Patients Receiving Maintenance Therapy Research Articles

Usefulness of Nutritional Assessment Indicators in Predicting Treatment Discontinuation Due to Adverse Events from PARP Inhibitors in Ovarian Cancer Patients

Background: Nutritional status is an important factor influencing toxicity of treatment. Nutritional assessment indicators such as the Prognostic Nutritional Index (PNI), Controlling Nutritional Status (CONUT) score and modified Glasgow Prognostic Score (mGPS) have been reported to be associated with treatment-related adverse events (AEs) for various malignancies. However, there are no reports investigating the relationship between nutritional status and AEs from poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPi), which are widely used in recent years as maintenance therapy for ovarian cancer. Objective: The primary objective was to investigate the usefulness of nutritional assessment indicators in predicting treatment discontinuation due to AEs from PARPi. Methods: This multicenter retrospective study included patients diagnosed with ovarian cancer who received maintenance therapy with PARPi from January 2018 to December 2023. PNI, CONUT score, and mGPS were calculated based on hematological parameters measured within 7 days before the start of PARPi therapy. Results: A total of 272 patients received maintenance therapy with PARPi during the period, but due to the absence of the blood collection of albumin levels within one week or other exclusion criteria, 71 patients were finally included in this analysis. AEs were seen in 59 patients (83.1%), including 25 (35.2%) severe events (grade ≥3 in Common Terminology Criteria for Adverse Events v5.0). Eighteen patients (25.4%) discontinued treatment due to PARPi-related AEs. Low PNI (<48.44) and high mGPS (≥1) were predictors of treatment discontinuation in both univariate and multivariate analyses. CONUT was not a significant predictor in this study. Conclusions: Our study suggested that PNI and mGPS can predict the risk of treatment discontinuation due to PARPi-related AEs before starting maintenance therapy. This insight opens avenues for more personalized treatment plans, potentially improving patient outcomes.

Sintilimab plus GemOx is an effective salvage therapy in patients with refractory/relapsing nodal peripheral T cell lymphomas

PurposeThe retrospective study was to explore the effectiveness and safety of GemOx (gemcitabine, oxaliplatin) plus sintilimab (belongs to the class of drugs known as immune checkpoint inhibitors, particularly targeting the PD-1 receptor) in relapse or refractory nodal PTCLs.MethodsPatients with nodal PTCL who initiated salvage therapy with sintilimab and GemOx between January 2020 to September 2021 were identified from the database of the hematology department of the Second Affiliated Hospital of Zhejiang University School of Medicine. All patients received 2–4 cycles (3 weeks/cycle) of treatment of sintilimab (200 mg, I.V, D1) in combination with GemOx. Treatment response was assessed every six weeks during the salvage treatment phase. Eligible patients received maintenance therapy according to the investigator’s decision. Follow-ups were routinely conducted every three months.Results31 patients with r/r nodal PTCLs were enrolled, including 23 PTCL-NOS, 4 AITL, and 4 ALCL. 21 (67.7%) patients received at least two lines of therapy. 71.0% (95% CI, 53.4%-83.9%) of patients documented objective response of 2–4 cycles of sintilimab plus GemOx therapy, including 9 complete response and 13 partial response. 21 (67.7%) patients received consolidation therapy, including 5 autologous stem-cell transplantation and 12 histone deacetylase inhibitors. After a median 25.6 months follow-up, the median PFS was 22.0 (95% CI,11.8–24.7) months, and the median OS was 26.2 (95% CI, 24.4 –NA) months. 29 (93.5%) patients experienced at least one adverse event, and 26 (83.9% patients only had mild (grade 1–2) AEs.Univariable Cox regression showed the progression risk of AITL is 22.7 (3.9- 131.0, p < 0.01) times of PTCL-NOS, while the HR of ALCL was 1.14 (0.33–3.96,p = 0.833).ConclusionSintilimab plus GemOx showed encouraging activity and manageable toxicity for patients with r/r PTCL.

Surgical indication and management of obstructive colonic metastasis from primary lung adenocarcinoma: report of a case and review of the literature

BackgroundColonic metastasis from lung cancer is very rare and is typically associated with poor prognosis. Herein, we report the case of a patient who achieved intermediate-term survival using a multimodal treatment approach, including chemotherapy, immunotherapy, radiotherapy, and surgical resection for obstructive colonic metastasis from primary lung adenocarcinoma.Case presentationA woman in her 50s presented with anemia and a positive fecal occult blood test. Computed tomography revealed a tumor in the right upper lobe of the lung with mediastinal lymphadenopathy and wall thickening in the transverse colon. Colonoscopy revealed a stricture involving 50% of the colonic lumen. Biopsy revealed a poorly differentiated adenocarcinoma positive for CK-7 and TTF-1, very focally positive for napsin A, and negative for CK-20 and CDX-2. Furthermore, positron emission tomography/CT (PET/CT) showed a high maximum standardized uptake value (SUVmax) of 8.2 in the iliac bone. Based on these findings, the patient was diagnosed with primary lung adenocarcinoma with simultaneous metastasis to the transverse colon and iliac bone (cT4N3M1c, cStage IVB).After receiving first-line chemotherapy with atezolizumab, pemetrexed, and carboplatin, the tumors shrank after 4 courses. Subsequently, the patient received maintenance therapy with atezolizumab and pemetrexed. However, the tumor enlarged after 10 courses. Second-line chemotherapy with docetaxel and ramucirumab (3 courses) failed to achieve tumor reduction. Colonoscopy revealed an impassable colonic tumor. Nineteen months after diagnosis, surgery was planned for imminent intestinal obstruction.We determined that the colonic tumor was resectable, because laparoscopic exploration revealed no other metastases. The tumor was resected by partial colectomy with ileocolonic anastomosis. The postoperative course was uneventful. Pathological examination revealed a resection margin that was negative for malignancy, and the histological type was consistent with metastatic lung adenocarcinoma.The patient then received nab-paclitaxel therapy; however, she developed symptoms of superior vena cava syndrome after 3 courses. The patient received palliative irradiation (30 Gy/10 fr) followed by nivolumab. She soon developed a solitary brain metastasis, and stereotactic irradiation was planned. After 3 courses of nivolumab, the metastasis was reduced significantly, and stereotactic brain irradiation was canceled. The lung tumor and mediastinal lymphadenopathy gradually shrank, and the patient survived for 13 months after surgery without disease progression.ConclusionsIn this case, surgical resection of colonic metastasis from primary lung adenocarcinoma may have contributed to the short-term prognosis as a bridge-to-next available multimodal treatment.

