AREAL was perceived as an innovative project and an opportunity to pay attention to the critical issues of the patients' therapeutic experience on CTT. However, it is needed to optimize the experience in order to free the operator from extra commitments as much as possible that could impact the quality of hospital work routine. AREAL seems to be an opportunity to reduce discomfort and anxiety during CCT in the subset of pts with a profile borderline for anxiety and depression but needs to tailor the intervention to specific subsets of patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Updated Results of CPX-351 in Combination with Gemtuzumab Ozogamicin (GO) in Relapsed Refractory (R/R) Acute Myeloid Leukemia (AML) and Post-Hypomethylating Agent (Post-HMA) Failure High-Risk Myelodysplastic Syndrome (HR-MDS)

Background: Treatment outcomes in patients (pts) with AML and HR-MDS who progress after HMA +/- venetoclax (VEN) based regimen remains poor and warrants new therapeutic strategies. CPX-351 (Vyxeos™) is a dual liposomal formulation of cytarabine and daunorubicin, at a fixed synergistic 5:1 molar ratio, approved by US Food and Drug Administration (FDA) for the treatment of newly diagnosed therapy-related AML or AML with myelodysplastic related changes (AML MRC). GO (Mylotarg™) is a humanized IgG4 antibody directed against CD33 and conjugated to the DNA toxin calicheamicin and approved by the FDA for the treatment of newly diagnosed or R/R CD33-expressing AML. We hypothesized that the combination of CPX-351 and GO could be synergistic in this high risk pt population and have potent anti-leukemic activity. Aim: To determine the safety and efficacy of CPX-351 in combination with GO in patients with R/R AML or post-HMA failure HR-MDS. Methods: We present here the updated results of the Phase 2 single-arm pilot study (NCT03672539) of CPX-351 and GO (CPX-GO) combination therapy in pts with CD33 positive R/R AML or post-HMA failure HR-MDS. Pts received induction cycle (C) CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) administered via intravenous (IV) infusion on days (D) 1, 3, and 5. GO was administered at a dose of 3 mg/m2 (capped at 4.5 mg) IV on D1. Pts not attaining complete remission (CR) or CR with incomplete count recovery (CRi) after C1, could receive a 2nd induction cycle of CPX at the same dose, but only on D1 and D3 with GO 3 mg/m2 on D1. Pts attaining CR/CRi could receive up to 2 consolidation cycles, after a minimum of 4 weeks from the start of the previous cycle with CPX (daunorubicin 29 mg/m2 and cytarabine 65 mg/m2) IV on D1 and D3 and GO at 3 mg/m2 on D1. GO was only administered during the second consolidation cycle if there was evidence of measurable residual disease (MRD+) as measured by flow cytometry. GO could also be administered as a single agent for maintenance treatment on D1 every 6 weeks, in case of persistent detection of MRD. CD33 genotyping to assess for GO sensitivity was available for a subset of pts. Response was denoted as per the ELN 2017 criteria for AML and IWG 2018 criteria for MDS. Results: From Nov 2018- Apr 2022, 31 pts were treated on the trial, 29 (93%) pts with AML and 2 pts (7%) with HR-MDS. Baseline disease, treatment and response characteristics are mentioned in Table 1. The median lines of prior AML therapy were 2 (range, 1-6). Eleven pts (38%) had baseline de novo AML, while 15 (52%) and 3 (10%) pts had secondary (s-AML) and therapy-related (t-AML) AML respectively. Twenty-three AML pts (79%) had prior VEN exposure. Both the prior HR-MDS patients had bone marrow (BM) blasts >15% and one pt had prior VEN exposure. Overall, 21 pts with AML (72%) were adverse risk and only 1 pt (3%) had favorable risk AML (diploid karyotype with NPM1 mutation). Four pts (all AML; 13%) had undergone a prior stem cell transplantation (SCT). The median number of cycles on trial were 1 (range, 1-6). At the time of data cutoff, none of the pts were on active study therapy and the median follow up was not reached. Sixteen pts (52%) had an overall response; 9 pts had CR/CRh/MLFS (8 AML and 1 MDS= responders), after a median of 1 cycle of therapy, and 7 pts had a partial response (all AML). CD33 genotype did not affect response rates (no response in 5 pts with C/C vs 2/6 responders in C/T genotype, p=0.45). Amongst prior VEN exposed pts, 5/24 (21%) responded versus 3/7 (43%) non VEN exposed pts (p=0.15) One pt could directly proceed to a SCT in CR after the trial therapy. For relapse free survival (RFS) analysis partial responders were grouped under non-responders. The median RFS and overall survival (OS) for the whole cohort was 6.3 and 6.8 months (mos) respectively, and median OS was 12.9 mos for responders(Fig. 1). One pt had a grade 2 infusion reaction to GO. Overall, adverse events at least possibly attributed to the trial medications were seen in 5 pts, of which 2 events were ≥ grade 3 (mucositis and seizures). No pt had hepatic veno-occlusive. Eight pts (all non-responders) (26%) died on the trial from infections/leukemia progression and there were no deaths in remission. Conclusion: In a cohort composed predominantly of heavily pre-treated and VEN exposed adverse risk AML and HR-MDS pts, CPX-GO led to overall response (CR/CRh/MLFS/PR) rates of 52% and year-long median survival in responders (CR/CRh/MLFS) with no major non-hematological adverse event. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

