Prior Relapse Research Articles

Assessing the impact of aprepitant on response to dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP).

Despite evidence demonstrating the effectiveness of aprepitant for chemotherapy-induced nausea and vomiting (CINV), its use in stem cell transplant settings across Canada is not standard. While pharmacokinetic data exists, the clinical significance of cytochrome P450 3A4 (CYP 3A4) inhibition of cyclophosphamide by aprepitant is unclear. Reduced activation of cyclophosphamide may reduce the effectiveness of dose-intensive cyclophosphamide, etoposide, and cisplatin (DICEP). To compare response rates to DICEP in patients with Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) in the presence and absence of aprepitant. A retrospective review of patients who received full-dose DICEP for relapsed/refractory HL or DLBCL between June 1995 and September 2018 at the Foothills Medical Centre (FMC) in Calgary, Alberta, Canada was conducted. Descriptive statistics were used to assess response rate, as defined by the 2007 International Working Group response criteria. Of the 218 patients included in this study, 87.6% of patients in the control group and 88.5% of patients in the aprepitant group responded to DICEP (difference 0.025 [95% CI, -0.066 to 0.114], p = 0.827). Univariate analyses for age, sex, type of cancer, stage of cancer, number of prior relapses, and relapse status were not significant. No significant differences were observed for secondary outcomes. Response rates to DICEP in relapsed/refractory HL and DLBCL patients were similar regardless of aprepitant use. Considering these results and the effectiveness of aprepitant in CINV, its addition to standard antiemetic therapy in patients receiving DICEP should be given strong consideration in the transplant setting.

Comparing ocrelizumab to interferon/glatiramer acetate in people with multiple sclerosis over age 60

BackgroundOngoing controversy exists regarding optimal management of disease modifying therapy (DMT) in older people with multiple sclerosis (pwMS). There is concern that the lower relapse rate, combined with a higher...

Survival outcomes in patients with high-risk neuroblastoma (HRNB) in remission after relapsed or refractory treatment receiving eflornithine (DFMO) maintenance.

10060 Background: Five-year overall survival in newly diagnosed HRNB patients is around 50%, with relapse as the primary cause of mortality. While survival for newly diagnosed HRNB has improved with new treatment advances, relapsed or refractory (R/R) patients continue to have poor outcomes, with a high risk of subsequent relapse even among those who achieve remission, underscoring the need for treatments to improve EFS in this group. DFMO has been evaluated as a chemopreventative therapy in a single arm phase 2 study designed to compare Event Free Survival (EFS) and Overall Survival (OS) outcomes with published data for HRNB. The results of patients treated after standard therapy have been previously published. We now present an analysis of EFS/OS for patients with R/R disease, who historically have had a two-year EFS of approximately 10%. Methods: A total of 140 HRNB patients were enrolled, prospectively divided into two strata. S1 included patients in initial remission after upfront therapy, whereas S2 included patients who had either relapsed or had disease refractory to standard induction chemotherapy but achieved remission with additional therapy. Patients received 2 years of continuous treatment with oral DFMO 750 ±250 mg/m2 BID and were followed for up to 7 years. Results: A total of 35 patients withR/R disease who had achieved remission after additional therapy were enrolled onto S2, including 28 patients in remission after one or more prior relapses and 7 refractory patients in remission after subsequent therapies. Of the relapsed patients, 23 had one prior relapse, while 5 patients had two or more relapses prior to enrollment; only one previously relapsed patient had received chemoimmunotherapy prior to enrollment in the study. For the entireS2 cohort, two-year EFS was 46% (95% CI 29%, 61%) with the lower confidence interval above the 10% historical control estimate. Four-year EFS was 46% (95% CI 29%, 61%) and OS 62% (95% CI 44%, 76%), with no relapses occurring after 18 months. For patients enrolled with refractory disease only (n=7) the four-year EFS was 85.7%. In the 28 relapsed patients, the four-year EFS was 35.7%, with single relapse patients (n=23) having an EFS rate of 39.1% and multiple relapsed patients (n=5) 20.0%. Conclusions: Patients in remission after chemotherapy for relapsed or refractory HRNB and treated with DFMO had improved EFS compared to the best historical estimate available at the time of the study. Although the number of patients is too small to support clear conclusions, the subgroup of refractory patients had outcomes that trended better than the relapsed subgroup with an EFS rate that was unexpectedly similar to prior reports of DFMO-treated S1 patients in remission after standard upfront therapy. Clinical trial information: NCT02395666 , NCT00026312 .

Naxitamab chemo-immunotherapy regimens other than with irinotecan/temozolomide for patients with relapsed/refractory high-risk neuroblastoma.