Achievement of Endoscopic Remission After Induction Reduces Hospitalization Burden in Crohn's Disease: Findings From a Pooled Post Hoc Analysis of Risankizumab and Upadacitinib Phase III Trials.

Endoscopic remission has emerged as an important treatment target in Crohn's disease (CD) and has been associated with improvement in long-term outcomes. We examined the relationship between achievement of endoscopic remission and hospitalizations using pooled 52-week Phase III risankizumab and upadacitinib maintenance trials for patients with moderate-to-severely active CD. Included patients received maintenance therapy after achieving a clinical response following a 12-week induction with risankizumab or upadacitinib. Endoscopic remission defined as a Simple Endoscopic Score for CD no greater than 4 with at least a 2-point reduction versus induction baseline and no subscore greater than 1. All subsequent hospitalization events were recorded until completion of the maintenance trial or discontinuation. Exposure-adjusted negative binomial regression models were estimated to assess the relationship between post-induction endoscopic remission and long-term hospitalization, controlling for demographics, clinical variables, and treatment arm. Post-induction hospitalization rates were lower in patients who achieved endoscopic remission at the end of the induction period. In multivariable models, post-induction endoscopic remission was independently associated with an IRR of 0.45 (95% CI [0.22-0.95], p=0.036) and 0.71 (95% CI [0.44-1.14], p=0.156) for long-term disease-related and all-cause hospitalizations, respectively. Week 12 endoscopic remission is independently associated with reducing 52-week disease-related hospitalizations. However, achieving this stringent endpoint within 12 weeks of therapy may be challenging. Endoscopic response may be a more realistic early endoscopic target in the post-induction timeframe. Additional research is needed to evaluate early achievement of alternative endoscopic endpoints in CD.

Optimizing the Outcome of Pediatric Metastatic Neuroblastoma in a Nontransplant Setting in a Developing Country: Retrospective Study from a Tertiary Cancer Center in India

Abstract Objective This article estimates the survival of children over 1 year of age diagnosed with metastatic neuroblastoma (NB) and treated in a nontransplant facility and determines the factors affecting survival. Materials and Method Case records of children aged 1 to 14 years treated for metastatic NB in our center from January 2008 to December 2017 were studied. Patients received conventional chemotherapy followed by surgery, radiotherapy, and metronomic maintenance chemotherapy. Results Eighty-nine patients with metastatic NB received treatment. Mean age was 3.5 years and male:female ratio was 1.1:1. The most common primary site was suprarenal (55%) and the most common site of metastasis was bone marrow (76%). Forty percent patients had multiple metastatic sites. Mean baseline lactate dehydrogenase (LDH) was 3724 U/L (range 303–16609 U/L) and 65% patients had LDH &gt; 750 U/L. Fifty-three patients (59.6%) had good response to chemotherapy as evidenced by clearance of metastatic disease, but out of them, 43 patients (81%) progressed subsequently. Twenty-six patients underwent surgery and 12 patients received maintenance therapy. Seventy-four patients (86%) developed recurrence and all but one died. Median time to recurrence and death were 9 months (range 0–120 months) and 10 months (range 1–123 months), respectively. At a median follow-up of 72 months (range 15–135 months), 16 patients are alive, with 5-year disease-free survival and overall survival of 17.6 and 18.4%, respectively. Age, baseline LDH, chemotherapy regimen, and response to treatment significantly affected survival. Conclusion Younger age, lower baseline LDH, and good response to chemotherapy appear to confer survival advantage in pediatric metastatic NB, and may be used for optimization of treatment in the nontransplant setting in developing countries.

Early Maintenance Treatment Initiation and Relapse Risk Mitigation After a First Event of MOGAD in Adults: The MOGADOR2 Study.

Because myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder, the natural history of MOGAD is still not well described. The objective of this study was to describe the long-term outcomes of adult patients with MOGAD. In addition, we aimed to identify factors affecting relapse risk and neurologic outcomes. Clinical and biological data were obtained from patients with a first event of MOGAD and included in the French nationwide incident cohort between February 2014 and March 2017. Only patients aged 18 years or older at disease onset and with observation period of at least 3 months were included. Data were collected prospectively until July 2023 and registered in the dedicated French nationwide database. This form includes every relapse with phenotype description during follow-up, date of last assessment, final clinical outcome with Expanded Disability Status Scale score and visual acuity, and maintenance therapy. The probability of recurrence-free survival was assessed using the Kaplan-Meier method. We included 128 patients. The onset phenotype was isolated optic neuritis in 81 patients (63.3%) and isolated myelitis in 25 patients (19.5%). The median follow-up duration was 77.8 months (range 3.2-111.2), with 49 patients (38.3%) experienced at least one relapse. Median times from onset to second and third attacks were 3.2 (1.0-86.2) and 13.0 (2.6-64.4) months, respectively. At the last assessment, Expanded Disability Status Scale Score was ≥3 and ≥6 in 22 (17.2%) and 6 (4.7%) patients, respectively. Eighty patients received at least one maintenance treatment. This treatment was initiated after the first attack in 47 patients (36.7% of the whole cohort) and at the time of a second attack in 25 (19.5%). Multivariate analysis revealed that initiating maintenance treatment after the first attack was associated with a lower relapse risk (OR = 0.26 [95% CI 0.11-0.62], p = 0.002). In patients receiving maintenance therapy after first attack, the 2-year, 4-year, 6-year, and 8-year relapse risks were 11%, 15%, 20%, and 20%, respectively. In other patients, the risks were 41%, 46%, 51%, and 56%. The highest risk of a relapse in MOGAD occurs early, and initiating maintenance therapy from the first attack substantially reduced the relapse risk. This study provides Class III evidence that initiating maintenance therapy from the first attack in patients with MOGAD reduces the relapse risk.

