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Introduction E1910 randomized pts with ALL aged 30-70 years who were measurable residual disease negative (MRD-) by multi-color flow cytometry (FC) after intensification to conventional chemotherapy (chemo) with or without blinatumomab (blina). The addition of blina resulted in improved overall survival (OS) (Litzow, NEJM 2024) and led to a new standard of care. Older ALL pts have inferior outcomes when compared to younger pts in part due to increased treatment toxicity. In E1910, exposure to dexamethasone and pegasparagase was reduced for older pts (age >55 years). We present results of subgroup analyses describing outcomes of older pts enrolled in E1910. Methods Details of the E1910 protocol remission induction (step 1), high dose methotrexate with pegaspargase intensification (step 2), blina randomization (step 3), and maintenance (step 4) or allogeneic hematopoietic stem cell transplant (HCT) were previously presented (Litzow, NEJM 2024). MRD status was determined after step 2 centrally with 6-color FC with MRD- defined as <0.01% in the bone marrow (BM). Following approval of blina in the US for MRD positive (MRD+) disease in 2018, MRD+ pts were assigned to the blina arm and no longer randomized. The primary objective was to compare the OS and relapse free survival (RFS) among older pts aged >55 years (pre-specified stratification factor) who received chemo + blina to that of pts who received chemo alone (step 3 treatment). Estimates of OS and RFS were calculated using the Kaplan-Meier method. Comparison of OS and RFS between treatment arms was conducted using the two-sided stratified log-rank test and Cox model with CD20 status, rituximab use, and whether pts intended to receive HCT or not as stratification factors. Stratified Multivariate Cox models of OS and RFS were used to further evaluate the effect of step 3 treatment, adjusted by gender, white blood cell count (WBC), platelets, hemoglobin, peripheral blood blasts, BM blasts, performance status and combined molecular risk category. Results Among the 488 enrolled pts, 211 were ≥55 years old with median age of 61 (range 55-70). Among older pts, 49.3% were female and 83.4% were white, 17 (8.1%) pts had WBC >30.000/uL at the time of diagnosis. 156 (73.9%) pts had CD10+ early B-ALL and 46 (21.8%) had CD10- B-ALL immunophenotype. The most common genetic subgroups were low hypodiploid (n=58, 27.5%), BCR::ABL1-like (n=34, 16.1%) and KMT2A rearranged (n=26, 12.3%). 8.1% of pts had low, 9.0% intermediate, 63.5% high combined molecular risk disease and in 19.4% of pts risk could not be assigned. Baseline characteristics were not significantly different in chemo + blina and chemo only pts. The median follow-up for this analysis from step 1 registration was 54.6 months. Complete response with (CR) or without (CRi) count recovery after induction was observed in 174 (82.5%) pts (167 CR, 7 CRi). 93 (44%) pts were MRD-. 32 (15.1%) pts received HCT on study and 24 (11.4%) pts received it off study. Among MRD- pts (n=93), 46 were randomized to and 45 received blina: 6 (13.3%) pts had 1, 14 (31.1%) had 2, 2 (4.4%) had 3 and 23 (51.1%) had 4 cycles. 3-year OS were 71% and 67% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.37-1.50; multivariate model: HR 0.56, 95% CI: 0.25-1.27). 3-year RFS were 69% and 59% for the blina and the chemo only arm (univariate model: HR 0.75, 95% CI: 0.39-1.45; multivariate model: HR 0.67, 95% CI: 0.32-1.42). Among MRD+ pts (n=25), 14 were randomized to and 11 received blina: 7 (63.6%) pts had 2, and 4 (36.4%) had 4 cycles. 3-year OS were 66% and 44% for the blina vs the chemo only arm (univariate model: HR 0.66, 95% CI: 0.12-3.64). 3-year RFS were 64% and 31% for the blina vs the chemo only arm (univariate model: HR 0.64, 95% CI: 0.15-2.74). Frequency of treatment-related toxicities among older pts during different study phases and treatment assignments will be presented. Conclusion Despite evidence of improved outcomes in the whole study cohort, the addition of blina to consolidation chemo for older pts with ALL was not associated with statistically significant improvement of OS or RFS in this exploratory analysis not powered to detect the difference in subgroups. This is possibly due to sample size but may be due to biologic differences in the older adult population. Further studies are needed to definitively determine tolerance and benefit of blina addition to consolidation for older pts with ALL.