S1637 Outcomes in Patient With Refractory Gastroparesis on Domperidone-A 12-Year Experience

Introduction: Domperidone (Domp), a prokinetic with less side effects than metoclopramide, the only FDA-approved medication for gastroparesis (GP), is only available via the FDA IND program. Our aim was to examine clinical response and side effects profiles of patients (pts) enrolled in our program to identify those most likely to benefit. Methods: Records of pts enrolled from 2010 through 2021 were examined. Pts who completed an initial (PAGI sym) were contacted for a repeat PAGI-sym. Pts self-reported quality of life. Records of disenrolled (DE) pts were reviewed for cause for disenrollment, adverse effects if any and improvement of symptoms on Domp. Data is reported at percentages and mean ± SD. Variables were compared using Chi-squared test (categorical) and t-test. P< 0.05 was considered significant. Results: 301 pts (85.7% F), were consented. 189 pts were disenrolled (DE), of which 31 never started drug, and 67 charts were reviewed in detail. 41 pts still enrolled (E) had initial and followup PAGI-sym. Of these, 32 (78%) were female, mean age on entry was 50 yrs, with 70.1% older than 40 yrs. Mean treatment duration was 39±39.3 mo. Top GP causes were idiopathic (43.9%), diabetes (24.4%) and post-surgical (12.2%). There was no significant difference in causes or initial symptom severity between genders. There was significant improvement in the severity of all symptoms on PAGI-sym scale after Domp treatment (Table). Gender and age groups did not affect this improvement. Overall self-reported quality of life (QoL) improved regardless of gender, age group and use of psychotropic medication. Reasons for disenrollment for all 189 DE pts are shown in Figure. Six had QTc prolongation (3.2%). In the 67 pts with detailed review, the GP cause was similar in those with symptom remission as in all the DE and E pts. Treatment duration of DE pts was 22.2±22.8 months, shorter than the 41 E pts (P< 0.005). Pts with symptom remission were on Domp treatment for 45.7 ± 26.74 mo, longer than pts withdrawn for other reasons (mean 14.83±15.54 mo, P< 0.001). Most (72%) DE pts reported improvement in symptoms. Conclusion: In summary, Domp improves symptoms related to GP regardless of etiology. Nearly 2 thirds disenrolled over time, but very few have prolonged QTc. Detailed review in a subset of pts suggest no specific etiologies result in better symptom response to domperidone, or predict likelihood of adverse events. Symptom remission can take several years to be sufficient to discontinue treatment.Figure 1.: Reasons for Disenrollemnt in 189 DE Patients. Table 1. - Comparison of Symptom Improvement in All Enrolled Patients PAGISYM-1 (mean +/- SD) PAGISYM-2 (mean +/-SD) P value Regurgitation 2.23 +/- 1.55 1.27 +/- 1.1 < 0.001 Nausea 3 +/- 1.7 1.66 +/- 1.15 < 0.001 Upper Abdominal Pain 2.66 +/- 1.59 1.37 +/- 1.18 < 0.001 Stomach Fullness 3.45 +/- 1.48 2.41 +/- 1.32 0.003 Loss of Appetite 2.9 +/- 1.74 1.46 +/- 1.4 < 0.001 Upper Abdominal discomfort 2.7 +/- 1.54 1.46 +/- 1.29 < 0.001 Bloating 3.48 +/- 1.55 2.2 +/- 1.5 < 0.001 Retching 1.4 +/- 1.53 0.61 +/- 0.92 < 0.001 Stomach or Belly Visibly Larger 2.69 +/- 1.89 1.55 +/- 1.45 0.001 Vomiting 1.89 +/- 1.84 0.78 +/- 1.17 0.001 Not Able to Finish a Normal Sized Meal 3.5 +/- 1.52 2.05 +/- 1.45 < 0.001 Feeling Excessively Full After Meals 3.75 +/- 1.28 1.93 +/- 1.44 < 0.001