HGG-45. HIGH GRADE GLIOMA PRESENTING AS A SYNCHRONOUS CANCER IN A PATIENT WITH DIFFUSE LARGE B CELL LYMPHOMA: A UNIQUE TREATMENT DILEMMA

Abstract BACKGROUND Patients with synchronous tumors pose significant treatment dilemmas. We present a pediatric patient found to have concomitant Diffuse Large B-cell Lymphoma (DLBCL) and a High Grade Glioma (HGG). His unique presentation and family history uncovered a familial diagnosis of Lynch Syndrome. CASE A 7-year-old male presented with acute appendiceal rupture. Surgical resection identified an appendiceal mass consistent with localized DLBCL. While undergoing staging evaluations, the patient complained of new onset blurry vision with normal neurologic and ophthalmologic exams. Subsequent imaging was concerning for a high-grade lesion. Biopsy confirmed HGG and he underwent gross total resection. Family history included a brother with relapsed leukemia status post bone marrow transplant and multiple first cousins with lymphoma and gastrointestinal cancers. RESULTS While awaiting genetics and mutational analysis, we initiated treatment. The HGG was treated with focal radiation to the tumor bed starting 2 weeks after resection. Lymphoma therapy was initiated concurrently per the REBOOT regimen with the goal of decreasing doxorubicin dosing during radiation. Lumbar punctures and intrathecal chemotherapy were deferred until completion of radiation. Biopsy of residual abdominal masses following consolidation 1 showed &amp;lt;5% viable cells and therapy was intensified to ANHL1331, Group C1. Evaluation of both lesions identified hypermutation (mutational burden &amp;gt; 150mutations/Mb). Two unique germline mutations of PMS2 were also identified, consistent with Lynch syndrome. After completion of above therapy, the patient received maintenance therapy with nivolumab checkpoint inhibition. The patient developed severe neutropenia leading to cessation of nivolumab and quick progression of his HGG. CONCLUSION Synchronous tumors pose significant treatment dilemmas given the need to treat multiple lesions while balancing side effects. While checkpoint inhibitors may provide a way to address multiple lesions, our patient had unacceptable side effects limiting the utility of this therapy.

Efficacy of Dose Escalation of Oral 5-Aminosalicylic Acid for Ulcerative Colitis With a Mayo Endoscopic Subscore of 1: An Open Label Randomized Controlled Trial.

Endoscopic healing is generally defined as Mayo endoscopic subscore (MES) ≤1 in ulcerative colitis (UC). However, patients with an MES of 1 are at higher relapse risk than those with an MES of 0. This study evaluated the therapeutic efficacy of proactive dose escalation of oral 5-aminosalicylic acid (5-ASA) in UC patients with an MES of 1. An open-label, randomized controlled trial was conducted in 5 hospitals between 2018 and 2022. Ulcerative colitis patients in clinical remission under oral 5-ASA therapy and diagnosed as having an MES of 1 were enrolled. Patients receiving maintenance therapy other than 5-ASA and immunomodulator were excluded. Patients were randomly assigned in a 1:1 ratio to receive either a dose-escalated (intervention) or constant dose (control) of 5-ASA. Concomitant immunomodulator was used as the stratification factor in the randomization. The primary end point was relapse within 1 year. The subgroup analysis was stratified for the use of immunomodulators. The full analysis set included 79 patients (39 intervention and 40 control). Immunomodulators were used in 20 (25.3%) patients. Relapse was less in the intervention group (15.4%) than the control group (37.5%; P = .026). In the subgroup with concomitant immunomodulators, relapse was also less in the intervention group (10.0%) than the control group (70.0%; P = .020). In patients without immunomodulators, the difference was not significant between 2 groups (intervention, 17.2%; control, 26.7%; P = .53). Dose escalation of 5-ASA reduced relapse within 1 year in UC patients in clinical remission with an MES of 1.

P966 The intra-patient variability of adalimumab clearance during an intensive sampling study of Crohn’s disease patients receiving maintenance therapy

Abstract Background Lower adalimumab (ADA) clearance (CL) is associated with improved outcomes in Crohn’s disease (CD) and may be a superior pharmacokinetic (PK) measure than ADA concentrations. We compared intra-patient variability in ADA CL and concentrations within a 14-day treatment cycle and across two consecutive cycles under maintenance treatment. Methods In a previous PK study of CD patients receiving maintenance ADA 40mg fortnightly, samples were collected intensively at 3 visits (day 4-6, 7-9, and 13-14 post dose) across 2 consecutive cycles. Available sera from this cohort were subsequently used to measure ADA concentrations (lower limit quantification: &amp;lt;1.6 µg/mL) and antibody to adalimumab (ATA) status using a drug tolerant homogeneous mobility shift assay, and albumin. Apparent ADA CL (L/day) was calculated incorporating these measure parameters in a nonlinear mixed effect model with Bayesian priors (under steady state assumption) with dose and inter-dose interval with ATA and albumin as covariate. Rates of sustained clinical and biochemical remission (Harvey Bradshaw Index (HBI) score consistently &amp;lt;5 and CRP levels consistently &amp;lt;3 mg/L) were estimated for each patient. Longitudinal changes in PK parameters within-and-across cycles were evaluated using intra-patient coefficient of variation and linear mixed effect models. Results Sera was available from 70 study visits in 12 patients (6 males, mean age 36 years). Median ADA concentrations and CL were 8 µg/mL (IQR 6.0-10.4) and 0.374 L/day (IQR 0.29-0.43), respectively, with ATA detected in one patient (#9). Estimated ADA concentrations and CL is presented in the Table. Intra-patient variability in CL was much lower across the two 14-day cycle (9% and 7%, respectively) compared to intra-patient variability in ADA concentration (15% and 13%, respectively). Linear mixed effect models confirmed these findings with no impact of sampling time on CL (intercept=0.46±0.12 L/day; slope estimate=0.002±0.002 L/day; p=0.16) as compared to significant change in ADA concentrations (intercept=10.6±1.2 µg/mL; slope estimate=-0.25±0.03 µg/mL; p&amp;lt;0.01) over inter-dose interval sampling time. Sustained clinical and biochemical remission was achieved in 5/12 patients (42%); none presented with CL &amp;gt;0.8 L/day (a cut-off previously associated with worse outcomes). Of 7 patients without sustained clinical and biochemical remission, two presented with optimal concentrations (&amp;gt; 10 µg/mL), thus suggestive of mechanistic failure, and one developed ATA, lower concentration and higher ADA CL. Conclusion CL is subject to less intra-patient variability than ADA concentrations, supporting its assessment at any time point within a 14-day treatment cycle.