10037 Background: Patients with relapsed/refractory (R/R) high-risk neuroblastoma (HR-NB) have dismal prognosis with chemotherapy-only salvage regimens. Naxitamab, a humanized anti-GD2 monoclonal antibody (mAb), when combined with Irinotecan and Temozolomide (I/T), has demonstrated clinically meaningful efficacy in R/R HR-NB patients (NCT03189706). We aimed to investigate the potential synergy of naxitamab with other cytotoxics. Methods: In this retrospective analysis, we examined patients treated at SJD with chemo-refractory disease, who received naxitamab in combination with chemotherapeutics other than I/T. Each cycle comprised naxitamab 2.25 mg/kg/day IV over 30 minutes, days 2, 4, 9 and 11 (total 9 mg/kg or 270 mg/m2 per cycle), and GM-CSF 250 mg/m2/day subcutaneously, days 6-10 combined with either a) cyclophosphamide (250mg/m2) and topotecan (0.75mg/m2) D1 to D5 (C/T), b) ifosfamide (1500mg/m2), etoposide (100mg/m2) D1-D3 and carboplatin (400mg/m2) D1 (ICE) or c) doxorubicin 37.5mg/m2 D1-D2 and cyclophosphamide (250mg/m2) D1-D3 (C/D). Toxicity was measured by CTCAE v4.0 and responses by INRC. Results: Twenty-nine patients received naxitamab plus GM-CSF with C/T (n=23), ICE (n=6) and C/D (n=1). One patient received both ICE and C/T. Seventeen patients had a variable number of prior relapses (1 n=14, 2 n=1, and 3 n=2). Twelve patients had refractory disease, most having received additional therapy post-induction. All but 4 patients had received naxitamab and I/T (n=20), and/or ICE (n=3/n=1), and dinutuximab-beta and I/T (n=1). Toxicities of the new regimens included myelosuppression expected with chemotherapy, and pain and hypertension expected with naxitamab. Hemorrhagic cystitis occurred in 2 patients treated with C/T, BK infection documented in one. A total of 113 cycles (median 2; 1-8) were administered, outpatient. Out of the 30 treatments, 5 achieved complete response (CR), 2 partial response (PR), and 2 mixed response (MR), providing an objective response (OR) of 30%. Eight patients achieved stable disease (SD) and 13 progressed on treatment. Disease control rate (DCR) (OR or SD) after 2 cycles was 56.6%. Patients who never responded with prior chemo-immunotherapy progressed through the new combinations. Contrary, patients who showed initial stabilization with I/T or ICE but ultimately progressed, switching drugs resulted in 60% DCR and 30% OR. Most favourable OR (75%) was seen in patients who achieved CR with prior chemoimmunotherapy and relapsed (3 out of 4). Conclusions: Naxitamab-based chemo-immunotherapy with regimens other than I/T exhibited similar and manageable toxicity profiles. Switching chemotherapeutics provided objective responses only to patients who had previously shown efficacy with I/T chemo-immunotherapy.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p=.79; HR=0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18months. Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.

Limited utility of adding 3T cervical spinal cord MRI to monitor disease activity in multiple sclerosis

Background: Performing routine brain magnetic resonance imaging (MRI) is widely accepted as the standard of care for disease monitoring in multiple sclerosis (MS), but the utility of performing routine spinal cord (SC) MRI for this purpose is still debatable. Objective: This study aimed to measure the frequency of new isolated cervical spinal cord lesions (CSLs) in people with MS (pwMS) undergoing routine brain and cervical SC-MRI for disease monitoring and determine the factors associated with the development of new CSLs and their prognostic value. Methods: We retrospectively identified 1576 pwMS who underwent follow-up 3T brain and cervical SC-MRI over a 9-month period. MRI was reviewed for the presence of new brain lesions (BLs) and CSLs. Clinical records were reviewed for interval relapses between sequential scans and subsequent clinical relapse and disability worsening after the follow-up MRI. Results: In 1285 pwMS (median interval: 13–14 months) who were clinically stable with respect to relapses, 73 (5.7%) had new CSLs, of which 49 (3.8%) had concomitant new BLs and 24 (1.9%) had new isolated CSLs only. New asymptomatic CSLs were associated with ⩾ 3 prior relapses (p = 0.04), no disease-modifying therapy (DMT) use (p = 0.048), and ⩾ 3 new BLs (p < 0.001); ⩾ 3 new BLs (OR: 7.11, 95% CI: 4.3–11.7, p < 0.001) remained independently associated with new CSLs on multivariable analysis. Having new asymptomatic CSLs was not independently associated with subsequent relapse or disability worsening after the follow-up MRI (median follow-up time of 26 months). Conclusion: Routine brain and cervical SC-MRI detected new isolated CSLs in only < 2% of clinically stable pwMS. Developing new asymptomatic CSLs was associated with concomitant new BLs and did not confer an independent increased risk of relapse or disability worsening. Performing SC-MRI may not be warranted for routine monitoring in most pwMS, and performing only brain MRI may be sufficient to capture the vast majority of clinically silent disease activity.

A genome-wide association study on hematopoietic stem cell transplantation reveals novel genomic loci associated with transplant outcomes.

Data on genomic susceptibility for adverse outcomes after hematopoietic stem cell transplantation (HSCT) for recipients are scarce. We performed a genome wide association study (GWAS) to identify genes associated with survival/mortality, relapse, and severe graft-versus-host disease (sGvHD), fitting proportional hazard and subdistributional models to data of n=1,392 recipients of European ancestry from three centres. The single nucleotide polymorphism (SNP) rs17154454, intronic to the neuronal growth guidant semaphorin 3C gene (SEMA3C), was genome-wide significantly associated with event-free survival (p=7.0x10-8) and sGvHD (p=7.5x10-8). Further associations were detected for SNPs in the Paxillin gene (PXN) with death without prior relapse or sGvHD, as well as for SNPs of the Plasmacytoma Variant Translocation 1 gene (PVT1, a long non-coding RNA gene), the Melanocortin 5 Receptor (MC5R) gene and the WW Domain Containing Oxidoreductase gene (WWOX), all associated with the occurrence of sGvHD. Functional considerations support the observed associations. Thus, new genes were identified, potentially influencing the outcome of HSCT.

