Treatment-related Mortality Research Articles

Utility of the frailty score for predicting prognosis and individualizing treatment intensity in elderly patients with diffuse large B cell lymphoma.

The optimal dose intensity of chemotherapy for elderly patients with diffuse large B cell lymphoma (DLBCL) remains controversial because of concerns about adverse events and comorbidities related to the patients' frailty. This single-center study retrospectively analyzed patients aged ≥ 70 years who were newly diagnosed with DLBCL and received chemotherapy between 2004 and 2022. Survival outcomes and treatment-related mortality (TRM) were stratified according to geriatric assessment variables, and the influence of chemotherapy dose intensity on outcomes was assessed using the frailty score with a Cox hazards model with restricted cubic spline (RCS) in patients aged 70-79 years. In total, 337 patients were included. The frailty score accurately predicted prognosis (5-year overall survival [OS]: 73.1%, 60.2%, and 29.7% in fit, unfit, and frail patients, respectively; P < 0.001) and TRM (5-year TRM: 0%, 5.4%, and 16.8 in fit, unfit, and frail patients, respectively; P < 0.001). Cox regression with RCS demonstrated a linear association between dose intensity and survival outcomes. Initial dose intensity (IDI) and relative dose intensity (RDI) had a significant impact on OS in fit patients. However, IDI and RDI had no significant effect on survival in non-fit (unfit and frail) patients. The frailty score identified non-fit patients with poorer survival and a higher risk of TRM. While fit patients were likely to benefit from full-dose R-CHOP, unfit and frail patients would likely benefit more from attenuated R-CHOP. This study suggested a potential role for the frailty score in individualizing treatment intensity in elderly patients with DLBCL.

Effective treatment of severe forms of RSV and Pneumocystis jirovecii infections in a child with Down syndrome and acute lymphoblastic leukemia treated with chemotherapy

There has been significant progress in acute lymphoblastic leukemia (ALL) treatment throughout the previous decades. However, infectious complications are still the main problem during cancer treatment. Literature reports show that treatment-related mortality is 2–4% and is mainly related to infection. Here, the authors report a 3-year-old patient with Down syndrome and ALL who was hospitalized in the Department of Pediatric Hematology, Oncology and Transplantology of the Medical University of Lublin. The patient was treated according to the AIEOP-BFM 2017 protocol and developed a severe co-infection of Pneumocystis jiroveci and respiratory syncytial virus during the induction phase of chemotherapy and P. jiroveci re-infection while receiving Protocol II. As a result, chemotherapy was interrupted for 51 and 31 days, respectively. The patient required the administration of broad-spectrum antibiotics, antiviral and antifungal therapy and passive oxygen therapy. Due to a severe clinical condition, the patient was also temporarily hospitalized in the Intensive Care Unit. Research revealed several risk factors for infectious complications in patients with ALL including intensive chemotherapy or Down syndrome. Therefore, despite anti-infective prophylaxis, increased medical vigilance is necessary. In the case of infectious symptoms, early diagnosis and prompt treatment should be implemented to enable the continuation of the ALL therapeutic protocol.

Autologous hematopoietic stem cell transplantation in multiple sclerosis: A 20-year single center’s experience in Mexico. (P14-3.015)

<h3>Objective:</h3> To describe the clinical characteristics and clinical outcomes of AHSCT in Mexican patients. <h3>Background:</h3> Autologous Hematopoietic Stem Cell treatment (AHSCT) is an immune reconstitution treatment option for Multiple Sclerosis (MS) that has grown in clinical evidence over the last decades; detailed efficacy and safety data is still lacking, especially outcomes data from low-income countries. <h3>Design/Methods:</h3> Retrospective single-center observational study of all MS patients that underwent AHSCT in a single reference center in Mexico City from January 2000 to January 2020. <h3>Results:</h3> We identified 24 patients, of which 22 had at least one year of follow-up after AHSCT and underwent analysis for clinical outcome. The median follow-up time was 85 months (range: 12–267); with a median age of 44.0 years (IR 38–52); 62.8% (n=15) were men and 31.8% (n=7) women; 50% were secondary progressive forms of MS (SPMS), and 27.3% were relapsing-remitting MS (RRMS); 59% (n=13) met the criteria for highly active MS (HAMS). The composite score of no evidence of disease activity 3 or NEDA3 (no relapses, no new MRI lesions, and no EDSS progression) was achieved in all the patients at a 24-month follow-up and in 72.1% (n=16) of the patients at the time of the last follow up visit. Relapse-free survival at the last follow-up visit was achieved at 77.3%; MRI event-free survival at 90.9%; Expanded disability status scale score progression-free survival in 95.4%. Only one patient required the re-initiation of disease-modifying therapy. There was no treatment-related mortality. One patient was diagnosed with premature ovarian failure. <h3>Conclusions:</h3> AHSCT in Mexican MS patients is an effective and relatively safe treatment option with no mortality and can be performed with a reasonable degree of safety at experienced centers. <b>Disclosure:</b> Dr. Rodriguez Estrada has nothing to disclose. Dr. Molina Carrion has nothing to disclose.