Prevalence and risk factors for medication-refractory reflux esophagitis in patients with systemic sclerosis in Japan.

Patients with systemic sclerosis (SSc) often have esophageal motility abnormalities and weak esophago-gastric junction (EGJ) barrier function, which causes proton pump inhibitor (PPI)-refractory reflux esophagitis (RE). The aims of this study were to clarify the current management of RE and prevalence and risk factors of medication-refractory RE in patients with SSc in Japan. A total of 188 consecutive patients with SSc who underwent both esophageal high-resolution manometry (HRM) and esophagogastroduodenoscopy (EGD) were reviewed. The presence of RE and grades of the gastroesophageal flap valve (GEFV) were assessed. Esophageal motility was assessed retrospectively according to the Chicago classification v3.0. When RE was seen on a standard dose of PPI or any dose of vonoprazan (VPZ), it was defined as medication-refractory RE. Approximately 80% of patients received maintenance therapy with acid secretion inhibitors regardless of esophageal motility abnormalities. Approximately 50% of patients received maintenance therapy with PPI, and approximately 30% of patients received VPZ. Medication-refractory RE was observed in 30 patients (16.0%). In multivariable analyses, the number of EGD and absent contractility were significant risk factors for medication-refractory RE. Furthermore, combined absent contractility and GEFV grade III or IV had higher odds ratios than did absent contractility alone. Patients with persistent reflux symptoms and those with absent contractility and GEFV grade III or IV should receive maintenance therapy with strong acid inhibition to prevent medication-refractory RE.

Development and validation of algorithms for identifying lines of therapy in multiple myeloma using real-world data.

Aim: To validate algorithms based on electronic health data to identify composition of lines of therapy (LOT) in multiple myeloma (MM). Materials & methods: This study used available electronic health data for selected adults within Henry Ford Health (Michigan, USA) newly diagnosed with MM in 2006-2017. Algorithm performance in this population was verified via chart review. As with prior oncology studies, good performance was defined as positive predictive value (PPV) ≥75%. Results: Accuracy for identifying LOT1 (N=133) was 85.0%. For the most frequent regimens, accuracy was 92.5-97.7%, PPV 80.6-93.8%, sensitivity 88.2-89.3% and specificity 94.3-99.1%. Algorithm performance decreased in subsequent LOTs, with decreasing sample sizes. Only 19.5% of patients received maintenance therapy during LOT1. Accuracy for identifying maintenance therapy was 85.7%; PPV for the most common maintenance therapy was 73.3%. Conclusion: Algorithms performed well in identifying LOT1-especially more commonly used regimens-and slightly less well in identifying maintenance therapy therein.

Encephalitis is an Important Phenotype of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Diseases: A Single-Center Cohort Study

BackgroundMyelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is considered a demyelinating disease of the central nervous system, but an increasing number of encephalitis cases associated with MOG antibodies have been reported recently. MethodsThis was a single-center, retrospective study. All data for pediatric patients with MOGAD diagnosed at Beijing Children's Hospital from January 2017 to January 2022 were collected. Clinical characteristics and outcomes were analyzed, and treatment responses were compared between the rituximab (RTX) and mycophenolate mofetil (MMF) groups. ResultsA total of 190 patients (age range: 5 months to 16 years; median age: 7.2 years; females: 97) were included in this study. The phenotypes of the first attack included acquired demyelinating syndromes (105 [55%]), encephalitis other than acute disseminated encephalomyelitis (82 [43%]), and isolated meningitis (3 [2%]). After a median follow-up of 30.4 months (interquartile range: 14.8-43.7), 64 (34%) patients had relapses. Fifty-one of the 64 (80%) patients who had relapse received maintenance therapy, including MMF (41), RTX (11), maintenance intravenous immunoglobulin (two), and tocilizumab (two). The annualized relapse rates decreased significantly after treatment in both the RTX and MMF cohorts (P < 0.05); however, there were no significant differences between the two groups (P = 0.56). A total of 178 (94%) patients had complete (175 patients) or almost complete (three patients) recovery (modified Rankin scale [mRS] < 2), and 12 had moderate to severe deficits (mRS ≥ 2). ConclusionsThe spectrum of pediatric MOGAD is broader than previously reported and includes demyelinating syndromes and encephalitis. Encephalitis is an important initial phenotype observed in pediatric patients with MOGAD.

Clinical analysis of allogeneic hematopoietic stem cell transplantation for seven cases of acute myeloid leukemia with BCR::ABL1 fusion

Objective: To explore the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute myeloid leukemia (AML) patients with BCR::ABL1 fusion. Methods: The clinical data of seven AML patients with BCR::ABL1 fusion from November 2012 to January 2022 were retrospectively analyzed, and their survival status was followed up. Results: The median age of patients at the time of diagnosis was 35 years. Four cases (57.1%) were diagnosed with high leukocyte counts. All cases were assayed as BCR::ABL1 positive and accompanied by four types of gene mutations (NPM1, RUNX1, ASXL1, PHF6) . Seven patients received tyrosine kinase inhibitor (TKI) combined with induction chemotherapy and bridged to allo-HSCT, and six patients received maintenance therapy with TKI. Before allo-HSCT, six patients achieved complete remission, and four patients achieved complete molecular remission (CMR) . After allo-HSCT, the three remaining cases also achieved CMR. All patients were in remission post-allo-HSCT. One case died of infection, and the remaining cases survived without relapse. The 3-year cumulative overall survival rate was (80.0±17.9) %. Conclusions: TKI combined with traditional chemotherapy could achieve a high response rate in AML patients with BCR::ABL1 fusion. In addition, allo-HSCT could enhance the molecular response rate. Maintenance therapy post-HSCT with TKI could improve prognosis.

Secondary cytoreductive surgery with and without hyperthermic intraperitoneal chemotherapy for recurrent ovarian cancer.