Background: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe thrombotic thrombocytopenia that predominantly occurs after adenoviral vector-based vaccines. VITT patients produce anti-platelet factor 4 (PF4) antibodies with restricted clonality (i.e., mono/oligoclonal) with lambda light chains. Long-term follow-up studies in VITT show a disconnect in the persistence of anti-PF4 antibodies, whereby ELISA-positive antibodies persist significantly longer than platelet-activating antibodies. The mechanistic basis of this is unclear and could be explained by a couple of hypotheses: (1) Epitope spreading where, with time, the specificity of platelet-activating anti-PF4 antibodies may “spread” to recognize only PF4 complexed to heparin vs. (2) Persistence of clonally restricted platelet-activating anti-PF4 antibodies which decrease in titers with time such that their levels are insufficient to crosslink platelet FcGRIIa and induce platelet activation. Methods: Acute, convalescent patient sera and affinity-purified anti-PF4 antibodies were evaluated in antigen-based, functional (platelet-activation-based), and mass spectrometry studies as previously described (Blood, 2022 Jul 7;140(1):73-77). The median time to last follow-up was 243 days after the acute episode (range: 114-664 days). Results: Follow-up samples were obtained from 6 VITT patients after Ad26.COV2.S vaccination. At last follow-up, anti-PF4 IgG antibodies reactive in PF4/polyanion ELISA were detected in the sera of 5/6 VITT patients. However, only one of these samples stimulated platelet activation in the PF4-dependent P-selectin expression assay (PEA; 199 days after acute presentation). Affinity-purified anti-PF4 antibodies were detected by ELISA in all follow-up samples and three of the six affinity-purified anti-PF4 antibody samples activated platelets in the PEA. Four of the six VITT patients demonstrated a monoclonal anti-PF4 antibody, while one each had a biclonal and triclonal profile. Five VITT patients produced IgG lambda light chain antibodies, while one produced an IgG kappa. All six VITT patients demonstrated synonymous anti-PF4 antibody profiles when comparing acute and follow-up antibody repertoires, without evidence of VITT patients producing new anti-PF4 antibodies after the acute episode. In all cases, levels of anti-PF4 antibodies were significantly lower in convalescent samples relative to acute samples. Given this data on the persistence of clonally-restricted VITT antibodies, samples from another VITT patient with thrombocytopenia (100-150,000/uL) persisting for more than three years were similarly evaluated. This patient, who experienced severe thrombosis after ChAdOx1 nCoV19 vaccination, demonstrated persistent ELISA and PEA positivity even three years after symptom onset but had not experienced breakthrough thrombosis while on anticoagulation therapy. Serum protein electrophoresis (SPEP) did not detect a monoclonal gammopathy. Anti-PF4 antibodies immuno-enriched from a sample obtained >2 years after acute presentation demonstrated a monoclonal profile. While non-availability of an acute sample for anti-PF4 antibody characterization precluded a firm determination of whether this “Long VITT” case represented a subset of monoclonal gammopathy of thrombotic significance (MGTS; Blood 2023 Apr 6;141(14):1772-1776; New Eng J Med 2024 Aug 8), the chronicity of thrombocytopenia, presence of a monoclonal anti-PF4 antibody and persistently positive anti-PF4 serology supports this diagnosis. Conclusions. Clonally-restricted VITT antibodies persist for months-years with no evidence for the production of novel anti-PF4 antibodies after the acute event. Decreased abundance of anti-PF4 antibodies leads to negative functional results with follow up samples. Some platelet-activating antibodies can persist for very long periods (>3 years) and mediate persistent thrombocytopenia, representing an SPEP-negative MGTS-like state. This study also demonstrates the first example of a VITT antibody with a kappa light chain. The requirement for anticoagulation in patients demonstrating ELISA-positive/functional test-negative results is not clear, but the persistence of mono/oligoclonal anti-PF4 antibodies raises the possibility for the upregulation of pathogenic antibody production in proinflammatory settings.

