Treatment-related Mortality Research Articles

Characteristics of relapsed and refractory paediatric Hodgkin lymphoma; a 10-year retrospective study of an LMIC.

With conventional standard treatment modalities, children and adolescents with Hodgkin lymphoma (HL) have long-term overall survival rates of over 90%. However, primary refractory disease may occur in 5%-10% of HL patients, while relapse occurs in 5%-10% of patients with early stage disease and up to 30% in an advanced stage. This retrospective study evaluated patient characteristics in cases of HL relapse and refractory and their response to second-line treatment of standalone chemotherapy or in combination with radiotherapy. A retrospective study was conducted by Indus Hospital and Health Network to determine the outcomes of paediatric patients with first and second relapses of HL between 2013 and 2022. A total of 742 patients were diagnosed with HL at Indus Hospital & Health Network. Of these, 48 (6.5%) patients presented with relapse and 35 (4.7%) with refractory disease after initial chemotherapy. In HL relapse patients, 57% were stage IV at initial diagnosis with the most common pathology being nodular sclerosis constituting 42.9% of patients. The most common age group was 6-10 years, 45.8%. B symptoms were experienced by 25 (52%) patients. A time to relapse of >12 months following diagnosis was seen in 69% and 3-12 months was seen in 31%.After receiving second-line treatment, complete remission was achieved by 34 (70.8%) patients, partial remission (PR) was seen in 5 (10.4%), disease progression in 5 (10.4%), 3 (6.3%) patients left during treatment and 1 (2.1%) had a treatment-related mortality. Re-radiation in second-line treatment was only required for 2 patients. The second relapse was seen in 11 (28.2%) of 39 complete and PR patients. Major limitations in the treatment of HL relapse in a low-resource setting are the non-availability of immunotherapy and autologous stem cell transplantation due to extreme financial burden and lack of capacity in facilities. Dedicated efforts are required to provide these facilities free of cost in low-middle income countries (LMICs).

The health risk of social disadvantage is transplantable into a new host

Low socioeconomic status (SES) is a risk factor for mortality and immune dysfunction across a wide range of diseases, including cancer. However, cancer is distinct in the use of allogeneic hematopoietic cell transplantation (HCT) as a treatment for hematologic malignancies to transfer healthy hematopoietic cells from one person to another. This raises the question of whether social disadvantage of an HCT cell donor, as assessed by low SES, might impact the subsequent health outcomes of the HCT recipient. To evaluate the cellular transplantability of SES-associated health risk, we analyzed the health outcomes of 2,005 HCT recipients who were transplanted for hematologic malignancy at 125 United States transplant centers and tested whether their outcomes differed as a function of their cell donor's SES (controlling for other known HCT-related risk factors). Recipients transplanted with cells from donors in the lowest quartile of SES experienced a 9.7% reduction in overall survival (P = 0.001) and 6.6% increase in treatment-related mortality within 3 y (P = 0.008) compared to those transplanted from donors in the highest SES quartile. These results are consistent with previous research linking socioeconomic disadvantage to altered immune cell function and hematopoiesis, and they reveal an unanticipated persistence of those effects after cells are transferred into a new host environment. These SES-related disparities in health outcomes underscore the need to map the biological mechanisms involved in the social determinants of health and develop interventions to block those effects and enhance the health of both HCT donors and recipients.

Outcomes Among Racial and Ethnic Minority Patients With Advanced Cancers in Phase 1 Trials