Long-term outcome in patients with mantle cell lymphoma following high-dose therapy and autologous stem cell transplantation.

Long-term clinical and molecular remissions in patients with mantle cell lymphoma (MCL) after autologous stem cell transplantation (ASCT) have been evaluated in only a few studies. Sixty-five patients with MCL received ASCT (54 first-line ASCT, 10 second-line ASCT, and 1 third-line ASCT). In the case of long-term remission (≥5 years; n = 27), peripheral blood was tested for minimal residual disease (MRD) by t(11;14)- and IGH-PCR at the last follow-up. Ten-year overall survival (OS), progression-free survival (PFS), and freedom from progression (FFP) after first-line ASCT were 64%, 52%, and 59% versus after second-line ASCT 50%, 20%, and 20%, respectively. Five-year OS, PFS, and FFP for the first-line cohort were 79%, 63%, and 69%, respectively. Five-year OS, PFS, and FFP after second-line ASCT were 60%, 30%, and 30%, respectively. Treatment-related mortality (3 months after ASCT) was 1.5%. So far 26 patients developed sustained long-term clinical and molecular complete remissions of up to 19 years following ASCT in first treatment line. Sustained long-term clinical and molecular remissions are achievable following ASCT.

Vertebral-Venous fistulas: Single center experience and practical treatment approach

Vertebral-venous fistulas (VVFs) are rare. Scarce literature exists to guide our understanding and management. We report our experience and propose a classification based on flow, feeder number, and involvement of accessible veins. Additionally, we include a practical treatment approach. Retrospective chart and imaging review of cerebrovascular arteriovenous fistulas treated in our center between July 2013 and April 2022. We reviewed patient demographics, presentation, imaging, treatment strategies, and outcomes. Nine patients with VVFs were identified, six were females. Ages ranged between 38-83 years. There were six high-flow and three low-flow. Most VVFs originated at the level of V3. Additional feeders from the internal carotid artery, external carotid artery, and/or subclavian artery were present in four cases (two were high-flow). Four cases had multiple arterial feeders. All cases were symptomatic. Origin was spontaneous in eight and iatrogenic in one case. Most common presenting symptoms were pain (7) and pulsatile tinnitus (4). Neurological deficits were present in two cases (1 high- and 1 low-flow). Four cases were treated with vertebral artery segmental sacrifice alone, three required multiple transarterial embolizations with or without VA sacrifice, one case had single transvenous approach, and one was treated with single targeted transarterial embolization. One patient had a minor transient neurological complication. No treatment-related mortality was seen. Treatment of high-flow and symptomatic low-flow VVFs is feasible and safe. Our classification and treatment approach might help guide patient selection and choice of endovascular approach. However, our approach warrants further validation with a larger number of patients.

Safety and efficacy of tisagenlecleucel in patients with relapsed or refractory B-cell lymphoma: the first real-world evidence in Japan.

Tisagenlecleucel, an autologous CD19-directed T-cell immunotherapy, can induce a durable response in adult patients with relapsed/refractory (r/r) B-cell lymphoma. To elucidate the outcome of chimeric antigen receptor (CAR) T-cell therapy in Japanese, we retrospectively analyzed the outcomes of 89 patients who received tisagenlecleucel for r/r diffuse large B-cell lymphoma (n = 71) or transformed follicular lymphoma (n = 18). With a median follow-up of 6.6-months, 65 (73.0%) patients achieved a clinical response. The overall survival (OS) and event-free survival (EFS) rates at 12months were 67.0% and 46.3%, respectively. Overall, 80 patients (89.9%) had cytokine release syndrome (CRS), and 6 patients (6.7%) had a grade ≥ 3 event. ICANS occurred in 5 patients (5.6%); only 1 patient had grade 4 ICANS. Representative infectious events of any grade were cytomegalovirus viremia, bacteremia and sepsis. The most common other adverse events were ALT elevation, AST elevation, diarrhea, edema, and creatinine elevation. No treatment-related mortality was observed. A Sub-analysis showed that a high metabolic tumor volume (MTV; ≥ 80ml) and stable disease /progressive disease before tisagenlecleucel infusion were both significantly associated with a poor EFS and OS in a multivariate analysis (P < 0.05). Notably, the combination of these 2 factors efficiently stratified the prognosis of these patients (HR 6.87 [95% CI 2.4-19.65; P < 0.05] into a high-risk group). We report the first real-world data on tisagenlecleucel for r/r B-cell lymphoma in Japan. Tisagenlecleucel is feasible and effective, even in late line treatment. In addition, our results support a new algorithm for predicting the outcomes of tisagenlecleucel.