Introduction Patients (pts) with relapsed/refractory (R/R) follicular lymphoma (FL) experience progressively worse outcomes with each successive line of therapy; complete response (CR) rates are 44% with third-line (3L), 27% with 4L, and 22% with 5L+ therapies (Ghione P et al. Haematologica 2023). CR duration is particularly important considering the rapid disease progression observed with 3L+ therapies in pts with FL, with especially poor outcomes in those with high-risk features (Liu J et al. Front Oncol 2023; Philips T et al. ASH 2023). In ELM-2 (NCT03888105), odronextamab (an investigational CD20×CD3 bispecific antibody) demonstrated deep and durable responses and generally manageable safety in pts with R/R FL who had received ≥2 prior lines of systemic therapy. Median progression-free survival (PFS) and overall survival (OS) in pts with CR were 28 months (95% CI 23.0-not evaluable [NE]) and not reached (95% CI 40.4-NE), respectively. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 86% of pts (Taszner M et al. EHA 2024). For the current analysis, we present details on the efficacy and safety of 3L+ odronextamab treatment in pts with R/R FL who attained CR in ELM-2, including those with high-risk features. Methods ELM-2 is an ongoing, open-label, multicenter, Phase 2 trial of odronextamab in pts with R/R B-cell non-Hodgkin lymphoma, including a cohort with FL Grade 1-3a. Intravenous odronextamab was administered in step-up doses with steroid prophylaxis during Cycle (C) 1, followed by 80 mg on Days 1, 8, and 15 of C2-4. After C4, dosing continued at 160 mg once every 2 weeks (Q2W); pts switched to Q4W dosing if they had a durable CR for ≥9 months. The primary endpoint was objective response rate (ORR) according to Lugano classification, by independent central review (ICR). Secondary endpoints included CR rate, PFS, OS, duration of response, and safety. Results Primary results in pts evaluable for efficacy and safety (N=128) using the Oct 20, 2023, data cutoff have been reported. Median duration of efficacy follow-up was 20.1 months (95% CI 17.3-27.8). The ORR was 80.5% (103/128 pts; 95% CI 72.5-86.9), and CR rate was 73.4% (94/128; 95% CI 64.9-80.9). Median duration of CR (DOCR) was 25.1 months (95% CI 20.5-NE), and median time to CR was 2.7 months (range 2.3-7.9). Baseline characteristics of pts with CR (n=94) were similar to those of the overall population, and median duration of treatment exposure was 13.8 months (range 1.8-45.0). In total, 88 pts (93.6%) had CR at the first response assessment (~Week 12) and 6 (6.4%) reached CR later, including 3 pts who had stable disease initially. Twenty-eight pts (29.8%) were still receiving treatment at data cutoff, and 66 (70.2%) had discontinued treatment. Of those who discontinued, 42 still had CR at the last response assessment. Primary reasons for treatment discontinuation were disease progression (n=17), TEAEs (n=16 [including 6 pts with COVID-19]), physician decision (n=12), withdrawal by subject (n=11), and death (n=8). All 8 deaths resulted from TEAEs, including COVID-19 in 5 pts. Eighty-five pts (90.4%) with CR had high-risk features (POD24, 48.9%; FLIPI score 3-5, 55.3%; refractory to last treatment, 70.2%); median DOCR and median time to CR in these pts were similar to those in all pts (23.7 months [95% CI 18.2-NE] and 2.7 months [range 2.3-7.9], respectively). At the time of the current analysis, 44 pts with CR by ICR (46.8%) had switched to Q4W dosing, with a median duration of exposure of 17.7 months (range 13.1-45.0). Among these pts, 22 had discontinued treatment at data cutoff due to adverse events (n=7 [including 1 with COVID-19]), physician decision (n=6), death (n=3), withdrawal by subject (n=3), progressive disease (n=2), and an “other” reason (n=1). Conclusions Pts with R/R FL and CR to 3L+ odronextamab treatment in ELM-2 had a median DOCR of 25.1 months that was prolonged beyond the median duration of treatment exposure (13.8 months). Almost half (46.8%) of pts proceeded to monthly odronextamab administration, with a median duration of treatment exposure of 17.7 months. These data show the sustainability of CR in pts with FL treated with 3L+ odronextamab, including in those with high-risk features. The safety profile of odronextamab was generally manageable in the overall population, including in pts with CR, despite their prolonged drug exposure. These findings support the potential of odronextamab as a treatment for R/R FL.