Patients from racial and ethnic minority groups (eg, Asian, Hispanic, and non-Hispanic Black patients) have low representation in clinical trials, especially in phase 1 trials in cancer. These trials represent valuable options for patients with advanced cancer who experience disease progression with standard therapy. To determine whether the benefit of enrollment to phase 1 cancer trials extends to Asian, Hispanic, and non-Hispanic Black patients as much as it does for non-Hispanic White patients. Patient records at a single institution from January 1999 to December 2016 were reviewed. Treatment-related responses, toxic effects, and deaths were recorded. All phase 1 studies were included. Data underwent independent extraction by multiple observers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. The primary outcome was overall survival (OS), assessed using univariate and multivariable time-to-event analyses. A total of 738 patients (median [range], 60 [22-93] years; 467 [63.3] female) including 197 Hispanic patients (26.7%), 238 non-Hispanic Black patients (32.2%), and 282 non-Hispanic White patients (38.2%), were enrolled in 64 phase 1 trials, including 33 cytotoxic trials (51.5%), 21 biologic trials (32.8%), and 10 combined therapy trials (15.6%). The primary cancer diagnoses were colorectal (187 patients [25.3%]), ovarian (141 patients [19.1%]), lung (58 patients [7.9%]), uterine (49 patients [6.6%]), and breast (41 patients [5.6%]). Patients underwent a median (range) of 3 (0-13) therapies prior to trial enrollment. Among 558 patients evaluated for response, the clinical benefit rate (ie, stable disease plus response rates) was 49.1%, and the overall response rate was 6.5%. Grade 3 or 4 nonhematological toxic effects were observed in 27.8% (95% CI, 24.6%-31.3%) of patients and grade 3 or 4 hematological toxic effects were observed in 19.7% (95% CI, 17.0%-22.8%) of patients. The treatment-related mortality rate was 0.9% (95% CI, 0.4%-1.9%). Median OS was 9.6 (95% CI, 8.2-11.0) months among Hispanic patients, 8.3 (95% CI, 6.7-10.4) months among non-Hispanic Black patients, and 9.8 (95% CI, 8.5-11.4) months among non-Hispanic White patients (P = .13). In a multivariable analysis, age older than 60 years, Eastern Cooperative Oncology Group performance status score of 2 or greater, more than 2 metastatic sites, lactate dehydrogenase grade 1 or 2, grade 2 or greater low albumin, grade 1 or greater total bilirubin, and grade 2 or greater anemia were associated with worse prognosis, whereas leukocytosis greater than grade 1 was associated with better OS. In this meta-analysis assessing outcomes in phase 1 cancer trials among patients from racial and ethnic minority groups, Hispanic and non-Hispanic Black patients had benefits similar to those of non-Hispanic White patients.

Response-adapted consolidation therapy strategy for patients with metastatic high-risk neuroblastoma: Results of the SMC NB-2014 study.

Tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) and incorporation of 131I-metaiodobenzylguanidine (131I-MIBG) treatment have shown positive outcomes in high-risk neuroblastoma. However, more optimized treatment strategies are still needed. The NB-2014 study was a nonrandomized, prospective trial that examined survival outcomes in metastatic high-risk neuroblastoma patients using response-adapted consolidation therapy. We used post-induction residual 123I-MIBG status at metastatic sites as a treatment response marker. Patients achieving complete resolution of MIBG uptake at metastatic sites underwent a reduced first HDCT/auto-SCT with a 20% dose reduction in HDCT. After the first HDCT/auto-SCT, patients with remaining MIBG uptake received dose-escalated (18mCi/kg) 131I-MIBG treatment. In contrast, those with complete resolution of MIBG at metastatic sites received a standard dose (12mCi/kg) of 131I-MIBG. We compared survival and toxicity outcomes with a historical control group from the NB-2009. Of 65 patients treated, 63% achieved complete resolution of MIBG uptake at metastatic sites following induction chemotherapy, while 29% of patients still had MIBG uptake at metastatic sites after the first HDCT/auto-SCT. The 3-year event-free survival (EFS) and overall survival (OS) rates were 68.2%±6.0% and 86.5%±4.5%, respectively. Compared to NB-2009, EFS was similar (p=.855); however, NB-2014 had a higher OS (p=.031), a lower cumulative incidence of treatment-related mortality (p=.036), and fewer acute and late toxicities. Our results suggest that response-adaptive consolidation therapy based on chemotherapy response at metastatic sites facilitates better treatment tailoring, and appears promising for patients with metastatic high-risk neuroblastoma.

Endovascular Treatment for Complex Vascular Pathologies in the Pediatric Population: Experience from a Center with Dual-Trained Neurosurgeons

Endovascular treatment of complex vascular pathologies in the pediatric population is often performed by non-pediatric subspecialists with adaptation of equipment and techniques developed for adult patients. We aimed to report our center's experience with safety and outcomes of endovascular treatments for pediatric vascular pathologies. We performed a retrospective review of our endovascular database. All patients ≤18 years who underwent endovascular treatment between January 1, 2004 and December 1, 2022 were included. During the study time frame, 118 cerebral angiograms were performed for interventional purposes in 55 patients. Of these patients, 8(14.5%) had intracranial aneurysms, 21(38.2%) had intracranial arteriovenous malformations (AVMs), 6(10.9%) had tumors, 5(9.1%) had arterial occlusions (n=3) or dissections (n=2), 8(14.5%) had vein of Galen malformations, and 7(12.7%) had other cerebrovascular conditions. Of the total 118 procedures, access-site complications occurred in 2(1.7%), intraprocedural complications occurred in 3(2.5%), and transient neurological deficits were observed after 2(1.7%). Treatment-related mortality occurred in 1(1.8%) patient. Neurointervention in pediatric patients was safe and effective in our experience.

Hepatic Arterial Infusion Chemotherapy Combined with Lenvatinib and PD-1 Inhibitors for Managing Arterioportal Shunt in Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Retrospective Cohort Study.