Phase 1 trial of TPI 287, a microtubule stabilizing agent, in combination with bevacizumab in adults with recurrent glioblastoma.

Recurrent glioblastoma (rGBM) has limited treatment options. This phase 1 protocol was designed to study the safety and preliminary efficacy of TPI 287, a central nervous system penetrant microtubule stabilizer, in combination with bevacizumab (BEV) for the treatment of rGBM. GBM patients with up to 2 prior relapses without prior exposure to anti-angiogenic therapy were eligible. A standard 3 + 3 design was utilized to determine the maximum tolerated dose (MTD) of TPI 287. Cohorts received TPI 287 at 140-220mg/m2 every 3 weeks and BEV 10mg/kg every 2 weeks during 6-week cycles. An MRI was performed after each cycle, and treatment continued until progression as determined via response assessment in neuro-oncology criteria. Twenty-four patients were enrolled at 6 centers. Treatment was generally well tolerated. Fatigue, myelosuppression, and peripheral neuropathy were the most common treatment emergent adverse events. Dose-limiting toxicity was not observed, thus the MTD was not determined. Twenty-three patients were evaluable for median and 6-month progression-free survival, which were 5.5 months (mo) and 40%, respectively. Median and 12-month overall survival were 13.4 mo and 64%, respectively. The optimal phase 2 dose was determined to be 200mg/m2. TPI 287 can be safely combined with BEV for the treatment of rGBM and preliminary efficacy supports further investigation of this combination.

A Phase 2 Trial of SCRI-CAR19 Demonstrates Favorable Leukemia-Free Survival (LFS), with a Pilot Study of CD19-Expressing T-Cell Antigen Presenting Cells (CD19t T-APCs) Demonstrating Safety and Tolerability

The value of CD19 directed CAR T cell therapy for relapsed, refractory B-ALL has been well established. Iterative and complementary clinical trials have identified subgroups with improved outcomes, including those with low disease burden at the time of treatment as well as those with prolonged CAR T cell in vivo persistence. PLAT-02 was a phase 1/2 study of SCRI-CAR19, a 2 nd generation murine CAR with 41BB co-stimulation. Phase 1 previously reported 1 year LFS, event-free (EFS) and overall survival (OS) of 55%, 51.2%, and 69.5%. Subjects with low CD19 antigen burden in the bone marrow (&amp;lt;15%) prior to lymphodepletion (LD) and those with a rapid contraction of CAR T cells between Day 10 and 14 (ratio ≥1.5) were at higher risk of early loss of persistence. Phase 2 of PLAT-02 was a multisite trial along with a single site pilot study, PLAT-03, to explore administration of exogenous CD19 antigen designed to boost CAR T cell engraftment in subjects at high risk of early loss of persistence. PLAT-02 (NCT02028455) enrolled subjects 1-26 years of age with relapsed, refractory CD19+ B-ALL. The primary efficacy cohort was defined as those who received fludarabine/cyclophosphamide (flu/cy) LD and were infused with CAR19. PLAT-03 (NCT03186118) was a pilot study of CD19t T-APCs (manufactured T cells with CD19 tag) administered at doses of 10x10 6/kg or flat dosing of 5x10 8 for subjects &amp;gt;25kg every 4 weeks up to 6 total doses. Cohort A included subjects with low CD19 antigen burden, and cohort B included those with rapid early contraction of CAR19. 88 subjects with B-ALL were enrolled on PLAT-02 with plans for treatment at the recommended phase 2 dose (RP2D) of 1x10 6 CAR+ T cells/kg. Eighty-six percent had at least one prior relapse and 42% had undergone prior hematopoietic cell transplant (HCT). The feasibility of manufacturing was 98%. 71 subjects were in the primary efficacy cohort with an 89% minimal residual disease negative complete remission (MRDneg CR) rate. EFS and OS probability estimates with 95% CI at 1 year following CAR19 were 0.65 (0.53, 0.75) and 0.76 (0.64, 0.84). LFS at 1 year from entering MRDneg CR was 0.71 (0.58, 0.81). Cytokine release syndrome (CRS) was grade (Gr) 1 (53%), Gr 2 (26%), Gr 3 (10%), and Gr 4 (3%). Neurotoxicity occurred in 53%: Gr 1 (24%), Gr 2 (13%), Gr 3 (15%), and Gr 5 (1%). 25 subjects were treated on PLAT-03, 10 as cohort A (10 received CAR19 on PLAT-03, 9 received T-APCs), and 11 as cohort B (5 received CAR19 on PLAT-02, 6 received CAR19 on PLAT-03, and 9 total received T-APCs). One was cohort C (retreatment) and 3 were cohort D (no T-APCs). A total of 72 infusions of T-APCs were administered, with no occurrence of CRS or neurotoxicity. Two subjects had grade 3 toxicities related to T-APCs, 1 febrile neutropenia and 1 infusion related reaction. EFS and OS probability estimates at 1 year following CAR19 were 0.67 (0.43, 0.83) and 0.95 (0.71, 0.99). Overall LFS at 1 year was 0.63 (0.38, 0.80); by cohort: cohort A, 0.44 (0.13, 0.72) and cohort B, 0.80 (0.41, 0.95). Median duration of persistence, as determined by cumulative incidence using B cell aplasia (BCA) as a surrogate, among all subjects who received RP2D of CAR19 with flu/cy LD across PLAT-02 and PLAT-03, engrafted and achieved MRDneg CR, was 12.9 months (m). For subjects who did not receive T-APCs, the median persistence was 12.1m. Impact of antigen burden prior to LD was again observed; those with &amp;gt;15% CD19 antigen burden had persistence of &amp;gt;12.1m vs. 3.9m in the low antigen burden group. For subjects treated with T-APCs, the median persistence was 16m; 9.9m in cohort A and &amp;gt;16m in cohort B. The improvement in LFS after SCRI-CAR19 in phase 2 compared to phase 1 is likely multi-factorial, with contributing factors including earlier treatment, uniform use of LD, enhanced persistence, and better allocation of patients who benefit from consolidative HCT. The use of T-APCs was well tolerated without recurrent CAR T cell mediated toxicity. Although not directly comparable, there did appear to be enhancement of CAR T cell persistence with the use of T-APCs in populations predicted to have inferior persistence, including those with low antigen burden. There was not a clear improvement of LFS in those who received T-APCs. However, subjects were not randomized to receive T-APCs and those enrolled on PLAT-03 were more heavily treated and more likely to have received a prior HCT. Further exploration of T-APCs is warranted to define and evaluate their impact on persistence and durable responses.