Phase II study of dose-adjusted EPOCH as initial therapy for adults with high-risk acute lymphoblastic leukemia

Treatments for adults with newly-diagnosed acute lymphoblastic leukemia (ALL) may be prohibitively toxic and/or resource-intense. To address this, we performed a phase II study of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-EPOCH). Imatinib or dasatinib was added for Ph + disease; rituximab was added when CD20+. Fifty-three patients were evaluable: 28 with Ph + disease, and 25 with Ph−. All patients had ≥1 high-risk clinical feature. Measurable residual disease-negativity by multiparameter flow cytometry within 4 cycles was achieved in 71% in patients with Ph + ALL and 64% in Ph − ALL. Median overall survival (OS) was 49 months, with a 2-year OS of 71%. Median relapse-free survival (RFS) in the 47 patients that attained morphologic remission was 24 months, with a 2-year RFS of 57%. Early mortality was 2%. In summary, DA-EPOCH yields deep and durable remissions in adults with ALL comparable to some resource-intense strategies but with a low rate of treatment-related death.

Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation.

The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes. The study population consisted of 2249 donor-recipient pairs treated for acute myeloid leukemia and myelodysplastic syndrome with alloHCT. A Cox proportional hazard model showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.01, 1.77, p = .046). Competing risk analyses identified the class I mHAs DLRCKYISL (GSTP), WEHGPTSLL (CRISPLD2), and STSPTTNVL (SERPINF2) were associated with increased GVHD mortality (HR = 2.84, 95% CI = 1.52, 5.31, p = .01), decreased leukemia-free survival (LFS) (HR = 1.94, 95% CI = 1.27, 2.95, p = .044), and increased disease-related mortality (DRM) (HR = 2.32, 95% CI = 1.5, 3.6, p = .008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR = 3.05, 95% CI = 1.75, 5.31, p = .02). WEHGPTSLL and STSPTTNVL were both present within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to the risk of mortality in an additive manner. Our study reports the first large-scale investigation of the associations of predicted mHA peptides with clinical outcomes following alloHCT.

Anakinra for Refractory Cytokine Release Syndrome or Immune Effector Cell-Associated Neurotoxicity Syndrome after Chimeric Antigen Receptor T Cell Therapy

Chimeric antigen receptor-engineered (CAR)-T cell therapy remains limited by significant toxicities, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The optimal management of severe and/or refractory CRS/ICANS remains ill-defined. Anakinra has emerged as a promising agent based on preclinical data, but its safety and efficacy in CAR-T therapy recipients are unknown. The primary objective of this study was to evaluate the safety of anakinra to treat refractory CRS and ICANS after CAR-T therapy. The secondary objective was to evaluate the impact of key treatment-, patient-, and disease-related variables on the time to CRS/ICANS resolution and treatment-related mortality (TRM). We retrospectively analyzed the outcomes of 43 patients with B cell or plasma cell malignancies treated with anakinra for refractory CRS or ICANS at 9 institutions in the United States and Spain between 2019 and 2022. Cause-specific Cox regression was used to account for competing risks. Multivariable cause-specific Cox regression was used to estimate the effect of anakinra dose on outcomes while minimizing treatment allocation bias by including age, CAR-T product, prelymphodepletion (pre-LD) ferritin, and performance status. Indications for anakinra treatment were grade ≥2 ICANS with worsening or lack of symptom improvement despite treatment with high-dose corticosteroids (n=40) and grade ≥2 CRS with worsening symptoms despite treatment with tocilizumab (n=3). Anakinra treatment was feasible and safe; discontinuation of therapy because of anakinra-related side effects was reported in only 3 patients (7%). The overall response rate (ORR) to CAR-T therapy was 77%. The cumulative incidence of TRM in the whole cohort was 7% (95% confidence interval [CI], 2% to 17%) at 28 days and 23% (95% CI, 11% to 38%) at 60 days after CAR-T infusion. The cumulative incidence of TRM at day 28 after initiation of anakinra therapy was 0% in the high-dose (>200 mg/day i.v.) recipient group and 47% (95% CI, 20% to 70%) in the low-dose (100 to 200 mg/day s.c. or i.v.) recipient group. The median cumulative incidence of CRS/ICANS resolution from the time of anakinra initiation was 7 days in the high-dose group and was not reached in the low-dose group, owing to the high TRM in this group. Univariate Cox modeling suggested a shorter time to CRS/ICANS resolution in the high-dose recipients (hazard ratio [HR], 2.19; 95% CI, .94 to 5.12; P=.069). In a multivariable Cox model for TRM including age, CAR-T product, pre-LD ferritin level, and pre-LD Karnofsky Performance Status (KPS), higher anakinra dose remained associated with lower TRM (HR, .41 per 1 mg/kg/day increase; 95% CI, .17 to .96; P=.039. The sole factor independently associated with time to CRS/ICANS resolution in a multivariable Cox model including age, CAR-T product, pre-LD ferritin and anakinra dose was higher pre-LD KPS (HR, 1.05 per 10% increase; 95% CI, 1.01 to 1.09; P=.02). Anakinra treatment for refractory CRS or ICANS was safe at doses up to 12 mg/kg/day i.v. We observed an ORR of 77% after CAR-T therapy despite anakinra treatment, suggesting a limited impact of anakinra on CAR-T efficacy. Higher anakinra dose may be associated with faster CRS/ICANS resolution and was independently associated with lower TRM. Prospective comparative studies are needed to confirm our findings.