This study aimed to assess the effectiveness and safety of combining hepatic arterial infusion chemotherapy (HAIC) with lenvatinib (LEN) and PD-1 inhibitors in treating arterioportal shunt (APS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT). Conducted retrospectively, the study enrolled 54 HCC patients with APS and PVTT treated with HAIC, LEN, and PD-1 inhibitors at our center between January 2021 and October 2023. APS improvement, APS recanalization, tumor response, PVTT response rate, overall survival (OS), intrahepatic progression-free survival (InPFS), and adverse events were evaluated. APS improvement was observed in 42 patients (77.8%), with all improvement occurring within two treatment sessions. Complete APS occlusion was achieved in 40 patients (74.1%), and no recanalization occurred. The best objective response rate (ORR) and ORR after two HAIC sessions were 74.1% and 66.7%, respectively. The best PVTT response and PVTT response after two HAIC sessions were 98.1% and 94.4%, respectively. The median OS and InPFS were 10.0 months and 5.0 months, respectively. OS and InPFS were longer in patients with APS occlusion compared to those without (OS 12.1 vs 4.4 months, P<0.001, InPFS 6.2 vs 2.3 months, P=0.049). ALBI grade, extrahepatic spread, APS disappearance were potential prognostic factors for OS, while APS grade and extrahepatic spread being independently associated with InPFS. No treatment-related mortality occurred. Combining HAIC with LEN and PD-1 inhibitors proves to be both effective and safe in managing APS in HCC with PVTT, potentially improving patient survival.

ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies

AbstractAtaxia-telangiectasia (A-T) is an autosomal-recessive disorder caused by pathogenic variants (PVs) of the ATM gene, predisposing children to hematological malignancies. We investigated their characteristics and outcomes to generate data-based treatment recommendations. In this multinational, observational study we report 202 patients aged ≤25 years with A-T and hematological malignancies from 25 countries. Ninety-one patients (45%) presented with mature B-cell lymphomas, 82 (41%) with acute lymphoblastic leukemia/lymphoma, 21 (10%) with Hodgkin lymphoma and 8 (4%) with other hematological malignancies. Four-year overall survival and event-free survival (EFS) were 50.8% (95% confidence interval [CI], 43.6-59.1) and 47.9% (95% CI 40.8-56.2), respectively. Cure rates have not significantly improved over the last four decades (P = .76). The major cause of treatment failure was treatment-related mortality (TRM) with a four-year cumulative incidence of 25.9% (95% CI, 19.5-32.4). Germ line ATM PVs were categorized as null or hypomorphic and patients with available genetic data (n = 110) were classified as having absent (n = 81) or residual (n = 29) ATM kinase activity. Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively. Absence of ATM kinase activity was independently associated with decreased EFS (HR = 0.362, 95% CI, 0.16-0.82; P = .009) and increased TRM (hazard ratio [HR] = 14.11, 95% CI, 1.36-146.31; P = .029). Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity.

Ruxolitinib for the treatment of acute graft-versus-host disease: a retrospective analysis

Steroid-refractory acute graft-versus-host disease (aGvHD) is a serious complication after allogeneic hematopoietic stem cell transplantation, associated with significant mortality. Ruxolitinib was the first drug approved for aGvHD, based on results of the REACH2 trial; however, real-world data are limited. We retrospectively analyzed the safety and efficacy of ruxolitinib for treatment of aGvHD at our center from March 2016 to August 2022 and assessed biomarkers of risk. We identified 49 patients receiving ruxolitinib as second- (33/49), third- (11/49), fourth- (3/49), or fifth-line (2/49) treatment. Ruxolitinib was started on median day 11 (range, 7–21) after aGvHD onset; median duration of administration was 37 days (range, 20–86), with 10 patients continuing treatment at last follow-up. Median follow-up period was 501 days (range, 95–905). In the primary analysis at the 1-month assessment, overall response rate was 65%, and failure-free survival was 78%. Infectious complications ≥ CTCAE Grade III were observed in 10/49 patients within 1-month followup. Patients responding to ruxolitinib therapy required fewer steroids and exhibited lower levels of the serum biomarkers regenerating islet-derived protein 3-alpha, suppression of tumorigenicity 2, and the Mount Sinai Acute GVHD International Consortium algorithm probability. A univariate regression model revealed steroid-dependent aGvHD as a significant predictor of better response to ruxolitinib. Within 6-months follow-up, four patients experienced recurrence of underlying malignancy, and eight died due to treatment-related mortality. Overall, ruxolitinib was welltolerated and showed response in heavily pretreated patients, with results comparable to those of the REACH2 trial. Biomarkers may be useful predictors of response to ruxolitinib.

Retrospective study on pomalidomide-PACE as a salvage regimen in aggressive relapsed and refractory multiple myeloma.