Introduction: Based on a donor versus no-donor analysis, UKALLXII/E2993 showed a survival benefit for adults with acute lymphoblastic leukemia (ALL) who underwent allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR1) compared to consolidation/maintenance chemotherapy alone. The follow-up phase 3 E1910 trial (NCT02003222) randomized BCR::ABL1-negative B-lineage ALL patients (pts) aged 30-70 years in measurable residual disease (MRD)-negative CR1 after intensification to conventional chemotherapy (CC) +/- blinatumomab (blin) and demonstrated significantly improved overall survival (OS) with blin (Litzow, NEJM 2024). The current exploratory subgroup analysis evaluates outcomes of MRD-negative pts randomized on E1910 who underwent alloHCT on trial. Methods: Among pts enrolled on E1910, pts in MRD-negative CR1 by 6-color flow cytometry after intensification who were randomized to CC +/- blin and subsequently underwent alloHCT were identified. We compared baseline characteristics, MRD status post induction, relapse-free survival (RFS) and OS using the Kaplan-Meier method and the two-sided log-rank test and Cox model. A multivariable analysis was performed with alloHCT included as a time-varying covariate as well as a landmark analysis comparing the outcome of pts with unfavorable risk on the CC + blin arm who underwent alloHCT versus those who did not. Results: Of 224 MRD-negative randomized pts, 44 underwent alloHCT on trial: 22 in each arm. The median time from randomization to transplant was 3.2 months (mos). The median follow-up from initial registration was 57.8 mos. Baseline demographics including age (median 55 years), gender (53% male), race (89% white) and ethnicity (89% non-Hispanic/Latino) were equally distributed. Compared to CC + blin, the median peripheral blood white cell (WBC) count and blast percentage at diagnosis were higher in the CC arm at 6,640 vs 3,740/uL and 55 vs 9%, respectively, while median marrow blast percentage and overall unfavorable risk as defined in E1910 (55% vs 64%) were similar. Of the 44 MRD-negative pts who proceeded to alloHCT on study, 77% in the CC arm and 64% in the CC+ blin arm were MRD-negative after induction. Myeloablative conditioning was given to the majority of pts (68% CC arm and 73% CC+blin arm) and the most common graft versus host disease prophylaxis was tacrolimus-based on both arms. Among the 44 pts who underwent alloHCT, the observed hazard ratio (HR) comparing relative risk of death between pts randomized to CC+blin or CC only was 0.59 (95% CI: 0.12-2.11) with a 3-year OS rate of 82% versus 71% and the HR comparing relative risk of relapse/death was 0.52 (CI: 0.15-1.79) with a 3-year RFS rate of 82% versus 67%. For patients with unfavorable risk, 3-year OS and 3-year RFS in each treatment arm were both 71% versus 65%. Among 50 pts with unfavorable risk in MRD-negative CR after intensification who were randomized to CC + blin, a landmark analysis performed at 5 mos post randomization showed 3-year OS and RFS rates of 71% versus 90% and 71% versus 86% between the 14 pts who underwent alloHCT and those who did not, respectively. Receipt of alloHCT was a time-varying covariate in a multivariable analysis with gender, WBC count, platelets, hemoglobin, peripheral blood blasts, bone marrow blasts, performance status, and combined molecular risk category. Age, CD20 status, rituximab use, and intention to receive alloHCT were used as stratification factors. In the entire cohort of MRD-negative pts who were randomized, there was a significant association between improved OS and the receipt of CC+blin vs CC alone (HR 0.46, 95% CI: 0.26 - 0.82; p=0.009), better performance status of 0-1 vs ≥2 and favorable vs unfavorable risk ALL. In contrast, the receipt of alloHCT had no significant effect on OS (HR 1.00, 95% CI: 0.49 - 2.01). Conclusions: Within the constraints of small numbers, this exploratory subgroup analysis demonstrates that in pts with newly diagnosed BCR::ABL1-negative B-ALL treated on E1910 who achieved MRD-negativity after intensification, alloHCT outcomes did not appear to be different with or without blin in consolidation. In a multivariate analysis of all MRD-negative pts, receipt of blin but not alloHCT was associated with improved OS. Further investigation is warranted to characterize the relative benefit of blinatumomab in pts receiving alloHCT in frontline consolidation.