Abstract A32: Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial

Abstract Introduction: In the Phase III CHRONOS-3 trial investigating the efficacy and safety of the PI3K inhibitor copanlisib in combination with rituximab (C+R), superior efficacy in progression-free survival (PFS) was demonstrated vs placebo plus rituximab (P+R) in patients (pts) with relapsed indolent non-Hodgkin lymphoma (iNHL; hazard ratio [HR] 0.52), including in the subset with follicular lymphoma (FL; HR 0.58) (data cut-off Aug 31, 2020) (Matasar et al. Lancet Oncol 2021). Here we report an updated 1-year follow-up analysis for the subset of pts with FL (data cut-off Aug 6, 2021).Methods: Eligible pts with relapsed iNHL who were progression- and treatment-free for ≥12 months (mo) after the last R-containing regimen, or for &amp;gt;6 mo if unwilling/unfit to receive chemotherapy, were randomized 2:1 to C+R or P+R. Treatment continued until progression or unacceptable toxicity. C 60 mg flat dose was administered i.v. on days 1, 8, and 15 (28-day cycle) and R 375 mg/m2 i.v. on days 1, 8, 15, and 22 of cycle 1 and on day 1 of cycles 3, 5, 7, and 9. Primary endpoint was centrally assessed PFS. Secondary efficacy endpoints included overall survival (OS), objective response rate (ORR), duration of response (DoR), complete response rate (CRR), and treatment-emergent adverse events (TEAEs). As part of biomarker analysis, PTEN expression level was evaluated using immunohistochemistry.Results: The FL subset comprised 275 pts (184 C+R and 91 P+R). C+R reduced the risk of progression or death by 43% vs P+R; median PFS was 23.2 mo (95% confidence interval [CI] 19.2, 33.1) for C+R and 16.6 mo (11.0, 19.6) for P+R (HR 0.57 [95% CI 0.41, 0.80]. ORRs were 85% vs 56% for C+R vs P+R; CRRs were 38% vs 21%. Median DoR was 25.7 mo (17.2, 31.5) for C+R vs 18.2 mo (12.3, 26.3) for P+R (HR 0.75 [95% CI 0.49, 1.14]); for pts achieving a complete response, median DoR was not reached for C+R vs 24.7 mo (10.8, 29.7) for P+R (HR 0.41 [0.19, 0.87]), with DoR rates at 36 months 63% vs 23%. Median OS was not estimable, and no significant benefit was seen for C+R over P+R (HR 0.95 [95% CI 0.52, 1.74]). Hyperglycemia (76%), hypertension (54%), and decreased neutrophil count (38%) were the most common TEAEs in the C+R arm, consistent with the study population. Grade 5 events occurred in 5 pts (3%) in the C+R arm; 1 (1%) was deemed treatment-related. Of 119 pts with FL who were evaluable for PTEN analysis, 41 (34%) were positive. Percent PTEN positivity was not correlated to best overall response (p=0.44) or responsiveness (p=0.08). Median PFS was improved in PTEN-negative pts regardless of treatment. PTEN-positive pts had improved PFS with C+R vs P+R (p=0.005).Conclusion: Pts with FL from the CHRONOS-3 trial continued to show superior efficacy with C+R vs P+R and an acceptable safety profile 1 year after the primary disclosure, supporting the long-term use of C+R in pts with relapsed FL. Exploratory analysis suggests pts with PTEN-positive disease may experience significant benefit with C+R. Citation Format: Marcelo Capra, Fangfang Lv, Wei Li, Tongyu Lin, Eduardo Yañez, Jifeng Feng, Aryan Hamed, Xiaoling Li, Toshiki Uchida, Ming-Chung Wang, Koji Izutsu, Antonio Salar, Katya Sapunarova, Guray Saydam, Jan Zaucha, Lidia Mongay Soler, Shalini Chaturvedi, Anjun Cao, Barrett H Childs, Pier Luigi Zinzani, Matthew J Matasar. Copanlisib plus rituximab vs placebo plus rituximab in patients with follicular lymphoma: 1-year follow-up of the Phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A32.