Preconditioning Single High-Dose Palifermin Alters the Posttransplant Inflammatory Cytokine Profile

Palifermin is a truncated form of human recombinant keratinocyte growth factor (KGF) that binds to the FGF receptor 2b expressed in epithelia including that of the epidermis, oral and GI mucosa, and thymus. In animal models, the cytoprotective and regenerative effects of KGF showed efficacy in controlling acute and chronic graft-versus-host disease (A/C GVHD), but these were not demonstrated in subsequent clinical studies using the FDA-approved dosing schedule for oral mucositis prevention (60 µg/kg/day for 3 consecutive days). The current study aims to investigate alterations in immune cell reconstitution and cytokine expression among patients (n=31) participating in the ongoing prospective open-label phase 1/2 trial NCT02356159. This trial evaluates the incidence of severe CGVHD (primary objective of phase 2) following the addition of a single high dose of palifermin to GVHD prophylaxis with TMS (tacrolimus, methotrexate, sirolimus). Four different dose levels of palifermin (DL1: 180 µg/kg; DL2: 360 µg/kg; DL3: 540 µg/kg; DL4: 720 µg/kg) were tested on day −7 in the phase 1 part of the trial, with the recommended phase 2 dose being 720 µg/kg. All patients received cyclophosphamide (total 4.8 g/m 2) and fludarabine (total 120 mg/m 2) as conditioning on days −6 to −3 followed by infusion of an 8/8 HLA-matched unrelated donor peripheral blood cell graft on day 0. Results of correlative studies were compared with patients of the identical TMS treatment arm of the NCT00520130 study without palifermin (n=31). In the DL4 group, a previous interim analysis revealed no cases of classic (day +100) AGVHD II-IV in 16 patients (P=0.014), whereas the TMS group showed a 22.6% (95% CI: 9.8% to 38.6%) incidence (Schulz et al. Cell Ther Transplant. 2023;29(2):S258). T, B and NK cells were routinely measured by flow cytometry at days +14, +28, +60, +100, +180, +365, +730. The V-PLEX human cytokine 36-plex kit and U-PLEX assays of human BAFF, CXCL9 and IL1RL1/ST2 (all MSD, Rockville, MD) were used to measure cytokine levels in plasma at days −8, 0, +14, +28, +60, +100. The measures at various time points were compared between two treatment groups using multiple Mann-Whitney tests, and the false discovery rate approach was applied with Q=0.05. Comparison between the four DL groups and the TMS group was performed using the Kruskal-Wallis H-test and Dunn's post-hoc test, with a significance threshold set at P&amp;lt;0.05. The statistical analyses were conducted using GraphPad Prism 9. In comparison to patients receiving TMS only, those treated with KGF exhibited reduced NK cell counts at day +28 (Q=0.0155) and increased B cell counts from day +60 (Q&amp;lt;0.01) onwards. However, there were no differences in the absolute numbers of CD3+, CD4+, and CD8+ T cells between patients from both trials. Additionally, no apparent dose-response relationship was observed. KGF-treated patients showed significantly reduced plasma levels of proinflammatory cytokines, including TNF-α at day 0, TNF-β at days 0, +14, +28, IL-12/IL23p40 at days 0 and +14, and CXCL9 at days 0 and +14, compared to patients receiving TMS only. Notably, levels of homeostatic IL-7, previously linked to AGVHD, were significantly lower in KGF-treated patients from day +28 (TMS vs. DL4, P=0.002) to +100. There was a trend towards lower levels of IL-22 at days 0 and +14 (both unadjusted P&amp;lt;0.05, Q&amp;gt;0.05) in KGF-treated patients. Other proinflammatory biomarkers showed increased levels in KGF-treated patients: IL-15 at day 0 (Q=0.0121), BAFF at days +14 and +28 (both Q&amp;lt;0.01), and ST2 at day 0 and day +14 (both Q&amp;lt;0.01). As reported previously by others, patients who developed classic or late onset AGVHD II-IV without prior relapse up to day +180 had higher ST2 levels at day +14 compared to patients without AGVHD II-IV (P=0.03). Here, this association was mainly observed in patients from the TMS and DL1 groups (6/8 tested patients with any AGVHD II-IV). The administration of a single high dose of palifermin (KGF) prior to conditioning treatment resulted in a notably distinct cytokine profile, characterized by a reduction in several GVHD associated pro-inflammatory cytokines, consistent with KGF's proposed cytoprotective effect. Further investigations focusing on GI microbiome and immune cell subsets are needed to elucidate the consequences of cytokine alterations induced by KGF on immune cell reconstitution. This research was supported by the Intramural Research Program of the NIH, NCI, CCR.