Despite major advances in treatment options for multiple myeloma (MM), patients refractory to the main drug classes and those with aggressive, especially extramedullary disease, still face a dismal outcome. For these patients, effective therapeutic options are urgently warranted. In this retrospective study, we report on the safety and efficacy of the intensive combination regimen of pomalidomide plus cisplatin, doxorubicin, cyclophosphamide, and etoposide (Pom-PACE) in patients with relapsed refractory MM (RRMM) or plasma cell leukemia (PCL). A study population of 20 consecutive patients treated with Pom-PACE at two academic centers was included for analysis. All patients had to have a confirmed relapse according to International Myeloma Working Group criteria and adequate organ function prior to the start of therapy. Data were collected by reviewing medical charts. Exploratory analyses were performed with regard to efficacy and safety. Patients were heavily pretreated with a median number of four prior therapies (range: 1-10). All patients were exposed to immunomodulators, proteasome inhibitors, and alkylating agents, 80% were double-class refractory, 40% were triple-class refractory. Extramedullary MM or PCL were present in 15 patients (75%). Overall response rate (ORR) was 68%, with 31% achieving at least a very good partial response. Responses were achieved rapidly with an ORR of 64% after one cycle. Median progression-free survival was 8.9 months (0.92-not reached [NR]) and median overall survival was 11.8 months (3-40.6). Pom-PACE was associated with significant toxicity. All evaluable patients experienced Grade 4 hematological toxicity. However, no treatment related mortality was observed. Pomalidomide-PACE was able to induce rapid responses in heavily pretreated, aggressive RRMM with a manageable toxicity profile and therefore offers an effective salvage regimen and a potential bridging strategy to further treatment options such as chimeric antigen receptor T-cell therapy.

Surgical aspects and outcomes after nephrectomy for Wilms tumour in sub-Saharan Africa: A report from Wilms Africa Phase II-CANCaRe Africa.

Wilms tumour (WT) is one of the common and curable cancer types targeted by the Global Initiative for Childhood Cancer. Tumour excision is essential for cure. This analysis focuses on surgical outcomes of patients with WT in sub-Saharan Africa. We implemented a risk-stratified WT treatment guideline as a multicentre, prospective study across eight hospitals and six countries. Eligibility criteria were age 6months to 16years, unilateral WT, surgery performed after preoperative chemotherapy and diagnosed between 1 January 2021 and 31 December 2022. Data collection included a specific surgical case report form (CRF). The study registered 230 patients, among whom 164 (71.3%) had a nephrectomy. Ninety-eight percent of patients had a completed surgical CRF. Out 164 patients, 50 (30.5%) had distant metastases. Median tumour diameter at surgery was 11.0cm. Lymph node sampling was done in 122 (74.3%) patients, 34 (20.7%) had intraoperative tumour rupture, and for 18 (10.9%), tumour resection involved en bloc resection of another organ. Tumour size at surgery was significantly correlated with tumour rupture (p<.01). With a median follow-up of 17months (range: 2-33), 23 (14.0%) patients have relapsed. Twenty-two (13.4%) patients abandoned treatment post nephrectomy. Two-year event-free survival was 60.4%±4.7% with treatment abandonment as an event. Survival post nephrectomy is challenged by treatment abandonment, treatment-related mortality and relapse. Large tumours after preoperative chemotherapy were associated with a higher risk of tumour rupture. Earlier diagnosis and access to radiotherapy are expected to improve survival.

LMIC-15. OUTCOMES OF PEDIATRIC MEDULLOBLASTOMA IN LOW- AND MIDDLE-INCOME COUNTRIES: A REPORT OF 330 PATIENTS FROM 8 COUNTRIES

Abstract BACKGROUND AND AIMS Reports from low-and middle-income countries (LMICs) indicate lower survival in medulloblastoma (MB), though these studies are mainly from single institutions. This multi-institutional, retrospective study aimed to analyze the outcomes for MB in 9 centers in 8 LMICs. METHODS Patients &amp;lt;18 years old with newly diagnosed MB, treated from January 2014 to December 2018 in Egypt, El Salvador, Malaysia, Mexico, Pakistan, Peru, Philippines, and Uruguay were included. Data on demographics, clinical presentation, treatment and biological characteristics were collected. Factors associated with patient outcomes were analyzed. RESULTS The study included 330 patients with a median age of 7.7 years. Of these, 49 patients (15%) were &amp;lt;3 years old and 212 (64%) were male. Eighty-eight patients (26%) had experienced symptoms for &amp;gt;3 months at diagnosis. Gross total resection was achieved in 153 (47%) patients. Sixty-three patients (19%) experienced post-operative infections. Eighty-four patients (24%) had metastatic disease at diagnosis. The histologic subtype was not specified in 98 cases (30%), and 25 patients (7%) had molecular subgroups identified. Radiotherapy was administered to 216 patients (64%). The median number of chemotherapy cycles was 8 (range 0-14). There were 64 patients (19%) who abandoned treatment, and 24 patients (7%) died due to treatment-related toxicity. The 5-year event-free survival (EFS) was 44±4%, while the 5-year overall survival was 58±4%. The 5-year EFS for patients &amp;lt;3 years was 42±9%, while 44±4% for older patients (p=0.49). The 5-year EFS for patients with metastasis was 38±7%, while it was 46±4% for patients without metastasis (p=0.13). CONCLUSIONS This large, multinational cohort of MB in LMICs describes poor outcomes, which may be attributed to delays in care, high abandonment rate, surgical complications, treatment-related mortality and a low fraction of patients receiving radiotherapy. Interventions to build care capacity can be prioritized based on these data.