Secondary cytoreductive surgery (CRS) can afford promising results in patients with recurrent ovarian cancer; however, the impact of hyperthermic intraperitoneal chemotherapy (HIPEC) remains unclear. We compared the outcomes of secondary CRS combined with and without HIPEC in patients with recurrent ovarian cancer. We retrospectively evaluated patients with recurrent ovarian cancer who underwent secondary CRS, with or without HIPEC (n=46), at the Yonsei Cancer Center between January 2006 and February 2021. Of the 46 included patients, 20 underwent secondary CRS-plus-HIPEC, while 26 underwent secondary CRS without HIPEC (henceforth referred to as secondary CRS-only). Of the 46 patients, 84.8% and 89.1% had undergone optimal surgery and platinum-based chemotherapy, respectively, as the initial treatment before the first relapse. Overall, 32.6% of patients received maintenance therapy, such as bevacizumab or polyadenosine diphosphate ribose polymerase inhibitors. The median follow-up period was 15.9 months. The median progression-free survival (PFS) was 32.7 and 25.1 months in the secondary CRS-plus-HIPEC and secondary CRS-only groups, respectively; however, both groups failed to reach the median overall survival (OS). Based on the Kaplan-Meier analysis, there was no difference in PFS (P=0.587) or OS (P=0.239) between the two groups. We identified patients with epithelial ovarian cancer and found that the median PFS was 25.1 months in the secondary CRS-only group; this was not achieved in the secondary CRS-plus-HIPEC group (P=0.244). In patients with recurrent ovarian cancer, secondary CRS with HIPEC did not improve survival when compared with CRS without HIPEC. However, on subgrouping patients with epithelial ovarian cancer, the addition of HIPEC to secondary CRS tended to improve PFS.

Increased Exceptional Response and Overall Survival Advantage for Patients with Multiple Myeloma Receiving Melphalan 200mg/m 2 Vs 140 Mg/m 2 Conditioning for Autologous Hematopoietic Stem Cell Transplantation

The standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplant (HSCT) is intravenous melphalan dosed at 200mg/m 2 (mel200). Prior retrospective studies indicated that dose reduction to melphalan 140 mg/m 2 (mel140) confers similar progression-free (PFS) and overall survival (OS), leading to increased use of mel140 in patients with comorbidities or advanced age. A recent single-center retrospective study (Sharma et al, Leukemia Lymphoma 2023) identified an OS advantage yet similar PFS for mel200 vs mel140, suggesting that certain patient cohorts may benefit from mel200. These findings require confirmation and better understanding of the risks and benefits to different dosing strategies. We performed a single-center retrospective study of mel dosing and transplant outcomes at the University of Nebraska Medical Center between 2008-2018. Three hundred and sixty-two patients underwent a first autologous HSCT with mel conditioning; 95 received mel140 while 267 received mel200. Nearly all patients received maintenance therapy (n= 357, 99%). Patient demographic and disease factors were largely comparable between mel140 and mel200 cohorts including sex, response prior to HSCT (both 73% for very good partial response or better), and presence of high-risk cytogenetics (t(4;14), t(14;16), t(14;20), del17p; 15% vs 14%). The mel140 group was older (65.1 years vs 59.7 years), had higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI) scores (64% vs 40% at ³3), and International Staging System (ISS) stages (40% vs 22% at stage III) than the mel200 group. Average creatinine clearance at transplant was 71 vs 91 mL/min/m 2 in the mel140 vs mel200 cohorts, respectively. OS favored mel200 with a median survival time of 94.4 vs 69.1 months (mel200 vs mel140, Figure 1, p = 0.002). There was no statistical difference in PFS between mel200 vs mel140 (median PFS 73.0 vs 60.5 months, p = 0.43, respectively). With Cox proportional hazards regression, we performed a multivariate analysis of risk factors on PFS and OS. For OS, age ( p = 0.02) retained statistical significance within the model. Mel dosing and high-risk cytogenetics (both p = 0.09) did not retain significance. HCT-CI may have an effect ( p = 0.04), but due to missing data on n= 125/362 subjects this could not be well evaluated. Response prior to HSCT, creatine clearance at transplant, and ISS stage were not statistically significant. Given the multiple variables assessed and missing data for HCT-CI we separately analyzed mel dosing together with the most significant variable in the model, age. In this subset OS model, mel200 was associated with an improved OS (hazard ratio (HR) 0.64, p = 0.03) while age was associated with an adverse effect (HR 1.11 per 5-year increase, p = 0.06). For the multivariate PFS model, only high-risk cytogenetics (HR 1.82 yes vs no, p = 0.004) retained statistical significance. Median engraftment was faster in mel200 cohort (67% vs 92% engraftment starting at ³D+12, p &amp;lt;0.001). We next examined the impact of mel dosing on the rate of exceptional response (Paquin et al, Blood Cancer Journal 2020), defined as alive and progression-free for 8 or more years. Twenty-nine of 362 patients (8%) met the requirements for exceptional response. Two (7%) received mel140 while 27 (93%) received mel200. Exceptional responders were younger and split evenly between male and female. The majority had at least a very good partial response prior to HSCT (79%). Only 2 exhibited high-risk cytogenetics; one received bortezomib and lenalidomide maintenance, the other only bortezomib. On multivariate analysis, only two factors contributed to exceptional response: mel dose (mel200 odds ratio (OR) 5.22, Table 1, p = 0.01) and HCT-CI (OR 0.66 for increasing score, Table 1, p = 0.02. High-risk cytogenetics was not associated with exceptional responders (OR 0.43 yes vs no, p = 0.38) which may be due to low sample size. We conclude that mel dosing impacts OS but not PFS in our cohort, though this effect is confounded by increasing age and potentially comorbidity. We report for the first time that mel200 dosing increases the rate of exceptional response compared to mel140. Overall, these data support recent conclusions by Sharma et al and challenge the previous reports of similar OS outcomes between mel200 and mel140 dosing.