Molecular Relapse after First-Line Intensive Therapy in Patients with Core-Binding Factor and NPM1-Mutated Acute Myeloid Leukemia - a Filo Study

Background: Patients with Core-Binding Factor (CBF) and NPM1-mutated acute myeloid leukemia (AML) are considered as favorable or intermediate-risk according to the European LeukemiaNet (ELN) 2022 classification and allogeneic hematopoietic cell transplantation (HCT) is usually not considered in those achieving first complete remission (CR) with good molecular response. Close molecular monitoring by quantitative PCR has been widely implemented over time and approximately 30% of patients will experience molecular relapse. However, there is no recommendation on how to manage these patients due to the lack of data from large patient series or clinical trials. In this study, we retrospectively analyzed the outcome of CBF or NPM1-mutated AML patients who had MRD monitoring after having achieved first CR. Methods: All CBF and NPM1-mutated AML patients, aged 18-60 years, who had MRD molecular monitoring (RT-qPCR of RUNX1-RUNXT1 or CBFB-MYH1 transcripts or classical NPM1 mutations) after first-line therapy including induction therapy with daunorubicin/idarubicin and cytarabine followed by intermediate or high-dose cytarabine consolidation, without allogeneic HCT in first CR, were included. MRD measurements were generally performed every three months during follow-up for 24 months in either bone marrow (BM) or peripheral blood (PB). Molecular relapse was defined according to ELN recommendations (Heuser M, Blood 2021) as a conversion from MRD negativity to positivity or an increase in MRD copy numbers &amp;gt;1 log between two positive samples. Results: Between 2010 and 2019, 303 patients from 9 centers with newly diagnosed CBF or NPM1-mutated AML ( RUNX1-RUNX1T1, 19%; CBFB-MYH11, 27%; NPM1, 53%) and available MRD monitoring after first-line therapy were included. Among these patients, 153 (51%) never relapsed, 95 (31%) had molecular relapse, with a median of 326 days (interquartile range [IQR]: 276-438) from initial diagnosis, and 55 (18%) had upfront morphologic relapse (i.e., without prior molecular relapse detected), with a median of 388 days (IQR: 280-559). Patients with molecular and upfront morphologic relapse had higher white blood cell (WBC) count at diagnosis (12 vs. 22 vs. 30 G/l in those without relapse, molecular relapse, and morphological relapse, respectively, P=0.003) and were more likely to have a FLT3-ITD mutation (7% vs. 25% vs. 19%, respectively, P=0.001). In addition, patients with upfront morphologic relapse had a lower log-reduction of MRD during first-line treatment (4.90 vs. 4.93 vs. 3.77, respectively, P=0.009) and were more likely to have CR with positive MRD at the end of treatment in peripheral blood (2% vs. 16% vs. 32%, respectively, P&amp;lt;0.001). Overall survival (OS) was significantly different according to whether patients never relapsed, had molecular relapse, or had upfront morphological relapse (three-year OS of 100% vs. 75% vs. 60%, P&amp;lt;0.001; Figure A). Among the 95 patients with molecular relapse, 53 (56%) received preemptive therapy (median of 48 days [IQR:24-68] from molecular relapse to treatment initiation) and 42 (44%) progressed to morphologic relapse before treatment was initiated (median of 58 days [IQR:36-134] from molecular to morphologic relapse). Patients who received preemptive therapy had a better OS than those who received salvage therapy after having progressed from molecular to morphologic relapse, and those who had upfront morphologic relapse (78% vs. 51% vs. 51% at three years, respectively, P=0.01; Figure B). Preemptive therapy included upfront allogeneic HCT (n=19), intensive chemotherapy (n=21), and non-intensive therapy (n=13) with different OS rates that did not reach statistical significance (92% vs. 79% vs. 58% at three years for upfront allogeneic HCT, intensive chemotherapy, and less intensive therapy, respectively, P=0.09). Conclusion: Up to 30% of patients with CBF or NPM1-mutated AML experienced molecular relapse in our cohort and more than 50% of them received preemptive therapy. Patients treated preemptively at molecular relapse had a better OS than those treated with active disease. Although these results need to be confirmed in larger studies, it supports molecular monitoring during follow-up to start preemptive therapy before overt morphologic relapse. Other techniques for MRD monitoring are urgently needed for AML patients who cannot be monitored by qPCR.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Active Primary Malignancy at HCT - a Bi-Institutional Retrospective Cohort Analysis