Abstract A25: Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial

Abstract Introduction: CHRONOS-3 randomized patients (pts) with relapsed iNHL to the PI3K inhibitor copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle in combination with standard rituximab (C+R) or placebo plus rituximab (P+R) and demonstrated superior progression-free survival (PFS) of C+R vs. P+R (hazard ratio[HR]: 0.52; Matasar et al. Lancet Oncol 2021). In an updated 1-year follow-up analysis, the benefit of C+R was confirmed in the overall relapsed iNHL population (Zinzani et al., EHA 2022) and in the subset of pts with FL (see Capra et al. AACR Lymphoma 2022 abstract). We investigated popPK and ER relationships for copanlisib efficacy and safety from a pooled analysis, with a particular focus on the 1-year follow-up of CHRONOS-3 to confirm copanlisib dose selection. Methods: A comprehensive popPK model for copanlisib was developed using plasma concentrations from 712 pts across 9 copanlisib clinical Phase 1-3 studies. Demographic, laboratory, and comedication covariates were investigated for their influence on copanlisib between-patient PK variability. Individual static and time-varying exposure estimates for pts enrolled in CHRONOS-3 were derived to investigate relationships to efficacy (PFS, overall response rate [ORR], complete response [CR]) and key treatment-emergent safety events using multivariate cox proportional hazards (CPH) and logistic regression analyses, after accounting for predefined potentially prognostic demographic, laboratory, and/or disease related baseline covariates. Results: Copanlisib PK was best described by a 3-compartment PK model with first-order elimination from the central compartment following intravenous infusion. Copanlisib PK was dose proportional and time independent with no accumulation. Covariates statistically selected as influencing copanlisib PK included rifampin (strong CYP3A inducer) and itraconazole (strong CYP3A inhibitor) co-administration, female sex, Japanese pts, mild or worse hepatic impairment, and a CHRONOS-3 study effect, however all identified covariates, aside from rifampin/itraconazole, had no clinically relevant effect (≤ 35%) on copanlisib AUC. In CHRONOS-3, CPH analyses demonstrated a statistically significant positive ER relationship for PFS where greater copanlisib exposure was associated with prolonged PFS. Relative to P+R, the HR for C+R at the 5th and 95th percentile of copanlisib time-varying exposure was 0.875 and 0.217, respectively. Thus, lower copanlisib doses may result in reduced efficacy in relapsed iNHL. CPH and/or logistic regression analyses demonstrated no significant ER relationship for ORR and investigated adverse events. Based on the modelling, lower starting doses of copanlisib are not anticipated to improve safety and tolerability. The ER analyses support the overall positive benefit/risk assessment of copanlisib reported from the clinical efficacy and results of CHRONOS-3 in iNHL. Conclusions: PopPK and ER analyses support copanlisib 60 mg administered on Day 1, 8, 15 of 28-day cycle dose selection in the relapsed iNHL population. Citation Format: Jonathan Moss, Dirk Garmann, Rupert Austin, Florian Hiemeyer, Patricia DeLora, Matthew J Matasar, Pier Luigi Zinzani, Vita Beckert, Lidia Mongay Soler, Barrett H Childs, Peter N Morcos. Copanlisib population pharmacokinetics (popPK) and exposure-response (ER) in relapsed indolent non-Hodgkin lymphoma (iNHL): Analysis from the 1-year follow-up of the phase III, randomized CHRONOS-3 trial [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A25.

1538P Prognostic impact of leptin (LEP)-mediated meta-inflammation (MI) in patients (pts) receiving maintenance immunotherapy (IT) for extensive-stage small cell lung cancer (ES-SCLC)

Immune-checkpoint inhibitors (IT) combined with platinum-based chemotherapy (CT) have become the new standard-of-care in the treatment of extensive-stage SCLC (ES-SCLC), however little is known about the small – but not negligible – subset of pts that obtains long-term benefits. Adipokines-induced metabolic dysfunctions and MI have been related to enhanced responsiveness to IT in obese pts; however, their prognostic role in SCLC is currently controversial.