Introduction: Response assessment is used to evaluate effectiveness of hypomethylating agent (HMA)-based therapy in myelodysplastic syndromes/neoplasms (MDS) in clinical practice and trials. Recently, the clinical response criteria (IWG 2023) and the clinical-molecular risk assessment (IPSS-M) in MDS were published. However, it remains unknown whether the IWG 2023 response criteria have an independent impact on overall survival (OS) when adjusting for baseline IPSS-M risk. Additionally, the association of IWG 2023 response criteria with OS in patients (pts) undergoing allogeneic stem cell transplantation (allo-HCT) versus those who do not is unknown. Lastly, it is unclear if optimal time-to-transplant impacts OS in MDS pts who achieve a IWG 2023 defined remission with HMA therapy. We examined these questions in a large population of MDS pts within the multi-institutional international consortium for MDS (icMDS) VALIDATE database. Methods: High-risk MDS pts with IPSS ≥1.5 or IPSS-R >3.5 treated with HMA-based therapy were included in the study. Baseline IPSS-M risk was stratified into very low/low/moderate low (VL+L+ML), moderate-high/high (MH+H), and very high (VH). Response to treatment was evaluated using the IWG 2023 criteria and grouped into: composite complete response (cCR) and no cCR. cCR included: complete response (CR), CR equivalent (CRequ), CR bilineage (CRbi), CR unilineage (CRuni), and CR with partial hematologic recovery (CRh). We analyzed the differential impact of achieving cCR on HMA-based therapy prior to transplant on OS in pts who either did or did not undergo allo-HCT, while adjusting for their baseline IPSS-M risk in Cox regression analysis. Optimal time-to-transplant was determined based on age and IPSS-M category as described by Tentori et al. (JCO 2024). Pts proceeding to allo-HCT were stratified on whether they underwent transplant within the optimal time-to-transplant timeframe after MDS diagnosis or not. VALIDATE protocol was exempted, acknowledged, or approved by all centers' IRBs. VALIDATE is supported by an independent grant from AbbVie. Results: We analyzed 762 MDS pts. The median age at MDS diagnosis was 68 years (range: 19-95 years) and 64% of pts were male. Distribution of the baseline IPSS-M risk was: VL+L+ML in 110 (14%) pts, MH+H in 347 (46%) pts, VH in 305 (40%) pts. Pts received azacitidine monotherapy, decitabine monotherapy, and HMA-based combination therapy (e.g. HMA + venetoclax) in 52%, 21%, and 28% of cases, respectively. A total of 282/762 (37%) pts achieved cCR as their best response to HMA-based therapy. The median OS for all pts was 18.7 months (95% CI: 16.6-21.3 months). Pts who did not undergo allo-HCT (n=436, 57%) had an improved median OS if they achieved cCR when compared to pts in the no cCR group in all IPSS-M risk groups (VL+L+ML: 23.5 months vs. 10.7 months; MH+H: 20.8 months vs. 11.6 months; VH: 13.8 months vs. 7.5 months). Cox analysis demonstrated an independent effect of cCR on OS in these pts when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 0.60, 95% CI 0.48-0.76, p<0.001). In contrast, in pts who subsequently received an allo-HCT (n=326, 43%), achieving cCR with HMA prior to allo-HCT did not provide an additional OS benefit, when adjusted for baseline IPSS-M risk (cCR vs. no cCR: HR 1.00, 95% CI 0.73-1.38, p=0.986). The median time-to-transplant was 6.7 months and 34% of transplanted MDS pts received their allo-HCT during the optimal timeframe. Among pts who achieved cCR with HMA-based therapy prior to allo-HCT, optimal time-to-transplant was associated with significantly improved OS (optimal vs. non-optimal timing: HR 0.55; p=0.033). Conclusion: Baseline IPSS-M risk and allo-HCT had an independent impact on OS, while IWG 2023 defined cCR had an independent effect on OS only in non-transplanted MDS pts. While this retrospective analysis occurred at large academic centers with specific expertise in the management of MDS, our data may have an impact on clinical practice: (i) failure to achieve cCR on HMA therapy prior to transplant should not impact the decision to proceed to allo-HCT, (ii) upfront allo-HCT without prior HMA therapy might also be an option if the clinical situation and availability of donors allow, and (iii) allo-HCT should ideally be performed during the timeframe that is considered optimal as defined by pt age and baseline IPSS-M.