Background: Patients diagnosed with hematologic malignancies may be candidates to proceed to allogeneic hematopoietic cell transplantation (HCT). In those with active solid malignancy, given the cumulative toxicity associated with additional chemotherapy and the intensive immunosuppression required after HCT, there has been a concern that outcomes of HCT would be suboptimal. Specifically, prior malignancy may relapse early after HCT or transform to a more aggressive phenotype. We aimed to evaluate the bi-directional relationship between HCT and active solid malignancy. Methods: We retrospectively reviewed charts of patients in 2 large transplant centers who received first allogeneic HCT between 2012 and 2022 with concurrent active solid malignancy (defined as receiving any treatment for solid malignancy within 5 years prior to HCT). Hematologic relapse was treated as a competing event in time-to-event analyses of graft vs. host disease (GVHD) and non-relapse mortality (NRM). Analysis of chronic GVHD was performed only among patients who survived more than 3 months post HCT. Mortality was treated as a competing event in the analysis of relapse of solid malignancy. Modified GVHD-relapse free survival (mGRFS) was defined as survival with no prior GVHD and/or relapse of either solid or hematology malignancies. This trial was approved by the hospital ethic committee. Results: Between 01/2012 and 12/2022 we identified 45 patients (females, 62%) who fulfilled the eligibility criteria. Median age was 63 (range, 21-74) years and median post HCT follow-up was 41 (range, 7.1-122.5) months. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (n=35 and n=6, respectively) were the most common hematologic malignancies. Status of hematologic malignancy at HCT was complete remission (n=27, 60%), partial remission (n=1, 2%) and stable/progressive disease (n=17, 38%). Most common diagnoses of active solid malignancies were breast cancer (n=22, 49%) and colon cancer (n=6, 13%) with 24% patients receiving active treatment at HCT and 7% with progressive disease at HCT. HCT comorbidity index (HCT-CI) was 3-5 in 82% (&amp;gt;5, 18%). Majority received reduced intensity conditioning (n=29, 64%) with an allograft mainly derived from unrelated donors (n=31, 69%). Early HCT complications included severe mucositis (16%), bacteremia (20%), and invasive fungal infections (4%). There were no cases of sinusoidal obstruction syndrome. 27% resumed maintenance treatment for solid malignancies post HCT with no significant toxicity. Incidences of grade 2-4 and 3-4 acute GVHD at day 200 were 48% and 3%, respectively. Incidences of overall and moderate-severe chronic GVHD at 3 years were 53% and 24%, respectively. Hematologic relapse incidence at 6 months, 1 and 3 years were 31%, 37%, and 48%, respectively with no impact of conditioning intensity (p=.95). Incidences of NRM at 3 months, 1 and 3 years were 7%, 15%, and 25%, respectively. Cumulative progression of solid malignancies at 3 years was 12%, Figure 1A. Incidence of mRGFS at 1 year was 16%. Overall survival at 3 years was 53% in all cohort, 54% in patients with AML/MDS and 61% in patients with concomitant breast cancer, Figure 1B. Cox regression model identified both progressive solid and hematologic malignancy to be associated with increased risk of mortality (HR=4.3, p=.049 and HR=1.8, p=.028, respectively), while sex, age, conditioning intensity and HCT-CI did not impact survival. Conclusions: HCT is safe and efficacious in patients with active solid malignancy. However relapse incidence of hematologic malignancy is high and mGRFS is low. Progression of the solid malignancy after HCT is in fact uncommon. Therefore in this specific patient cohort, improved transplantation techniques to better control the hematologic disease post-transplant are warranted to make HCT more effective and long lasting.

The Impact of Relapses on Pain and Quality of Life in Patients with Multiple Sclerosis Treated with Corticosteroids.

We assessed the prevalence and risks associated with pain during and after a multiple sclerosis (MS) relapse, and the impact of pain on quality of life (QoL), in MS patients. 117 patients suffering an acute MS relapse were evaluated with clinician- and patient-reported outcomes, including the expanded disability status scale (EDSS), Multiple Sclerosis Impact Scale (MSIS-29), and MS Walking scale-12 (MSWS-12). Relapse-related pain was assessed via the short-form 36 (SF-36) questionnaire upon first visit (relapse onset) and at 6 weeks after treatment with intravenous methylprednisolone (follow-up visit). Pain was present in 80% of patients at relapse onset. Patients with pain were more impaired physically (higher mean scores on MSIS-29phys and MSWS-12 and lower mean scores on SF-36 role physical, physical, and vitality scales) at relapse and six weeks after. In total, 74% of patients with MS relapse reported a poorer QoL due to pain. A lower psychological well-being was correlated with greater pain (MSIS29psy score). An increased number of prior relapses was a predictor of more pain at relapse onset. Pain was common at the time of MS relapse and improved, but was still significant, six weeks after treatment with corticosteroids. Further studies are required to better understand relapse-related pain.