Abstract 6309: Anti-tumor efficacy of SI-B001, a novel EGFR × HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin

Abstract EGFR is a member of the human epidermal growth factor receptor (ErbB) family with tyrosine kinase activity. Evidence indicates that EGFR is involved in the pathogenesis and progression of human carcinoma of different types. HER3 is a unique pseudokinase receptor of the ErbB family and known to mediate resistance to EGFR-targeting therapies. Therefore, we created SI-B001, an EGFR × HER3 bispecific antibody, which can bind EGFR × EGFR homodimers and EGFR × HER3 heterodimer to block their downstream pathways. We performed non-clinical studies to investigate in vitro and in vivo anti-tumor effects. In vitro, the inhibition of tumor cell growth by SI-B001 was stronger than cetuximab and duligotuzumab in FaDu (mRNA expression levels of EGFRhigh/HER3high/NRG1medium). Importantly, testing with the cell line Oka-c-1 (mRNA expression levels of EGFRhigh/HER3high/NRG1low), showed that NRG1 supplementation did not change the potency of cetuximab. However, SI-B001 showed much stronger potency than cetuximab and duligotuzumab under conditions of NRG1 supplementation. This result indicates that the functionality of the bi-specific SI-B001 is competitive against a HER3 natural ligand and capable to act against cancer with HER3 ligand mediated resistance to cetuximab. In vivo, single agent SI-B001 exhibited superior anti-tumor activity to cetuximab in the FaDu xenograft model. Meanwhile, SI-B001 in combination with paclitaxel and carboplatin led to a significant synergistic antitumor effect, which was stronger than the combination of cetuximab + paclitaxel + carboplatin. Compared to chemotherapy alone in this model, which could result in weight loss and treatment related mortality, no serious weight loss or deaths occurred in the single agent SI-B001 and the combination of SI-B001 with chemotherapy. These results suggest that SI-B001 alone and in combination with chemotherapy can exhibit favorable safety and robust anti-tumor activity. Currently, 6 phase II clinical trials of SI-B001, either alone or in combination with chemotherapy, have been conducted in different epithelial carcinomas. These studies have shown a potential break-through activity in NSCLC and HNSCC with a very good safety profile. Citation Format: Blair Renshaw, Jahan Salar Khalili, Sa Xiao, Yi Zhu. Anti-tumor efficacy of SI-B001, a novel EGFR × HER3 bispecific antibody, against EGFR-driven epithelial tumors alone or in combination with paclitaxel and carboplatin. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6309.

Abstract 484: VIP236: A small molecule drug conjugate with an optimized camptothecin payload has significant activity in patient-derived and metastatic cancer models