Intensive salvage chemotherapy with VDTPACE or mCBAD followed by hematopoietic stem-cell support for refractory/relapsed multiple myeloma.

Triple- and quad-refractory multiple myeloma patients usually have an aggressive course and a poor prognosis. Available therapeutic options are scarce. The objective of the current study was to evaluate responses and toxicities of VDTPACE or mCBAD with hematopoietic stem-cell support as a bridge to subsequent therapies in patients with refractory/relapsed multiple myeloma. Thirteen patients were included (11 mCBAD, 2 VDTPACE), and 21 cycles of chemotherapy with hematopoietic stem-cell support were delivered. Mean number of previous therapies was 4.8. Stem cells were infused on a median day 9.9 after chemotherapy. Mean time to neutrophil recovery was 18.2 days in patients receiving the first cycle and 15.9 following subsequent cycles. Before therapy, most patients were in PD (77%), PR (15%), or VGPR (8%). Following treatment, the best responses achieved were PR (46%), VGPR (46%), and CR (8%). Median overall and progression-free survivals were 17 and 9 months. There has been no case of non-relapse mortality. In the 21 cycles, the main complications were infectious. Intensive chemotherapy can decrease disease burden in patients with relapsed/refractory MM, and stem-cell support can successfully decrease toxicities and treatment-related mortality associated with these regimens and may be a good bridging option.

Efficient bone marrow irradiation and low uptake by non-haematological organs with an yttrium-90-anti-CD66 antibody prior to haematopoietic stem cell transplantation

We report the results of a Phase I radiation dose escalation study using an yttrium-90 (90Y) labelled anti-CD66 monoclonal antibody given with standard conditioning regimen for patients receiving haematopoietic stem cell transplants for myeloid leukaemia or myeloma. The 90Y-labelled anti-CD66 was infused prior to standard conditioning. In total, 30 patients entered the trial and 29 received 90Y-labelled mAb, at infused radiation activity levels of 5, 10, 25, or 37.5 megaBequerel (MBq)/kg lean body weight. A prerequisite for receiving the 90Y-labelled mAb was favourable dosimetry determined by single-photon emission computerised tomography (SPECT) dosimetry following administration of indium-111 (111In) anti-CD66. Estimated absorbed radiation doses delivered to the red marrow demonstrated a linear relationship with the infused activity of 90Y-labelled mAb. At the highest activity level of 37.5 MBq/kg, mean estimated radiation doses for red marrow, liver, spleen, kidneys and lungs were 24.6 ± 5.6 Gy, 5.8 ± 2.7 Gy, 19.1 ± 8.0 Gy, 2.1 ± 1.1 and 2.2 ± 0.9, respectively. All patients engrafted, treatment-related mortality 1-year post-transplant was zero. Toxicities were no greater than those anticipated for similar conditioning regimens without targeted radiation. The ability to substantially intensify conditioning prior to haematopoietic stem cell transplantation without increasing toxicity warrants further testing to determine efficacy. clinicaltrials.gov identifier: NCT01521611.

Outcome of patients with peritoneal metastasis from ovarian cancer treated with Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC).

There are few data on Pressurized IntraPeritoneal Aerosol Chemotherapy with cisplatin and doxorubicin (PIPAC C/D) in women with primary unresectable or recurrent platinum-resistant peritoneal metastasis (PM) from ovarian cancer (OC). We evaluated survival, histological and cytological response, Quality of Life (QoL) and toxicity after PIPAC C/D in these patients. Retrospective analysis of patients from the prospective PIPAC-OPC1 and -OPC2 studies. The histological response was evaluated by the Peritoneal Regression Grading Score (PRGS). QoL questionnaires were collected at baseline and after third PIPAC or 60days. Adverse events were collected until 30days after the last PIPAC. Demographic and survival data were analysed based on intention to treat. Response, QoL and toxicity were analysed per protocol (≥1 PIPAC). Twenty-nine patients were included. Five patients (17 %) were non-accessible at PIPAC 1. One patient was excluded due to liver metastases at PIPAC 1. Thus, 23 patients had 76 PIPACs (median 2, range 1-12). Median overall survival was 8.2months (95 % CI 4.4-10.3) from PIPAC 1. Biopsy data were available for 22 patients, and seven (32 %) patients had a major/complete histological response (PRGS≤2) at PIPAC 3. No cytological conversions were registered. Symptoms and function scores worsened, while emotional scores improved. Three patients had severe adverse reactions (two ileus, one pulmonary embolism); no life-threatening reactions or treatment-related mortality was observed. PIPAC C/D was feasible and induced histological regression in a substantial proportion of patients with platinum-resistant PM from OC. Larger studies are needed to evaluate impact on survival.