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

Ocrelizumab, a humanized monoclonal antibody targeted against CD20+ B cells, reduces the frequency of relapses by 46% and disability worsening by 40% compared with interferon beta 1a in relapsing-remitting multiple sclerosis (MS). Rituximab, a chimeric monoclonal anti-CD20 agent, is often prescribed as an off-label alternative to ocrelizumab. To evaluate whether the effectiveness of rituximab is noninferior to ocrelizumab in relapsing-remitting MS. This was an observational cohort study conducted between January 2015 and March 2021. Patients were included in the treatment group for the duration of study therapy and were recruited from the MSBase registry and Danish MS Registry (DMSR). Included patients had a history of relapsing-remitting MS treated with ocrelizumab or rituximab, a minimum 6 months of follow-up, and sufficient data to calculate the propensity score. Patients with comparable baseline characteristics were 1:6 matched with propensity score on age, sex, MS duration, disability (Expanded Disability Status Scale), prior relapse rate, prior therapy, disease activity (relapses, disability accumulation, or both), magnetic resonance imaging lesion burden (missing values imputed), and country. Treatment with ocrelizumab or rituximab after 2015. Noninferiority comparison of annualized rate of relapses (ARRs), with a prespecified noninferiority margin of 1.63 rate ratio. Secondary end points were relapse and 6-month confirmed disability accumulation in pairwise-censored groups. Of the 6027 patients with MS who were treated with ocrelizumab or rituximab, a total of 1613 (mean [SD] age; 42.0 [10.8] years; 1089 female [68%]) fulfilled the inclusion criteria and were included in the analysis (898 MSBase, 715 DMSR). A total of 710 patients treated with ocrelizumab (414 MSBase, 296 DMSR) were matched with 186 patients treated with rituximab (110 MSBase, 76 DMSR). Over a pairwise censored mean (SD) follow-up of 1.4 (0.7) years, the ARR ratio was higher in patients treated with rituximab than in those treated with ocrelizumab (rate ratio, 1.8; 95% CI, 1.4-2.4; ARR, 0.20 vs 0.09; P < .001). The cumulative hazard of relapses was higher among patients treated with rituximab than those treated with ocrelizumab (hazard ratio, 2.1; 95% CI, 1.5-3.0). No difference in the risk of disability accumulation was observed between groups. Results were confirmed in sensitivity analyses. In this noninferiority comparative effectiveness observational cohort study, results did not show noninferiority of treatment with rituximab compared with ocrelizumab. As administered in everyday practice, rituximab was associated with a higher risk of relapses than ocrelizumab. The efficacy of rituximab and ocrelizumab administered at uniform doses and intervals is being further evaluated in randomized noninferiority clinical trials.

Comparison of next-generation sequencing and flow cytometry in detecting minimal residual disease in adult acute lymphoid leukemia: Evaluating clinical outcomes in a single-center study.

7033 Background: Detection of measurable residual disease (MRD) is an important biomarker to direct treatment for adult patients with acute lymphoblastic leukemia (ALL). Currently, multiparameter flow cytometry (MFC) is standard of care and can detect residual leukemia cells in 1 out of 100,000 cells (1 × 10−5). Routine use of next-generation sequencing (NGS) assays with higher levels of sensitivity may improve disease-free survival and overall survival in adult ALL patients. The clonoSEQ MRD assay (Adaptive Biotechnologies Corporation, USA) can detect MRD at a sensitivity of 1 × 10−6 . In this study, we compare the detection of MRD by clonoSEQ assay and MFC in adult ALL patients at a single institution. Methods: We performed a retrospective study evaluating 92 adult patients with B- or T-ALL admitted to Norris Comprehensive Cancer Center between 2014 and 2022. Patients were excluded if they did not achieve complete remission (N=9) or if they presented with prior relapse (N=27). Median time to first complete remission (CR1) was 2.38 months. Among our cohort (N=56 patients), all patients underwent pre-treatment bone marrow sampling which was used for Clonoseq assay. 52 patients had contemporaneous MFC which was used for comparative analysis. MRD on MFC was defined as residual leukemia cells at a sensitivity of 1 × 10−5. MRD on Clonoseq assay was evaluated at 1 × 10−6; residual cells under this limit were considered MRD−. Results: Demographics are summarized in the table. Median time to follow-up from MRD assessment was 18.0 months. 10 patients relapsed (17.9%), 3 patients died (5.4%), and 20 patients (35.7%) underwent allogeneic transplant during first remission. Among 52 patients analyzed by both MFC and NGS at CR, 26 (50%) were concordantly MRD− by NGS and NGF, 13 (25%) were discordantly MRD− by NGF but MRD+ by NGS, and 13 (25%) concordantly MRD+ by NGS and NGF. Residual cell levels between NGS and NGF were strongly correlated (R-Squared = 0.6744, p&lt;0.001), however, MRD status was significantly different between NGS and NGF (p&lt;0.001 using Fisher’s Exact Test). This difference was likely driven by disparities in the limits of detection between both methods. Conclusions: Assessment of MRD using the clonoSEQ assay over a standard MFC-based approach adds crucial prognostic information among adult ALL patients who achieved CR. [Table: see text]

AI-driven real-time patient identification for randomized controlled trials.