Abstract Introduction: We previously presented the design and preliminary characterization of VIP236—an SMDC consisting of an αvβ3 integrin binder linked to an optimized camptothecin topoisomerase I (TOP1) inhibitor payload released by neutrophil elastase in the tumor microenvironment (Lerchen et al, Cancers 2022). Herein we evaluate VIP236 in patient-derived and metastatic models of cancer. Methods: Subcutaneous patient-derived xenograft mouse models in non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colorectal cancer (CRC), and triple negative breast cancer (TNBC) were treated with VIP236. Metastasis formation was measured by human DNA PCR in an orthotopic TNBC mouse model. Gastric cancer models included patient-derived and cell line xenograft mouse models. Tumor/control (T/C) ratios were calculated, and body weight was measured. Pharmacodynamic (PD) effect of VIP236 in a gastric cancer SNU16 xenograft mouse model was investigated. Tumor samples from vehicle- and VIP236-treated groups collected up to 144 hours postdose were analyzed for % positive γH2AX cells by a fit-for-purpose qualified immunohistochemistry assay. Results: VIP236 is efficacious in vivo patient-derived models of NSCLC, RCC, CRC and TNBC with T/C ratios of 0.0, 8.9,14.5 and 5.6 compared with vehicle control (p&amp;lt;0.0001, CRC p&amp;lt;0.01). VIP236 showed statistically improved in vivo efficacy in gastric cancer models versus trastuzumab deruxtecan (a commercial antibody-drug conjugate [ADC] with a camptothecin payload) in NCIH87 (HER2high, p&amp;lt;0.05), SNU16 (HER2neg, p&amp;lt;0.001), and GXA3040 (patient-derived, HER2low, p&amp;lt;0.001) xenografts. VIP236 induced statistically significant tumor growth inhibition in a patient-derived CRC liver metastasis model (p&amp;lt;0.01) and statistically significant reduction in lung (p&amp;lt;0.001) and brain (p&amp;lt;0.01) metastasis from an orthotopic TNBC model was observed. Across all in vivo models no clinically significant weight loss or treatment-related mortality were observed. Furthermore, a time-dependent increase of γH2AX % positive cells in SNU16 in vivo VIP236-treated tumors confirms that VIP236 drives robust TOP1 inhibition and subsequent DNA damage. Conclusions: In summary, VIP236 monotherapy efficacy in NSCLC, gastric, TNBC, RCC, CRC, and metastatic TNBC in vivo cancer models provides a rationale for clinical investigation in advanced metastatic solid tumors. In gastric cancer, VIP236 showed improved efficacy compared with the approved ADC, trastuzumab deruxtecan, regardless of HER2 expression. These results warrant further evaluation in clinical trials. Citation Format: Beatrix Stelte-Ludwig, Melanie M. Frigault, Hans-Georg Lerchen, Tibor Schomber, Raquel Izumi, Amy J. Johnson, Ahmed Hamdy. VIP236: A small molecule drug conjugate with an optimized camptothecin payload has significant activity in patient-derived and metastatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 484.

Abstract 5657: HK010, a novel anti-PDL1 × CD137 bispecific antibody, exhibits potent anti-tumor immunity and low toxicity

Abstract Background: Checkpoint inhibitors targeting the PD-1/PD-L1 have changed the treatment and prognosis for patients with advanced solid tumors. There remains a unmet need for additional therapies due to treatment resistance. Tumor-necrosis superfamily members, such as CD137 and CD40, have been shown to synergize with the checkpoint inhibitors in preclinical studies. However, agonists antibodies have exhibited limited clinical activity for severe liver toxicity. Here we have developed a Fc-silenced bispecific antibody targeting PD-L1 and CD137, HK010, which could overcome these limitations by tumor-directed T-cell activation and checkpoint blockade. Methods: The antigen binding specificity and affinity of HK010 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) and flow cytometry. The functional activity of HK010 was determined using in vitro cell-based assays and reporter gene assay. Transgenic mice expressing human PD-L1 and 4-1BB were transplanted with human PD-L1-expressing murine MC38 cells to assess in vivo antitumor activity. Cytokine release assay was conducted by incubating HK010 with peripheral blood mononuclear cells (PBMCs) from healthy donors (n=6). The pharmacokinetic (PK) behavior and safety profiles of HK010 were characterized in cynomolgus monkeys. Results: HK010 is a IgG4 PD-L1 × 4-1BB bsAb, which was designed to maintain a high affinity for human PD-L1 and a low affinity for human 4-1BB (KD PD-L1: 2.27 nM; KD 4-1BB: 493 nM) to achieve strong blocking of PD-1/PD-L1 and appropriate agonism of 4-1BB. HK010 retained full blockade activity on PD-1/PD-L1 signaling and enhances T-cell proliferation and IFN-γ production in vitro primary cell assays and Mixed lymphoid reaction (MLR). In addition, it led to a dose-dependent increase in the CD137-driven NFκB reporter gene activation through the bridging of PD-L1 on target cells and CD137 on effector cells. In humanized PD-L1/4-1BB transgenic mice bearing with MC38/hPDL1 tumor, HK010 showed robust single agent anti-tumor activity and induced durable antigen-specific immunological memory that prevents the growth of the same tumor cells in the mice re-challenged. There were no signs of toxicity in human cytokine release assay for HK010. Toxicology data in cynomolgus monkeys showed that HK010 was well-tolerated up to 150 mg/kg (MTD≥150mg/kg) dose without systemic toxicity. Furthermore, HK010 was confirmed to be highly safe in the 5-week repeated-dose toxicity study with no observed treatment-related mortality, abnormality in hematological indexes, important organs. Conclusion: These data demonstrate that HK010, an anti-PD-L1 × CD137 bispecific antibody, may exert a strong localized anti-tumor therapeutic efficacy with a low risk of liver toxicity through tumor-directed T-cell activation and checkpoint blockade in tumors. Citation Format: Liangwei Li, Wenting Liu, Guodong Shen, Dayan Zhang, Weiming Zhou, Fengrong Wang, Xiaoli Zeng, Yang Huang, Liansheng Cheng. HK010, a novel anti-PDL1 × CD137 bispecific antibody, exhibits potent anti-tumor immunity and low toxicity. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5657.