Background: Randomized studies in newly diagnosed (ND) AML patients with a FLT3 mutation show that adding 14 days of a FLT3 inhibitor to each intensive chemotherapy cycle improves overall survival. For patients unsuitable for intensive chemotherapy due to older age or comorbidities, the presence of a FLT3-ITD mutation is associated with high rates of early relapse and short remission duration. There is a limited survival benefit of venetoclax (ven) plus azacitidine (aza) compared to aza alone among patients with AML with a FLT3-ITD mutation. Accordingly, there is significant interest in adding FLT3-targeted therapy to lower intensity chemotherapy for patients with ND AML and FLT3 mutations, but to date no randomized data have demonstrated a survival benefit for this approach.Gilteritinib (gilt) is a highly potent and FLT3-selective oral tyrosine kinase inhibitor that is the standard therapy of relapsed/refractory FLT3-mutated AML, based upon superior survival in randomized studies. Gilt can also be combined safely with ven and/or aza, though myelosuppression remains a concern. Despite this, single institution studies of ven, aza, and gilt therapy of ND AML patients with FLT3-mutations show that this three-drug regimen is associated with near-universal complete remission rates (CR 90%, CRi 6%) and a majority of studied patients eliminate detectable FLT3-ITD (<1 x10-5) within four cycles by an ultrasensitive, amplicon-based NGS assay (Short, et al. JCO 2024). Rates of CR with full count recovery and survival appear superior to historical comparisons, but myelosuppression is potentially increased with the triplet regimen. These data demonstrate a need for multi-institutional comparative trials, not only to determine whether adding FLT3-inhibitors to ven and aza improve deep remission rates, but also to refine schedules of the triplet combination that improve tolerability for widespread use.Methods: This tier 1 MyeloMATCH substudy is an open-label, randomized phase 2 trial that will enroll ND AML patients older than age 60 or individuals judged by their treating physician to be best served by azanucleoside + ven-based therapy due to comorbidity. Subjects provide samples to the central MyeloMATCH Master Screening and Reassessment Protocol (MSRP, NCT05564390 ) and are assigned to the MM1OA-EA02 substudy (NCT06317649) based upon the presence of a FLT3-ITD or FLT3-TKD (D835) mutation by NGS. Subjects are randomized to one of three arms (regimens 1, 2, or 3), stratified by age (<70 years vs. older) and FLT3-ITD burden (ITD VAF>33% vs. lower VAF or D835). All study arms contain aza and ven administered in 28-day cycles with two study arms also including gilt. Regimen 1 is ven and aza administered as per the pivotal VIALE-A study. Regimen 2 adds gilt 80 mg once daily on days 1-28 and regimen 3 adds gilt on days 8-21 only. A marrow biopsy is performed during the first cycle (day 14-21, depending on study arm) and all chemotherapy is held until count recovery if a morphologic leukemia-free state or aplasia is seen. Patients receive up to two induction cycles to achieve remission and then receive ongoing consolidation cycles of therapy with a similar pattern of gilt administration up to 2 years. To minimize risk of cumulative myelosuppression, during consolidation azacitidine administration is reduced to days 1-5 on regimens 2 and 3 and ven limited to days 1-7 on regimen 2 and days 1-14 on regimen 3. For all arms, treatment-related adverse events prompt further reduction in ven, aza, or gilt dose or duration. Response will be measured after cycles 2 and 4, including centrally-performed MRD by flow cytometry. The primary endpoint is the rate of MRD(-) CR (<1 x 10-3) after up to 4 cycles. Key secondary endpoints include safety data, response rate, EFS, and OS. The study is powered to detect a 25% absolute improvement in MRD(-) CR rate in either triplet arm from a target accrual of 147 patients. A safety run-in for regimens 2 and 3 to confirm tolerability and feasibility will be performed after 20 subjects enroll to these arms; an interim futility analysis will be performed once response assessment of 50% of all planned accrual occurs. Study was activated on June 6, 2024 and is expected to continue until December 2025.