Trametinib Maintenance in Patients with RAS Mutated Hematologic Malignancy Undergoing Allogeneic Haematopoietic Stem-Cell Transplantation: A Retrospective Transplant Study

Aim: The abnormal activation of MAPK signaling pathway plays an important role in the occurrence and development of leukemia. Whether MEK inhibitors can effectively reduce the recurrence of hematologic malignancy, We reviewed the efficacy and safety of trametinib maintenance in post-transplant patients with RAS mutations. Methods: Our study retrospectively analyzed 61 hematologic malignities with RAS mutation who underwent allo-HSCT at Beijing Gaobo Boren Hospital between January 2018 and January 2023. Twenty-five patients received maintenance therapy with trametinib post-HSCT(trametinib group), and 36 patients did not receive any maintenance therapy (control group). Trametinib group and control group also achieved CR at 2 months post-HSCT. Results: The diagnosed including AML (23, 37.7%), B-ALL (33, 54.1%), T-ALL (3, 5.0%), and 2 others (3.3%). Male: female = 29:32, The median age was 15 (1-68) years old. Before transplantation, 5 patients (8.2%) had extramedullary lesions and 16 patients (26.2%) had chromosomal abnormalities. The disease status before transplant was CR (42,68.9%),PR(6,9.7%),NR (13,21.3%) . 53 patients (86.9%) received second-line treatment. Fifteen cases (24.6%) were secondary transplants. Donor type included haploidential (45, 73.8%), identical sibling (5, 8.2%), and unrelated (11, 18.0%). Myeloablative conditioning regimen with eitherTBI/fludarabine (33, 54.1%) based or busulfan/fludarabine (28, 45.9%) based were applied. There were no significant differences between the two groups in age, sex, extramedullary disease,central nervous leukemia, karyotype analysis, disease status, conditioning regimen, donor type,acute and chronic GVHD and acute GVHD grades. The median follow-up time was 16.5 months (95%CI: 16.8-24.8 months), and the overall survival(OS) was 81.2% (95%CI: 68.6-89.1%). The disease-free survival (PFS) was 73.0% (95%CI: 59.7-82.5%). Trametinib group, the OS was 91.5% (95%CI: 70.0-97.8%), PFS was 88.0% (95%CI: 67.3-96.0%). Control group, the OS was 73.9% (95%CI: 55.9-85.6%), PFS was 65.8% (95%CI: 47.7-78.9%). Trametinib significantly improved the OS and DFS (P=0.044; P=0.041). In the trametinib group, 4 patients died after treatment, of which 3 died of relapse and 1 died of respiratory failure. In the non-trametinib group, 13 patients died, of which 6 died of relapse and 7 died of infection, stroke, GVHD and other causes. Trametinib treatment was initiated at a median of 94 days (range 63-178) at a median dose of 1 (range 0.5-2) mg daily.Trametinib was temporarily discontinued in 9 patients and dose modification in 12 patients because of side effects. mainly due to side effects including hematotoxicity in 5 patients, nosebleed in 4 patients, diarrhea in 1 patient, fatigue in 1 patient, and disease recurrence in 1 patient. The median modified daily dose was 0.5mg (range 0-1mg). Grade 2 AES occurred during the course of trametinib treatment, and no ≥ grade 3 AES was observed. The most common adverse events were neutropenia, anemia, thrombocytopenia, epistaxis, neutropenic fever, and fatigue, all of which were tolerable and reversible. No cardiorespiratory, renal, or neurotoxicity, or treatment-related deaths were observed. The median duration of trametinib maintenance therapy was 270 days (range 30-630 days). Conclusions: In this study, We have observed that trametinib maintenance post-transplantation can significantly improve the prognosis of patients with RAS mutations.Trametinib can be used as maintenance therapy with different conditioning regiments post-HSCT, which does not increase the risk of GVHD and organ injury, and is safe and effective. Future prospective clinical trials with larger sample sizes are needed for further research.

Olutasidenib for the Treatment of mIDH1 Acute Myeloid Leukemia in Patients Relapsed or Refractory to Hematopoietic Stem Cell Transplant, Prior mIDH1 Inhibitor, or Venetoclax

Introduction. Olutasidenib is a small molecule, oral, mutated-IDH1 (mIDH1) inhibitor approved for the treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). In the pivotal cohort of the registrational phase 1/2 trial, 51/147 (35%) patients achieved a complete remission (CR) or CR with partial hematologic recovery (CRh) to olutasidenib, with a duration of response of 25.9 months and an overall response rate (ORR) of 48%. The phase 1/2 study included 10 cohorts for a total of 335 patients, and there were patient subsets that were R/R to previous hematopoietic stem cell transplant (HSCT), ivosidenib (IVO) or venetoclax (VEN). We conducted post hoc analyses to better understand the response to olutasidenib in these poor-prognosis subgroups of mIDH1 AML. Methods. This Phase 1/2, open-label, multi-center study enrolled patients with confirmed AML or intermediate, high-, or very high-risk myelodysplastic syndromes/neoplasms (MDS). Patients received olutasidenib 100mg QD, 150mg QD or 150mg BID monotherapy or the combination of olutasidenib 150mg BID plus azacitidine. Patients were grouped by prior therapy. Baseline demographics and disease characteristics are shown in Table 1. The study was not powered to statistically evaluate subpopulations; descriptive statistics are provided. Data cutoff date is June 2021. Results. The post-HSCT group (n=31) had a relatively high median baseline bone marrow blast count (58%) and a median of 4 prior treatment regimens ( Table 1). Six (19%) of these patients had a CR (including the 1 patient with MDS), and 3 (10%) patients had a CR with incomplete count recovery (CRi) resulting in a 29% composite complete remission (CRc) rate. One patient had a morphologic leukemia-free status, resulting in a 32% ORR. Half the responders received monotherapy, and half received a combination of olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CR to prior HSCT; one of these patients maintained a CR for 13 months before progressing, and the other patient progressed and discontinued due to a new central nervous system disease ( Table 2). For the 10 patients with responses (ORR), the median duration of response was 7.1 months (range 1-23.4+). At data cutoff, 2 patients were ongoing responders, 3 patients proceeded to a second HSCT, and 3 to donor lymphocyte infusion (DLI). The post-IVO group (n=9) had a high median baseline bone marrow blast count (83%) and a median of 4 prior treatment regimens ( Table 1). Two patients (22%) achieved a CR; both CRc and ORR were 22% ( Table 2). Both responders had received olutasidenib in combination with azacitidine. One responder proceeded to HSCT after 3.1 months, and one responded for 5.6 months and then had disease progression. Response rates in the post-VEN group (n=20) included CR in 6 patients (30%), CRh in 1 (5%), and CRi in 2 (10%) resulting in a CRc of 9 (45%) and an ORR of 45% ( Tables 1 and 2). One responder received combination olutasidenib and azacitidine. Two patients were enrolled in the monotherapy maintenance cohort while in CRi to prior treatment; both improved their response to a CR. Median duration of response was not reached and ongoing at 28.5 months. At data cutoff, 5 patients continued treatment, and 15 had discontinued. Conclusions. This descriptive analysis suggests that olutasidenib alone or in combination with azacitidine may induce complete remissions in patients with mIDH1 AML or MDS that is R/R to VEN, IVO or even HSCT. Further investigation of these difficult-to-treat subpopulations is needed. Although only a small number of patients receiving maintenance therapy were included in this analysis, the data show that maintenance of a CR and even improvement of response from CRi to CR is possible with olutasidenib.