Is Old (Fludrabine/Busulfan/Cyclophosphamide/rAntiThymocyteGlobulin) Conditioning Still Gold for Allogeneic Transplants in Transfusion Dependent Beta-Thalassemia of All Risk Categories in 21st Century?

Allogeneic stem cell transplant (allo-SCT) is the only curative option for transfusion dependent thalassemia (TDT) until the gene therapy could bring paradigm shift. We analysed TDT allo-SCTs performed with Flu/Bu/Cy/rATG conditioning between October 2018 and April 2022 at our center. A retrospective analysis of 55 consecutive HLA matched alloSCT for TDT and was approved by hospital's Institutional Review Board. Median age was 7(2-13) years. On presentation, number of patients with Class I, II, III were 18 (32.7%), 14(25.4%) and 23(41.8%) respectively {ClassIIIA = 14(25.4%),ClassIIIB = 9(16.3%)}. After downstaging, Class I, II, III were 22(40%), 15(27.2%) and 18(32.7%) patients respectively {ClassIIIA = 15(27.2%),ClassIIIB = 3(5.4%)}. Graft was bone marrow in 53(96.4%) and peripheral blood stem cell in 2(3.6%) patients. Mean CD34 stem cell dose was 3.28(1.2-6.5) × 106/kg. Neutrophils and platelets engrafted at a median of 16(12-32) and 17(12-48) days. Median duration of follow-up was 20.7(1.8-43.9) months. There was no primary rejection. Although, mixed chimerism was common {17(30.9%)}, there was only one secondary rejection (1.8%). Venoocclusive disease was seen 12(21.8%) patients {mild = 9(75%), moderate = 2(16.6%) and severe = 1(8.3%)}. Acute and Chronic graft versus host disease was observed in 4(7.2%) and 4(7.2%) patients respectively. There was no treatment related mortality. Overall survival and Thalassemia Free Survival were 100% ± 0% and 98% ± 2% respectively. Flu/Bu/Cy/rATG conditioning with BM graft is a safe and effective regimen even in higher risk. It also highlights the importance of pretransplant downstaging of risk class in improving the outcomes.

Efficacy and Safety of Allogeneic Hematopoietic Stem Cell Transplantation with Decitabine-containing Regimen in Myelodysplastic Syndromes and Myelodysplastic Syndromes Transformed Acute Myeloid Leukemia

To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML). The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m2 /d×3 d). Among the 93 patients, 63 males and 30 females, were diagnosed as MDS（n ＝77）, MDS-AML（n ＝16）. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host disease（aGVHD） and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host disease（cGVHD） and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OS（P =0.008）and DFS (P =0.019). Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.

Use of granulocyte colony-stimulating factor in patients with chemotherapy-induced neutropaenia.

Febrile neutropaenia (FN) and resultant infections are the major cause of treatment-related morbidity and mortality in patients receiving chemotherapy. Clinical practice guidelines recommend the use of granulocyte colony-stimulating factors (G-CSF) to reduce the risk of FN and ensuing complications in patients receiving chemotherapy. Despite these recommendations, inappropriate usage of G-CSF has been reported. To assess prescribing patterns and adherence to international guidelines of G-CSF in adult patients with chemotherapy-induced neutropaenia (CIN) at the haematology oncology wards of the Dr George Mukhari Academic Hospital (DGMAH) and compliance to guidelines. Medical records of adult patients who received G-CSF were reviewed retrospectively between 01 January 2018 and 31 July 2018. Of the 128 patient files screened, 57 cases met the inclusion criteria. Duration of treatment with G-CSF was not in accordance with guidelines in more than 50% of the patients and in 43.86%, G-CSF dosing deviated from recommended guidelines. The study demonstrated over-prescribing of G-CSF due to either increased doses or duration of G-CSF therapy. Although prescribed for the correct indication, the dosage was often too high or the duration was too long, even once an acceptable neutrophil nadir count was reached. Interventions to optimise the use of G-CSF are required and the pharmacist may play a role in this regard. The administration of the correct doses of G-CSF can reduce both the severity and duration of neutropaenia. Over-prescribing and incorrect dosing may contribute to patient morbidity and add to the financial burden of healthcare.