High-dose chemotherapy and autologous hematopoietic stem cell transplantation for progressive systemic sclerosis: a retrospective study of outcome and prognostic factors

PurposeSystemic sclerosis (SSc) is a rare autoimmune disease associated with high morbidity and mortality. SSc treatment is still challenging, and evidence is scarce. In the last decades high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) has proven to be effective. However, treatment related morbidity and mortality (TRM) are high. We conducted a retrospective, single-center analysis of SSc patients following HD-ASCT focusing on TRM and risk factors.Methods32 patients who underwent HD-ASCT at our hospital between June 2000 and September 2020 were included. Clinical characteristics were evaluated based on chart review before and after HD-ASCT. Analyses focused on overall survival (OS), TRM, and response to HD-ASCT.ResultsMedian OS was 81 months (range 0–243). Within one year, 20 of 32 (76.9%) patients responded to HD-ASCT. Overall, 6 patients (18.8%) died in the context of HD-ASCT. Patients with subjective response to HD-ASCT (p = 0.024) and those with shorter time to platelet engraftment (p = 0.047) had significantly longer OS. Impaired renal function, age at HD-ASCT ≥ 55, disease duration < 12 months, high Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and Charlton Comorbidity Index (CCI) scores were associated with higher TRM. Patients receiving conditioning chemotherapy with thiotepa needed longer time for neutrophil (p = 0.035) and platelet engraftment (p = 0.021).ConclusionThis study confirms the efficacy of HD-ASCT for patients with SSc in a single center real-world setting. High TRM is still a challenge. However, TRM could be reduced by exclusion of high-risk patients and attention to prognostic parameters and scores as suggested in this study.

Treatment of acute myeloid leukemia with Orca-T.

6552 Background: Allogeneic hematopoietic stem cell transplants (alloHSCT) offer a potential curative treatment for many hematological cancers, however, traditional alloHSCT is associated with high mortality from complications including infection, graft versus host disease (GvHD) and relapse. Orca-T is an investigational allogeneic T-cell immunotherapy that includes stem and immune cells, derived from allogeneic donors, that leverages highly purified, polyclonal donor regulatory T cells to control alloreactive immune responses. In this sub-group analysis, we evaluated the safety and efficacy of patients with acute myeloid leukemia who were treated with Orca-T. Methods: Data from 37 patients with the diagnosis of acute myeloid leukemia (AML) in CR/CRi who received myeloablative conditioning with busulfan, fludarabine, and thiotepa (BFT) followed by Orca-T by 6/30/22 as part of a multicenter phase 1b single-arm trial (NCT04013685) are reported here. Patients enrolled in the phase 1b trial who did not meet these criteria were not included in this analysis. Patients received BFT prior to Orca-T, followed by single-agent GvHD prophylaxis with tacrolimus, and had an 8/8 related or unrelated matched donor. Donors were matched via DNA-based high-resolution typing of HLA-A, -B, -C, and -DRB1. Results: Orca-T was successfully manufactured at a centralized GMP facility, distributed, and infused at study sites throughout the U.S. Vein-to-vein time (i.e. time between end of donor apheresis to start of recipient’s Orca-T infusion) was &lt; 72 hours for all patients, with the majority &lt; 60 hours. Median age was 51 years, 49% were female and 16% were of Hispanic or Latino ethnicity. Twenty-three (62%) had matched related donors and 14 (38%) had matched unrelated donors. Baseline HCT-CI score was 3 and 4 in 27% and 8% of the patients, respectively. The majority had intermediate DRI scores (89%) and 41% were MRD positive at baseline. The median duration of follow-up was 14 months. Relapse-free survival at 12 months was 81.4% (95% CI: 62.9, 91.2). Non-relapse mortality and overall survival were 0% and 100% at 12 months, respectively. Conclusions: These encouraging results suggest that investigational Orca-T could represent a reduced toxicity alternative to conventional alloHSCT. This combination of Orca-T with myeloablative BFT led to &gt; 80% RFS without treatment related mortality, and 100% overall survival in this AML patient population. These outcomes were accomplished with consistent and reliable cell manufacturing and distribution of Orca-T at a national scale. A multi-center randomized controlled phase 3 trial comparing Orca-T to SOC, utilizing BFT or TBI-based conditioning, will complete enrollment during the first half of 2024. (NCT05316701). Clinical trial information: NCT04013685 .