Introduction: Inotuzumab ozogamicin (INO) is an antibody targeting CD22 conjugated with a cytotoxic antitumor antibiotic (calicheamicin) approved for treatment of relapsed/refractory CD22 positive B-cell acute lymphoblastic leukemia (ALL) (Kantarjian et al. NEJM 2017). CD22 is expressed on the surface of lymphoblasts in ALL (~95%). Young adult patients (pts) 18-39 years (yrs) treated on the pediatric regimen CALGB 10403 resulted in a 3-yr event-free survival (EFS) of 59% (95% CI: 52-67%) and an estimated 3-yr overall survival (OS) of 73% (95% CI: 68-78%) (Stock et al. Blood 2019). Alliance A041501(NCT03150693), a phase 3 NCTN sponsored cooperative group trial was conducted to determine if the addition of INO to the CALGB 10403 pediatric regimen would significantly improve EFS. Methods: Eligibility included pts 18-39 years with newly diagnosed CD22 positive ALL, defined as baseline expression in > 20% of lymphoblasts by local institution. Pts with Burkitt-type ALL, BCR::ABL1 positive ALL, or Down syndrome were excluded. Eligible pts received the CALGB 10403 regimen modified to omit extended induction, include dexamethasone as opposed to prednisone as steroid backbone, cap the pegaspargase dose to 3750 units, and adding rituximab for pts with CD20 expression (> 20%). An amendment added blinatumomab for minimal residual disease (MRD) positivity. Pts achieving a complete remission (CR/CRi) or partial remission (PR) were eligible for randomization. Following a 6 pt safety run-in with INO, pts were randomized 1:1 to receive INO or continue CALGB 10403 backbone. Two cycles of INO (1.5 mg/m2/cycle) were administered following induction in the experimental arm. Pts were stratified by age, disease status post induction (M0/M1 vs M2), CD20 status, and LDA Card, which tests for the Ph-like status. The primary endpoint was to determine if the addition of INO would improve the EFS of the pediatric regimen CALGB 10403 without censoring for stem cell transplant (SCT). Key secondary endpoints included the impact of INO on disease-free survival (DFS), OS, and MRD. The Alliance Data and Safety Monitoring Board halted enrollment after 273 out of a planned 341 pts were registered because of increased grade (gr) 5 events in the INO arm compared with the control arm. Results: 273 pts were enrolled between 6/15/2018, and 5/24/2022. Median age was 27.0 yrs, 65.2% were White, 30.4% were Hispanic, and 63.4% were male. Baseline CSF analysis revealed 14% with CNS-2/3 disease. The overall CR rate was 86.8% (82.8-90.8%). 46 pts were not randomized due to death (5), withdrawal (6), ineligibility (3), toxicity (5), receipt of non-protocol therapy (8), progression (5), and other (14). 227 eligible pts were randomized 1:1 to receive INO (N=111) or not (N=116)). For randomized pts, 92.5% achieved M0/M1 marrow status, 48.9% had a positive LDA Card defining Ph-like ALL, 50.7% were CD20 positive. Only 36 pts (13%) received a SCT. With a median follow up of 28.3 months for randomized pts, 3-yr EFS was 69.0% (59.1-80.5%) for the INO arm and 66.7% (57.1-78.1%) for the control (HR=0.97; 0.58-1.63). Similarly, the 3-yr OS was 79.4% (71.0-88.7%) for the INO arm and 80.3% (71.9-89.6%) for the control (HR=1.05; 0.55-2.01). The MRD undetectable rate at Course II Day 56 was 80.6% in the INO arm and 74.2% in the control arm. Univariate analysis suggests improved EFS with INO in pts with a positive LDA card (Ph-like ALL) and of Hispanic ethnicity. There were 22 gr 5 events, 7 occurred prior to randomization. Of the 15 gr 5 events on the randomized cohort, 12 were reported in the INO arm and 3 in the control arm. Of the 12 gr 5 events in the INO arm, all occurred during intensive consolidation courses complicated by prolonged pancytopenia infection/sepsis (8), hepato-biliary in setting of infection (2), multi-organ failure (1), or post-surgical complication (1). These events occurred after INO during Course II (3), Course III (5), or Course IV (4). Conclusions: Although this trial did not meet the primary EFS endpoint for the addition of INO to the pediatric regimen CALGB 10403, these data provide compelling evidence for continued use of pediatric regimens in young adults with ALL as the EFS and OS compares favorably with prior published results. INO may still be efficacious if late toxicity can be mitigated. A pilot study is planned that will decrease INO dose, add 2 cycles of blinatumomab and strict infectious prophylaxis guidelines. Support: U10CA180821, U10CA180882