1213P DKN-01 and tislelizumab + chemotherapy as first-line (1L) investigational therapy in advanced gastroesophageal adenocarcinoma (GEA): DisTinGuish trial

Despite recent approval of anti-PD-1 antibodies as 1L therapy in advanced GEA, benefit is largely limited to PD-L1 combined positive scores (CPS) ≥5 patients (pts); novel therapeutic approaches are needed. DKN-01 is a targeted anti-DKK1 mAb which has demonstrated activity in GEA pts with elevated tumoral DKK1 expression, a subset of pts with more aggressive disease and shorter overall survival. Phase IIa single arm trial investigating DKN-01 300 mg (D) + tislelizumab (TS) + CAPOX as 1L therapy in advanced HER2(-) GEA regardless of DKK1 status. Tumoral DKK1 mRNA expression was assessed by a chromogenic in situ hybridization RNAscope assay and assigned an H-score (0-300). Primary endpoint was ORR in modified intent to treat (mITT) population (>1 dose D); secondary endpoints included PFS and OS in intent to treat (ITT) population overall and by DKK1 expression: high (H-score ≥35) vs low. 25 pts enrolled (01 Sept 2020 - 08 Apr 2021). Median age 61 years (22, 80); 17 pts gastroesophageal junction adenocarcinoma; 8 pts gastric cancer. 21 GEA pts had RNAscope DKK1 expression; 57% were DKK1-high. 22 of 25 pts had vCPS: 73% were vCPS <5. Median duration of treatment 11.3 mos. 7 pts on therapy and only 9 of 25 pts have died. 12 mo survival: 76%. 14 pts (56%) experienced D-TRAEs (treatment related adverse events), most (96%) were G1/2. Most common regimen TRAEs were nausea (72%), fatigue (64%), and diarrhoea (56%). 5 pts experienced ≥G3 D-TRAEs: hypophosphatemia (2), pulmonary embolism (2, one regimen related G5), neutropenia (1), diarrhoea (1).Table: 1213PORR mITT*, n=22 (n,%)Median DoR, mos (n=15)*Median PFS, mos, ITT (n=25)CRPRSDNEOverall15 (68)1 (5)14 (64)6 (27)1 (5)10.011.3DKK1 high, n=109 (90)-9 (90)-1 (10)10.611.6DKK1 low, n=95 (56)1 (11)4 (44)4 (44)-10.612.0DKK1 unk, n=31 (33)-1(33)2 (67)-7.08.4*4 responders ongoing (2 high, 2 low) Open table in a new tab *4 responders ongoing (2 high, 2 low) D/TS + CAPOX is a well-tolerated, active 1L combination, including in DKK1-high and CPS low patients, aggressive subpopulations of GEA. With only 36% of pts deceased as of the data cut, OS is not mature. Further study with DKN-01 plus standard of care therapy in IL GEA is warranted.

369P Irinotecan is superior to oxaliplatin in KRAS-G12C-mutated (K-G12C-m) colorectal cancer (CRC) and should be preferred in combination strategies with K-G12C inhibitors. A multicenter propensity score-matched (PSM) retrospective analysis

K-G12C inhibitors have recently become available, yet limited activity has been observed when used as monotherapy in CRC. Given their good safety profile, combination strategies with other targeted agents or chemotherapy (CT) are being considered to increase efficacy. A multicenter analysis was conducted to assess the efficacy of standard first-line CT in K-G12C-m metastatic CRC patients(pts). K-G12D-m pts were used as control group. Only pts treated with first-line FOLFIRI or FOLFOX +/- bevacizumab (bev) were included. Primary and secondary outcome measures were progression free survival (PFS) and objective response rate (ORR), respectively. Both an unmatched and a PSM analysis were conducted. 86 pts were included: 51 K-G12C-, 35 K-G12D-m. Median age was 63 yrs (range 34-83), 49 were male, 37 female. Liver mets were present in 71% of pts, 51% had 2 or more metastatic sites. FOLFIRI, FOLFIRI-bev, FOLFOX and FOLFOX-bev was the first-line for 15, 36, 10 and 25 pts, respectively. In K-G12C-m pts a statistically significant benefit in PFS was demonstrated for FOLFIRI+/-bev vs FOLFOX+/-bev: HR 0.52 (95%CI 0.28-0.98), p 0.04. The benefit was even more pronounced in the PSM analysis based on age, gender, receipt of bev, grading, KPS, metachronous vs synchronous mets, number of metastatic sites, presence of peritoneal mets: HR 0.24 (95%CI 0.08-0.71), p 0.01. No difference in ORR was seen: 48% vs 47%, p 0.87, respectively. Also median PFS was not numerically different: 11.7 vs 11.6 months, however 12-, 18-, 24-month PFS rates were 48%, 43%, 32% and 46%, 18%, 5% for FOLFIRI+/-bev and FOLFOX+/-bev, respectively. In the K-G12D-m group, no significant differences were observed between FOLFIRI+/-bev vs FOLFOX+/-bev for both PFS and ORR, p 0.09 and 0.45, respectively. Irinotecan (i.e. FOLFIRI+/-bev) was significantly superior to oxaliplatin (i.e. FOLFOX+/-bev) in K-G12C-m CRC pts, with a subset of pts (32%) achieving a long-lasting (> 2 yrs) PFS. Irinotecan should be the preferred chemotherapy to be used in combination strategies with K-G12C inhibitors.