Evolving patterns of transplant strategies for mantle cell lymphoma in the era of BTK inhibitors and CAR-T therapy.

e19012 Background: Mantle cell lymphoma is an aggressive lymphoma with poor survival after chemotherapy alone. Both autologous (auto) and allogeneic (allo) transplants have improved outcomes over the years, but transplant strategies most beneficial for MCL are not clearly defined. Recently, BTK inhibitors and chimeric antigen therapies (CAR T) therapy approach has changed the landscape of Mantle cell Lymphoma. Methods: Patient Population:A total of 71 patients underwent transplant for diagnosis of MCL at Penn State Cancer Institute, between March 1993 and March 2023. Median follow up was 3.1 years (32 days-9883 days) after transplant. Patient Characteristics: A total of 71 patients (62 M: 9 F) underwent transplants, including autologous (n=30), allogeneic (n=32), and CAR T (n=9). Since 2020, 19 transplants were performed: CAR T (n=9) auto transplants (n=9) and allogeneic transplants (n=1). Relapsed and refractory MCL (n=4) patients received CAR T whereas patients achieving CR 1 (n=8) and PR1 (n=1) received auto transplants. Most patients were Caucasian (n= 68), with few Hispanic (1), African American (1), or Asian (1). Results: Median age at the time of transplant was 61 (37-70) years for autologous, 56 (33-67) years for allogenic and 63 (55 -75) years for CAR T respectively. Disease status at transplant was CR 52.1% (n=37), primary induction failure or relapsed/refractory 36.6% (n=26), PR 11.3% (n=8). High LDH was seen at the time of transplant in 16.9% (n=12) patients and normal in 83.1%(n=59) patients. Blastoid morphology was seen in only 13.8% (n=4) autologous, 37.9% (n=11) allogenic and 33.3% (n=3) CAR T patients. Outcomes: Overall survival (OS) at 1 year and 3 years was 93.3% and 85.9% for autologous (auto) transplants, 62.5% and 52.9% for Allogeneic (allo) transplants, 88.9% and 76.2% for CAR-T therapy respectively (P = 0.007). Progression free survival at 1 year and 3 years was 86.3% and 75.0% for auto transplants; 50.0% and 43.3% for allo Transplants; 66.7% and 66.7% for CART Therapy (P = 0.03). Primary cause of death was Treatment Related Mortality (TRM) (n= 9) (GVHD=4; Pulmonary=3; MOF=2) and disease progression (n=10); unknown (n=4); other (n=1). Primary cause of death for CAR T therapy was grade IV ICANS and disease progression. Conclusions: Recently CAR T therapies have changed the landscape of MCL treatment algorithm in both Blastoid and non-Blastoid histology MCL patients. But in the era of CAR T therapy and BTK inhibitors for MCL, achieving CR at the time of transplant predicts improved long-term outcomes. Randomized studies or larger retrospective CIBMTR data analysis may be important to answer best transplant strategy for MCL patients. [Table: see text]

End of life treatment in gynecological cancers in an integrated care model: A single institution experience from Oman.

e24036 Background: The use of chemotherapy closer to the end of life (EOL) and the optimal time of initiating palliative care interventions are subjects of ongoing debate. In a traditional care model (TCM), the institution of EOL care is a complex decision-making process, that involves patient, family members, and the oncologist, and involves transfer of patients from one to the other service. Integrated care model (ICM) is a newer concept, is designed around the needs of the patients, and may have the potential to improve quality of life and reduce the cost of healthcare towards EOL. At our center, we work in ICM in organ-based clinical programs and report the use of systemic treatment in patients with gynecological cancers (GC) nearing EOL. Methods: We analyzed retrospectively the use of chemotherapy and other systemic cancer-directed therapies in patients with GC, who died between Sept 2021 and December 2023 at a single institution. Information on the cancer-type, intention of treatment, and the time between last treatment and death was obtained from electronic patient records (EPR). Results: Over the study period, a total of 22 patients passed away. All patients received palliative care as part of the integrated care. All patients had been declared ‘not for resuscitation’ before death. Twelve patients had ovarian cancer, 5 had endometrial cancer, 4 had cancer of cervix, and one had vulvar cancer. The median age at diagnosis was 53 years (29-80). The systemic treatment was 1st line in 5 patients (23%), 2nd line in 8 patients (36%), and 3rd or more line in 6 patients (27%) respectively. Three patients (14%) did not receive any cancer-directed treatment (aged 80, 71 and 61). The ultimate line of treatment was cytotoxic chemotherapy for all patients, except for one who received Olaparib, and one who received trastuzumab with chemotherapy. There was no treatment-related mortality. The median time from last treatment to death was 55 days. Of the 19 patients who received treatment, 6 patients (32%) received treatment in the last 30 days, 5 between 30 and 60 days (26%), 5 between 60 and 90 days (26%), and 3 more than 90 days before death. Four patients died at home. Age at diagnosis (51 vs 55 years), age at death (51.5 vs 57.5 years), or time from diagnosis to death (11.5 vs 22 months), did not predict whether patients received treatment within the 30 days of death or earlier. Conclusions: All patients received palliative care as part of integrated cancer care. The ICM may have led to lower use of cancer treatment near EOL. The data may provide a benchmark for the region.

Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors

Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized. To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and nonrelapse mortality (NRM), we studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n = 73) or MDS/AML (n = 8). With a median follow-up among survivors of 74.0 (range: 10.4 to 187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27% to 48%), 32% (23% to 44%), and 35% (26% to 47%). The rate of NRM at 100 days and 18 months was 20% (12% to 29%) and 28% (19% to 39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (ie, morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or treatment-related mortality (TRM) scores. After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR] = 3.19, P = .006) and shorter RFS (HR = 2.41, P = .008) as well as OS (HR = 2.17, P = .027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease. Similarly, a relapse-free interval ≤6 months after the first allograft was associated with higher risk of relapse (HR = 5.86, P < .001) and shorter RFS (HR = 2.86; P = .001) and OS (HR = 2.45, P = .003). Additionally, a high HCT-CI score was associated with increased NRM (HR = 4.30, P = .035), and shorter RFS (HR = 3.87, P = .003) and OS (HR = 3.74, P = .006). Likewise, higher TRM scores were associated with increased risk of relapse (HR = 2.27; P = .024) and NRM (HR = 2.01, P = .001), and inferior RFS (HR = 1.90 P = .001) and OS (HR = 1.88, P = .001). A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.

A phase II clinical trial of metformin combined with FOLFIRI plus bevacizumab as second-line therapy in patients with RAS-mutant metastatic colorectal cancer.

3534 Background: Metastatic colorectal cancer (mCRC) patients with RAS mutations are confronted with limited novel targeted therapy. We previously reported that KRAS mutation mediated MATE1 down-regulation sensitizes colorectal cancer cells to metformin. Based on our preclinical research, we designed a study to explore whether metformin combined with FOLFIRI plus bevacizumab would improve efficacy in RAS mutant mCRC. Methods: This single-arm, multicenter trial (ChiCTR2000037943) recruited patients with RAS mutant mCRC that had failed to first-line bevacizumab plus an oxaliplatin-based regimen of systemic therapies. Patients received metformin 1000mg PO twice daily on day 1-14, plus irinotecan 180 mg/m² IV, calcium folinate 400 mg/m² IV, fluorouracil 400 mg/m² IV, and a 46-h CIV of fluorouracil 2400 mg/m², and bevacizumab 5 mg/kg IV, repeated every 14 days. We used Simon's two-stage design. The primary endpoint was objective response rate (ORR). The secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. Results: One hundred sixteen patients were recruited between July 2020 and March 2023. KRAS codon 12 mutations were present in 81 cases (69.8%), codon 13 mutations in 17 cases (14.7%), codon 61 mutations in 6 cases (5.2%), and codon 146 mutations in 3 cases (2.6%). For the 81 patients with KRAS codon 12 mutation, 42 were with G12D (51.9%), 21 with G12V (25.9%), 7 with G12A (8.6%), and 6 with G12C (7.4%) mutation. The ORR was 21.6% (25/116), and DCR was 76.7% (89/116). The median PFS was 8.0 months, and patients without liver metastasis had longer PFS than those with liver metastasis (9.5 months vs. 5.6 months, P &lt; 0.001). For the 45 patients without liver metastasis, the administration of metformin combined with FOLFIRI plus bevacizumab as second-line therapy resulted in significantly longer PFS than the first-line bevacizumab plus an oxaliplatin-based regimen (9.5 months vs. 7.9 months, P = 0.037). The median OS was not reached. The most common treatment-emergent adverse events (TEAEs) were neutropenia (73.7%), nausea (56.9%), anemia (54.3%) and diarrhea (49.1%). Grade 3 and above TEAEs occurred in 52 (44.8%) patients. No treatment-related mortality occurred. Conclusions: Metformin combined with FOLFIRI and bevacizumab had promising efficacy and tolerable toxicity in RAS mutant mCRC patients as second-line therapy. Further study in phase 3 trials is warranted. Clinical trial information: ChiCTR2000037943.