Effectiveness of pegfilgrastim prophylaxis in preventing febrile neutropenia during R-FC chemoimmunotherapy for chronic lymphocytic leukemia: A multicenter prospective phase II study.

A chemotherapy of rituximab, fludarabine and cyclophosphamide (R-FC) has been accepted as a promising frontline chemotherapy in selected patients with chronic lymphocytic leukemia (CLL). Although R-FC regimen is a relatively dose-dense regimen and neutropenia incidence is more than 50%, primary prophylactic pegfilgrastim was not fully recommended in the clinical field. Therefore, the study evaluated the prophylactic effectiveness of pegfilgrastim to reduce the incidence of febrile neutropenia associated with R-FC of patients with CLL. A single-arm, multicenter, prospective phase II study was designed to assess the efficacy of prophylactic pegfilgrastim. Thirty-four CLL patients were enrolled and analyzed for neutropenia and other related factors, and comparative analysis was performed with historical cohort. Compared with our historical cohort, incidence of grade 3-4 neutropenia and febrile neutropenia was remarkably reduced during any cycle of chemotherapy (14.7% vs. 48.2% of study cohort vs. historical cohort during C1, 5.9% vs. 65.8% during C2, 12.9% vs. 80.6% during C3, 10% vs. 84.6% during C4, 3.4% vs. 83.6% during C5, and 10.7% vs. 85.7% during C6, p <0.001). Also, cumulative incidence of disrupted chemotherapy was noticeably reduced in study cohort on any cycles of R-FC regimen (8.8% vs. 22.2% of study cohort vs. historical cohort on C2, 9.7% vs. 25.2% on C3, 13.4% vs. 26.9% on C4, 13.8% vs. 45.2% on C5, 17.9% vs. 47.3% on C6, p=0.007). In addition, treatment-related mortality was 5.9%, which significantly reduced compared to 9.6% of our historical cohort (HR 0.64, 95% CI 0.42-0.79, P = 0.032). Primary prophylactic pegfilgrastim is effective in the prevention of neutropenia/febrile neutropenia, and infection-related mortality during R-FC regimen in patients with CLL.

Acute and sub-acute toxicity evaluation of Merremia tridentata (L.) stem extract on mice

The acute and sub-acute toxicity studies were performed in male and female Swiss albino mice as per the guidelines mentioned in OECD. The oral administration of M. tridentata stem extract (MSE) showed no treatment-related mortality and body weight change in mice up to the single dose of 30,000 mg/kg body weight in the acute toxicity study and up to a dose of 30,000 mg/kg/day body weight in the sub-acute toxicity study. Moreover, the clinical signs, body weight, gross pathology, organ weight, hematology (except for platelet count), biochemical analysis, and histopathology did not show significant variation at a medium dose of 15,000 mg/kg/day body weight compared to the control group. However, toxicological signs in behavior, very mild interstitial nephritis, as well as significant variation in platelet count and total protein parameters were observed at a dose of 30,000 mg/kg/day in the 28-day oral toxicity study. Thus, the no-observed-adverse-effect level was determined at a dose of 15,000 mg/kg/day body weight. Based on study results, it is concluded that MSE showed LD50 of greater than 5000 mg/kg/day body weight. Hence, this could be a potential candidature as a future safe pharmaceutical product.

Are more courses of immunochemotherapy beneficial for the short-term outcome of locally advanced esophageal squamous cell carcinoma?