The Efficacy of Modified Melphalan and Busulfan-Based Conditioning Regimen for Autologous-HSCT in Low-Risk and Intermediate-Risk AML Patients

Abstract: Background: Treatment options for patients with low-risk and intermediate-risk acute myeloid leukemia (AML) patients (non-M3) who achieved complete response (CR) after one course of induction chemotherapy include consolidation chemotherapy, autologous hematopoietic stem cell transplantation (auto-HSCT) and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Compared with chemotherapy, auto-HSCT could significantly reduce relapse rate, as was associated with significantly lower transplant-related mortality compared with allo-HSCT, but relapse rate was relatively high. The selection of conditioning regimen was crucial to reduce relapse rate after transplantation. In this study, we made refinements in the conditioning regimen with two alkylating agents, namely MCBA (the combination of melphalan, cladribine, busulfan, and cytarabine). We aim to investigate the efficacy of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. Methods: This prospective multi-center clinical trial was conducted in 5 tertiary hospitals in China, and enrolled low-risk and intermediate-risk AML patients (non-M3) who achieved CR after one course of induction chemotherapy, followed by 1-3 courses of high-dose cytarabine consolidation chemotherapy, and underwent auto-HSCT from May 2021 to June 2023 (ChiCTR Registration ID: ChiCTR2200056167). The MCBA conditioning regimen consists of melphalan 70mg/m 2/d, day -6~-5, cladribine 5mg/m 2/d, day -4~-2, busulfan 3.2mg/kg/d, day -8~-7, cytarabine 2g/m 2/d, day -4~-2. Results and Discussion: This study included a total 21 AML patients, 14 males, 7 females, with median age 41 years (ranged 20-56 years). There were 8 of low-risk and 13 of intermediate-risk. The median infused mononuclear cell and CD34+ cell counts were 12.22×10 8/kg (ranged 1.79-34.68×10 8/kg) and 2.28×10 6/kg (ranged 1.05-17.15×10 6/kg) respectively. Neutrophil and platelet engraftment were achieved in all patients, with a median time of 13 days (ranged 11-27 days) and 32 days (ranged 12-150 days) respectively. On the day of reconstitution, all patients exhibited good responses, including hematologic CR and minimal residual disease (MRD) negativity rates of 100%. 11 (52.4%) patients received maintenance therapy after auto-HSCT, with a median time of 3.5 months (ranged 1-9 months). Azacytidine, venetoclax or geritinib were the main maintenance therapies. With a median follow-up of 306 days（ranged 43-798 days）, the estimated 1-year overall survival (OS) and 1-year disease-free survival (DFS) were 80.4±13.4% and 70.9±12.8%, respectively. 4 patients relapsed within 1year, and the median time from HSCT to relapse was 240 (101-314) days. The probability of relapsed rate was 29.1±12.8%. Mucositis was the main reported regimen-related toxicity, mostly were mild and well tolerated. Severe mucositis included grade Ⅱ liver damage (4.8%), grade Ⅱ oral mucositis (4.8%) and grade Ⅲ-Ⅳ diarrhea (9.5%), respectively. Conclusion: The preliminary data demonstrated the efficiency of MCBA conditioning regimen for auto-HSCT in low-risk and intermediate-risk AML patients who achieved CR after one course of induction chemotherapy. The regimen-related toxicity was well tolerated.

Association of Vaccination and Current Immunotherapy with COVID-19 Outcome in Patients with Follicular Lymphoma: A Retrospective Study