e13565 Background: In India, clinical trial recruitment is a challenging process, often relying on the time- and labor-intensive process of investigators reviewing handwritten charts to identify potential candidates. We developed an AI-driven, real-time solution to address this issue and demonstrated its feasibility by identifying patients that would have been candidates for a 2017-2018 study of metastatic breast cancer (mBC) patients who failed prior chemotherapy. The original trial recruited 46 patients across 16 sites over 7 months in India. Methods: The study protocol was reviewed and applied to six years (2017-2022) of retrospective electronic medical records (EMR) data from a cancer hospital in India’s National Capital Region. Trial inclusion and exclusion criteria were translated to data elements which were extracted from both structured (e.g., lab) and unstructured (e.g., clinical notes) EMR data. For the unstructured data specifically, natural language processing algorithms were developed and implemented over the span of three weeks to extract the specific data elements. The veracity of the extracted data was confirmed via manual review by an oncologist. To assess the sensitivity of the results to the study criteria and provide a range of the potential candidate population size, the criteria were applied in two ways – as a strict application (e.g., ECOG must be reported and must be &lt; = 2) and as a relaxed application (e.g., ECOG may be unreported or, if reported, must be &lt; = 2). Results: Among the initial cohort of 112,239 females between 18 and 65 years of age, 3,203 (3%) were identified as having mBC and failure of prior chemotherapy or relapse. 537 patients remained after applying all inclusion criteria (ECOG status &lt; = 2, LVEF &gt; = 50%, no prior radiotherapy, prior chemo completed 4+ weeks prior, adequate bone marrow, renal, and hepatic function). Exclusion criteria (prior taxane exposure, 2+ prior chemotherapies, cardiac conditions, CNS lesions, motor/sensory neurotoxicities, HBV/HCV/HIV infection) were then applied, resulting in 37 patients that would be potential candidates for the trial, per the strict application of criteria. The relaxed version of the analysis yielded a candidate pool that was five times larger than the strict application, which was largely driven by cases where information was unavailable in the EMR. Conclusions: We demonstrated that the use of an AI-driven platform to apply clinical trial criteria to Indian real-world data can provide an efficient solution to identifying candidate trial patients. Once the criteria are defined and algorithms are developed, patient identification can happen in real time and reduce patient recruitment timelines by months. Future applications will include other cancer types and expand the breadth of data elements extracted to enable the rapid assessment of additional inclusion and exclusion criteria.

Predicting MRI Changes in Patients with MS in the Absence of Acute Inflammation (P11-3.010)

Predicting MRI Changes in Patients with MS in the Absence of Acute Inflammation (P11-3.010)

Characterization of Disease Severity and Stability in NMOSD: A Global Clinical Record Review with Patient Interviews.

We sought insights into the classification of and factors associated with relapse severity and disease stability in neuromyelitis optica spectrum disorder (NMOSD) clinical practice worldwide. Neurologists recruited from six countries (the USA, Germany, Italy, Brazil, South Korea, and China) participated in a 30-60minute online survey and submitted two to four clinical records for aquaporin-4-immunoglobulin G (AQP4-IgG)-seropositive adults with NMOSD, which included patient demographics, diagnosis, maintenance treatment history, relapse occurrence, and severity. Separately, patients with NMOSD receiving maintenance therapy were interviewed over the telephone about their treatment journey, as well as perceptions of relapse severity and disease stability, and their potential influence on treatment decisions. Clinical records for 1185 patients with AQP4-IgG-seropositive NMOSD were provided by 389 neurologists (July-August 2020); 33 patients were interviewed (October-November 2020). There was no clear consensus on how relapse severity was defined in clinical practice, with geographical variations in relapse classification also found. Neurologists tended to rely on clinical assessments when determining severity, viewing each relapse in isolation, whereas patients had a more subjective view based on the changes in their daily lives and comparisons with prior relapses. Similarly, there was a disconnect in the definition of disease stability: the complete absence of relapses was more important for patients than for neurologists. A clear consensus on how to assess relapse severity and disease stability is needed to ensure that patients receive appropriate and timely treatment. In the future, clinical measures should be combined with patient-focused assessments.

Comparative effectiveness in multiple sclerosis: A methodological comparison

Background: In the absence of evidence from randomised controlled trials, observational data can be used to emulate clinical trials and guide clinical decisions. Observational studies are, however, susceptible to confounding and bias. Among the used techniques to reduce indication bias are propensity score matching and marginal structural models. Objective: To use the comparative effectiveness of fingolimod vs natalizumab to compare the results obtained with propensity score matching and marginal structural models. Methods: Patients with clinically isolated syndrome or relapsing remitting MS who were treated with either fingolimod or natalizumab were identified in the MSBase registry. Patients were propensity score matched, and inverse probability of treatment weighted at six monthly intervals, using the following variables: age, sex, disability, MS duration, MS course, prior relapses, and prior therapies. Studied outcomes were cumulative hazard of relapse, disability accumulation, and disability improvement. Results: 4608 patients (1659 natalizumab, 2949 fingolimod) fulfilled inclusion criteria, and were propensity score matched or repeatedly reweighed with marginal structural models. Natalizumab treatment was associated with a lower probability of relapse (PS matching: HR 0.67 [95% CI 0.62-0.80]; marginal structural model: 0.71 [0.62-0.80]), and higher probability of disability improvement (PS matching: 1.21 [1.02 -1.43]; marginal structural model 1.43 1.19 -1.72]). There was no evidence of a difference in the magnitude of effect between the two methods. Conclusions: The relative effectiveness of two therapies can be efficiently compared by either marginal structural models or propensity score matching when applied in clearly defined clinical contexts and in sufficiently powered cohorts.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR]=0.52, 95% confidence interval [CI]=0.45-0.60), 46% lower risk of disability worsening (HR=0.54, 95% CI=0.41-0.71), and 32% greater chance of disability improvement (HR=1.32, 95% CI=1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.