Immune checkpoint inhibitor (ICI) monotherapy and neoadjuvant immunochemotherapy have shown promising results in esophageal carcinoma. However, it is still unclear whether more courses of immunochemotherapy are therapeutically better. We aimed to investigate the safety and efficacy of three courses of neoadjuvant treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC). Patients with locally advanced ESCC received three courses of camrelizumab plus nab-paclitaxel and capecitabine before undergoing surgery. Additionally, patients received safety, computed tomography (CT), and endoscopy (with endoscopic ultrasonography and mucosal biopsy) assessments before and in the second and third courses of treatment. We used the CT and endoscopic assessment results from the second and third courses for comparison. From May 2020 to December 2021, 47 patients were enrolled at Sun Yat-sen University Cancer Center. In our study, 43 patients completed three courses of preoperative chemotherapy combined with anti-Programmed cell death-1 (PD-1) therapy and radical surgical resection. The toxicity of the third course of immunochemotherapy was mild and well tolerated without increased treatment-related adverse events (TRAEs) and mortality compared with that of the second course of treatment. In terms of efficacy, an additional course of treatment after the second course of treatment was effective, with increased CT and endoscopy T (clinical T stage) downstaging rates by 16.3% and 25.9%, N (clincial N stage) downstaging rates by 7.0% and 11.1%, and objective response rates (ORRs) by 13.6% and 22.0%, respectively. Regardless of downstaging or ORR, three courses of immunochemotherapy appear to be superior to two courses of treatment without increasing TRAEs.

Feasibility of a New Model of Care for Allogeneic Stem Cell Transplantation Recipients Facilitated by eHealth: The MY-Medula Pilot Study

The use of allogeneic stem cell transplantation (allo-SCT) for the treatment of hematologic diseases is steadily increasing; however, allo-SCT has the downside of causing considerable treatment-related morbidity and mortality. Mobile technology applied to healthcare (mHealth) has proven to be a cost-effective strategy to improve care and offer new services to people with multimorbidity, but there are little data on its usefulness in allo-SCT recipients. Here we describe a new integrated healthcare model facilitated by an mHealth platform, EMMASalud-MY-Medula, and to report the results of a feasibility and usability pilot study. The MY-Medula platform was developed in 4 phases. First, patient and healthcare professional needs were identified, and technological development and pretesting tests were conducted (phases 1 to 3, January 2016 to March 2021). Then a nonrandomized, prospective, observational, single-center pilot study was conducted (October 2021 to January 2022) at the adult SCT unit of a tertiary university hospital. Twenty-eight volunteer allo-SCT recipients were included in the pilot study, of whom one-half were outpatients in the first-year post-SCT and one-half were affected by steroid-dependent graft-versus-host disease (SR-GVHD). All patients used the MY-Medula app during the 2-month follow-up period, with a median number of visits to the app of 143 (range, 6 to 477). A total of 2067 self-monitoring records were created, and 205 text messages were received, most of them related to symptoms description (47%) and doubts about medication (21%). In 3.4% of the cases, drug dosage was adjusted by the pharmacist because of dosing errors or interactions. At the end of the study, a 6-question Likert-type questionnaire for patients and a 22-question test for healthcare professionals showed a high degree of satisfaction (95% and 100%, respectively) with the new healthcare pathway. Reengineering the follow-up of allo-SCT recipients into an integrated, multidisciplinary model of care facilitated by mHealth tools is feasible and has been associated with high usability and a high degree of satisfaction by patients and healthcare professionals. A randomized trial aiming to determine the cost-effectiveness of MY-Medula-based follow-up post-SCT is currently enrolling participants.

Haploidentical vs. HLA-matched donor hematopoietic stem-cell transplantation for pediatric patients with acute lymphoblastic leukemia in second remission: A collaborative retrospective study of the Spanish Group for Bone Marrow Transplantation in Children (GETMON/GETH) and the Spanish Childhood Relapsed ALL Board (ReALLNet).

Studies addressing the role of haploidentical as alternative to HLA-matched donors for stem cell transplantation (SCT) often include patients with diverse hematological malignancies in different remission statuses. We compared outcomes of children with acute lymphoblastic leukemia (ALL) undergoing SCT in second complete remission (CR2) from haploidentical (n = 25) versus HLA-matched donor (n = 51). Patients were equally distributed across both groups according to age, immunophenotype, time to and site of relapse, relapse risk-group allocation, and minimal residual disease (MRD) before SCT. Incidence of graft failure, acute graft versus host disease (GVHD), and other early complications did not differ between both groups. We found no differences in overall survival (58.7% versus 59.5%; p = .8), leukemia free survival (LFS) (48% versus 36.4%; p = .5), event free survival (40% versus 34.4%; p = .69), cumulative incidence (CI) of subsequent relapse (28% versus 40.9%; p = .69), treatment related mortality (24% versus 23.6%; p = .83), CI of cGVHD (4.5% versus 18.7%; p = .2), and chronic GVHD-free and leukemia-free survival (44% versus 26.3%; p = .3) after haploidentical donor SCT. Chronic GVHD (HR = 0.09; p=.02) had protective impact, and MRD ≥ 0.01% before SCT (HR = 2.59; p=.01) had unfavorable impact on LFS. These results support the role of haploidentical donor SCT in children with ALL in CR2.