Introduction Immunotherapy (IO) based on anti-CD20 monoclonal antibodies significantly improves the prognosis of patients with follicular lymphoma (FL) in terms of disease progression, progression-free survival (PFS) and serious adverse events. Vaccination is protective in the general population, however, FL patients infected with COVID-19 have exacerbated damage to their immune system, and the effects of IO and vaccination on COVID-19 outcomes remain unknown. The aim of this study was to estimate the association between IO therapy based on anti-CD20 monoclonal antibody and COVID-19 severity by analyzing population-based data of FL patients. And to determine the true utility of vaccination in this immunocompromised population. Patients and methods We retrospectively assessed the clinical characteristics and follow-up data of patients with newly diagnosed FL from December 1, 2012 to April 1, 2023 at Shandong Provincial Hospital. Patients were divided into 2 groups: those who received IO, defined as anti-CD20 immunotherapy, within 12 months prior to COVID-19 diagnosis (IO group); those who received non-IO antitumor regimens with no systemic therapy (non-IO group), defined as cytotoxic chemotherapy, targeted therapies, endocrine therapies or those who did not receive any systemic therapy. Inclusion of data on anti-CD20 immunotherapy drugs Rituximab and Obinutuzumab applied in our center, stage of treatment, etc. COVID-19 outcomes were graded primarily on the basis of hospitalization, oxygenation, and need for mechanical ventilation, and patients' overall survival (OS) as well as PFS were studied. Multivariate logistic regression analyses were performed to assess associations between variables and COVID-19 outcomes, and unadjusted odds ratios (OR) and 95% confidence intervals (95%CI) were reported. Results Out of 160 patients included in the study ,77 (48.0%) were female, the median age was 53 (28-85 years) years, and the median follow-up was 54 (12-168 months) months. 131 (81.9%) patients had Ann Arbor stage III-IV on initial admission at our center, and 84 (52.5%) patients received the COVID-19 vaccine. Regarding COVID-19 infection, 137 (85.6%) were positive for COVID-19. 60 patients (37.5%) received IO, whereas 100 patients (62.5%) did not. Significant differences (P &amp;lt; 0.05) were found between the IO and non-IO groups in terms of COVID-19 outcome, time between COVID-19 diagnosis and FL diagnosis, and time to conversion after COVID-19 positivity (Figure 1A). There were also significant differences between the two groups in survival time and recurrent lung infection after COVID-19 cure (Figure 1B). No significant effect of vaccination on outcome of COVID-19 was found regardless of IO treatment. In the IO group, 42 (70.0%) patients received Rituximab and 18 (30%) patients received Obinutuzumab. No significant differences in COVID-19 infection rate, COVID-19 clinical outcome, time to COVID-19 conversion, and survival time were found between the two drugs. Of the patients who received IO therapy, 19 (31.7%) were in the induction phase and 41 (68.3%) were in the maintenance phase. Patients receiving maintenance therapy had a greater likelihood of longer survival（P&amp;lt;0.0001）and less severe COVID-19 outcomes（P=0.003）. Of the 60 patients treated with IO, 36 (60.0%) had an unchanged chemotherapy course and 24 (40.0%) had a delayed or interrupted chemotherapy course. No significant associations were found between IO therapeutic agents, vaccinations, or other variables with chemotherapy progression. Conclusions Among FL patients included in the analysis, IO was associated with worse COVID-19 outcomes, but no significant correlation was found between vaccination and COVID-19 infection rates and severity at this time. These findings provide insights into the immunocompromised population of FL-combined COVID-19 patients that can be used in the clinical setting to estimate COVID-19 outcomes based on factors such as chemotherapy stage and vaccination.

The Combination of Intravenous Immunoglobulin (IVIG) and Low Does Recombinant Human Thrombopoietin (rhTPO) for the Management of Corticosteroid/IVIG Monotherapy-Resistant Immune Thrombocytopenia in Pregnancy

Introduction Primary immune thrombocytopenia (ITP) is a common autoimmune disease characterized by a low platelet count resulting from antibody-mediated platelet destruction and insufficient platelet production. ITP, with a prevalence of 1 in 1000-10 000 pregnancies, accounts for approximately 3% of all causes of thrombocytopenia in pregnancy and is reported to be the most common cause of thrombocytopenia in the first and early second trimesters. It has been revealed that severe ITP is associated with devastating outcomes. It remains a challenge to manage pregnant patients with ITP. First-line treatment options in pregnant ITP patients currently include corticosteroids and intravenous immunoglobulin (IVIg). However, previous studies reported that the response rate of pregnant ITP patients to corticosteroids was less than 40% and that to IVIg was 38-56%, which was lower than that of nonpregnant ITP patients. The second-line treatment options are limited for pregnant ITP patients. Recombinant human thrombopoietin (rhTPO), a full-length and glycosylated TPO with a molecular weight of 90 000 Daltons developed by 3SBIO (Shenyang, China), has also been approved by the China State Food and Drug Administration as a second-line option for nonpregnant ITP patients. It cannot cross the placenta theoretically with such a large molecular weight, and thus, it has an apparent theoretical advantage over the two TPO mimetics since it would not impact the fetus. A study investigating the application of rhTPO in pregnancy suggested that rhTPO was a potentially effective and well-tolerated treatment option for ITP patients during pregnancy. It might be explained that the development of ITP was associated with increased platelet destruction and impaired platelet production, and the combination of IVIg and TPO mimetics impacts these two targets since IVIg could reduce platelet destruction, whereas TPO mimetics could increase platelet production. Therefore, we conducted a monocenter, single-arm, open-label study to investigate the efficacy and safety of low-dose rhTPO plus IVIg in pregnant corticosteroid/IVIg monotherapy-resistant ITP patients. Methods This study was registered at www.clinicaltrials.gov as NCT05634824.The following criteria were considered: patients have a diagnosis of primary ITP before or first onset during pregnancy; patients ≥ 18 years; patients complicated with bleeding manifestations and/or have a platelet count &amp;lt; 30 × 10^9/L and failed to respond to initial treatment of corticosteroids or intravenous immunoglobulin (IVIg) monotherapy or relapsed during the tapering or discontinuation of corticosteroids. For those patients, the initial combination therapy consisted of rhTPO at an initial dose of 150 U/kg once daily subcutaneously for 28 days and IVIg 400 mg/kg per day for 5 days. If the platelet count was in the range of 30 to 50 × 10^9/L, the combination therapy was repeated. To reduce the risk for thrombocytosis, patients received maintenance therapy consisting of rhTPO at a dose of 150 U/kg per day if the platelet count rose above 50 × 10^9/L, and treatment was discontinued when platelet counts exceeded 100 × 10^9/L. After delivery, the treatment consisted of rhTPO 150 U/kg per day, and the dose was maintained if the platelet count exceeded 30 × 10^9/L. In addition, IVIg 400 mg/kg per day for 5 days was added if the platelet count could not be maintained above 30 × 10^9/L. If patients did not achieve a count of 30 × 10^9/L within 4 weeks, treatment was also discontinued. Results The study included 19 patients with thrombocytopenia during pregnancy who were admitted to Peking University People's Hospital from December 1, 2022, to May 30, 2023, all of whom had failed hormone and IVIG treatment. The median age of those patients was 34 years old (range 20 to 42 years old), and the median platelet count before treatment was 13×10^9/L (range 1-30×10^9/L). The four-week response rate was 63.2% (12/19), and the median response time was 7.5 days (range 5 to 35 days). There were no treatment-related adverse reactions. Conclusions Low-dose rhTPO plus IVIg in pregnant corticosteroid/IVIg monotherapy-resistant ITP patients is effective and safe. These findings suggest that IVIg plus low-dose rhTPO may represent a potential combination therapy for pregnant patients with ITP.