P1735: IMPROVEMENTS IN PATIENT-REPORTED OUTCOMES IN MITAPIVAT-TREATED PATIENTS WITH PYRUVATE KINASE DEFICIENCY: A DESCRIPTIVE ANALYSIS FROM THE PHASE 3 ACTIVATE TRIAL

Background: Pyruvate kinase (PK) deficiency is a rare, inherited, non-spherocytic hemolytic anemia associated with acute and long-term complications, as well as a spectrum of signs and symptoms including jaundice, fatigue, and dyspnea. PK deficiency has a profound wide-ranging impact on health-related quality of life (HRQoL). Mitapivat (AG-348), a first-in-class, oral, allosteric activator of PK, was shown to improve hemoglobin (Hb), hemolysis, and hematopoiesis in a global, phase 3, randomized, placebo (PBO)-controlled trial evaluating mitapivat efficacy and safety in adults with PK deficiency who were not regularly transfused (ACTIVATE; NCT03548220). Furthermore, significant improvements in patient-reported outcomes (PROs) (measured by disease-specific PRO instruments: the PK deficiency diary [PKDD] and the PK deficiency impact assessment [PKDIA]) were demonstrated in patients (pts) receiving mitapivat compared with PBO. The PKDD is a self-administered, 7-item daily diary to assess the signs and symptoms of PK deficiency (including jaundice, tiredness, and shortness of breath), while the PKDIA is a 12-item weekly measure assessing the impacts of PK deficiency (pts rated the frequency of occurrence or difficulty of various activities). Aims: To describe PKDD and PKDIA outcomes for the subset of pts in the ACTIVATE trial who achieved the primary endpoint of Hb response, defined as a ≥1.5 g/dL increase in Hb from baseline (BL), sustained at ≥2 scheduled assessments at weeks (wks) 16, 20, and 24. Methods: Eighty pts were randomized 1:1 to receive mitapivat (5/20/50 mg twice daily) or PBO for 24 wks in the ACTIVATE trial. Change from BL to wk 24 in PKDD and PKDIA scores were prespecified secondary endpoints. For this post hoc analysis, changes from BL in PKDD weekly mean scores and PKDIA scores measured at scheduled visits (wks 4, 8, 12, 16, 20, and 24) were summarized for Hb responders, the overall mitapivat treatment arm, and PBO, using mean and 95% confidence intervals (CIs). For both the PKDD and the PKDIA, a lower score represents a lower disease burden. Results: In the ACTIVATE trial, 16/40 (40%) pts receiving mitapivat met the primary endpoint of Hb response compared with none for PBO (0/40; 0%). At wk 24, mean (95% CI) change from BL in PKDD weekly mean score was ‒7.12 (‒10.98, ‒3.27) for pts who achieved Hb response, ‒5.43 (‒7.47, ‒3.40) for the overall mitapivat treatment arm, and ‒1.86 (–4.04, 0.32) for the PBO arm (Figure 1a). At wk 24, mean (95% CI) change from BL in PKDIA score was ‒8.07 (‒11.05, ‒5.08) for pts who achieved Hb response, ‒4.82 (‒7.18, ‒2.46) for the overall mitapivat treatment arm, and ‒1.06 (‒3.70, 1.59) for the PBO arm (Figure 1b). Across both PRO instruments, improvements among mitapivat pts who achieved Hb response were sustained over time. Image:Summary/Conclusion: In the ACTIVATE trial, mitapivat-treated pts demonstrated significant improvements in signs, symptoms, and impacts based on PK deficiency-specific PRO instruments, compared with PBO. This analysis further reveals that improvements were greater in the subset of mitapivat-treated pts who achieved the primary endpoint. Together, these data indicate that mitapivat has the potential to improve HRQoL in pts with PK deficiency who are not regularly transfused.