Importance Vaginal fibroblast function is altered in people with pelvic organ prolapse. Thus, it is important to study vaginal fibroblasts to better understand the pathophysiology of prolapse. Objective This study aimed to compare 3 culturing methods of primary vaginal fibroblasts. Study Design This was an in vitro study. Patients who were undergoing surgery for vaginal prolapse were recruited. Excess vaginal epithelial tissue that would have otherwise been discarded was collected. The vaginal fibroblasts from each participant were cultured via (1) 3-hour digest, (2) coverslip, and (3) gelatin-coat methods. Differences in the efficiency of cell isolation, expression of known fibroblast-associated genes, and cellular function were compared between the 3 methods using one-way analysis of variance and Tukey test for post hoc pairwise comparisons ( P < 0.05). Results Five patients with pelvic organ prolapse were recruited. Fibroblasts cultured via the 3-hour digest method became confluent within 3–5 days in a 100-mm dish compared to 2–3 weeks in a 6-well dish for the coverslip and gelatin-coat methods. Cells from all culture methods expressed similar amounts of vimentin and α smooth muscle actin. There were no significant differences in morphology; gene expression levels of MMP1 , MMP2 , ACTA2 , COL1A1 , COL3A1 , and LOXL1 on qPCR; cell viability; proliferation; and migration between the 3 culturing methods. Conclusion Culturing primary vaginal fibroblasts via the 3-hour digest, coverslip, and gelatin-coat methods similarly resulted in reliable primary vaginal fibroblast growth and function.

Objective To define the natural history, patterns of recurrence and treatment modalities for local prostate cancer (PCa) recurrence following radical prostatectomy (RP) and radiation therapy (RT), and to investigate factors that could predict metastasis‐free survival (MFS) in this unique patient population. Methods We queried a prospectively maintained PCa registry to identify men developing in‐field recurrence (IFR) following RP and RT from 2008 to 2021 at a single institution. IFR was defined as biopsy‐proven recurrent PCa or the presence of persistent positron emission tomography‐avid lesions in the prior radiation field without evidence of metastasis. Cox regression was conducted to determine predictors of MFS. Kaplan–Meier methods were used to calculate MFS, cancer‐specific survival (CSS) and overall survival (OS) for patients in three primary therapy categories: cryoablation, androgen deprivation therapy (ADT) alone, and surveillance. Results Of 4575 patients from our registry, 108 (2.3%) with IFR were identified. The median (interquartile range [IQR]) time to IFR from salvage treatment was 78 (50–126) months. A total of 29 patients (26%) were managed with cryoablation, 23 (21%) with ADT, and 28 (25%) with surveillance. The median (IQR) follow‐up was 76 (48–100) months. There were no statistically significant differences in MFS ( P = 0.67) or OS ( P = 0.07) among the three primary treatment cohorts. Patients treated with ADT or cryoablation had longer CSS compared to patients managed with surveillance ( P = 0.047). Conclusions We found that IFR may present years after completion of primary treatment for PCa. While curative management strategies may be attempted, local and distant metastatic recurrence is common and often requires systemic therapy.