Nonmyeloablative Regimen Research Articles

Bloodless Medicine in Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHSCT) poses challenges for patients who decline blood products because of religious beliefs or other reasons. Despite potential curative prospects, many institutions refrain from offering alloHSCT to patients who decline blood products because of safety concerns associated with cytopenias. This review focuses on one institution's experience of conducting alloHSCT without blood components, emphasizing preparation and supportive care. The approach of conducting alloHSCT without blood components, which involves ABO-compatible donor matching, nonmyeloablative regimens, and pretransplantation optimization of red blood cell production, is discussed. The clinical team can minimize transfusion needs by using erythropoiesis-stimulating agents, thrombopoietin agonists, and peri- and post-transplantation management strategies. These recommendations can ensure patient safety and successful outcomes with bloodless medicine.

Volumetric modulated arc therapy total body irradiation improves toxicity outcomes compared to 2D total body irradiation.

Volumetric modulated arc therapy (VMAT) total body irradiation (TBI) allows for greater organ sparing with improved target coverage compared to 2D-TBI. However, there is limited evidence of whether improved organ sparing translates to decreases in toxicities and how its toxicities compare to those of the 2D technique. We aimed to compare differences in toxicities among patients treated with TBI utilizing VMAT and 2D techniques. A matched-pair single-institution retrospective analysis of 200 patients treated with TBI from 2014 to 2023 was performed. Overall survival (OS) and progression-free survival (PFS) were analyzed using the Kaplan-Meier method and compared using log-rank tests. Differences in characteristics and toxicities between the VMAT and 2D cohorts were compared using Fisher's exact test. Of the 200 patients analyzed, 100 underwent VMAT-TBI, and 100 underwent 2D-TBI. The median age for VMAT-TBI and 2D-TBI patients was 13.7 years and 16.2 years, respectively (p = 0.25). In each cohort, 53 patients were treated with myeloablative regimens (8-13.76 Gy), and 47 were treated with non-myeloablative regimens (2-4 Gy). For the entire VMAT-TBI cohort, lung Dmean, kidney Dmean, and lens Dmax were spared to 60.6% ± 5.0%, 71.0% ± 8.5%, and 90.1% ± 3.5% of prescription, respectively. For the non-myeloablative VMAT-TBI cohort, testis/ovary Dmax, brain, and thyroid Dmean were spared to 33.4% ± 7.3%, 75.4% ± 7.0%, and 76.1% ± 10.5%, respectively. For 2D-TBI, lungs were spared using partial-transmission lung blocks for myeloablative regimens. The VMAT-TBI cohort experienced significantly lower rates of any grade of pneumonitis (2% vs. 12%), nephrotoxicity (7% vs. 34%), nausea (68% vs. 81%), skin (16% vs. 35%), and graft versus host disease (GVHD) (42% vs. 62%) compared to 2D-TBI patients. For myeloablative regimen patients, rates of pneumonitis (0% vs. 17%) and nephrotoxicity (9% vs. 36%) were significantly lower with VMAT-TBI versus 2D-TBI (p < 0.01). Median follow-up was 14.3 months, and neither median OS nor PFS for the entire cohort was reached. In the VMAT versus 2D-TBI cohort, the 1-year OS was 86.0% versus 83.0% (p = 0.26), and the 1-year PFS was 86.6% and 80.0% (p = 0.36), respectively. Normal tissue sparing with VMAT-TBI compared to the 2D-TBI translated to significantly lower rates of pneumonitis, renal toxicity, nausea, skin toxicity, and GVHD in patients, while maintaining excellent disease control.

Outcomes of Patients with Myeloid Malignancies and Cardiovascular Disease Undergoing Allogeneic Stem Cell Transplantation

Introduction/Background: Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) regimens have enabled patients with cardiovascular disease (CVD) to undergo allogeneic stem cell transplantation (allo-HSCT). However, little is known about long-term outcomes, including cardiovascular (CV) complications. Methods: We retrospectively studied 99 consecutive patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who underwent allo-HSCT between September 1, 2013, and November 30, 2020. Overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GvHD) were compared in patients with and without CV risk factors or disease. Results: Preexisting CVD was present in 34 of 99 patients (34%). CVD patients more commonly had reduced-intensity conditioning (91% vs. 60%, p = 0.001) and unrelated donors (56% vs. 35%, p = 0.04). Early adverse cardiac events occurred more frequently in the CVD versus no-CVD group (38% vs. 14%), particularly arrhythmias (21% vs. 5%; p = 0.04). CVD patients tended to have poorer OS and PFS outcomes (HR = 1.98, [1.00, 3.92]; HR = 1.89, [0.96–3.72], respectively). OS rate at 1, 2, and 3 years for CVD versus no-CVD patients was 66% versus 72%, 55% versus 64%, and 46% versus 62%, respectively. Causes of death in the CVD and no-CVD groups were infections (53% vs. 28%), relapsed disease (32% vs. 52%), and CV events (10% vs. 3%). Conclusion: Based on these data, predictive models to identify patients with CVD with higher risk of post-allo-HSCT complications and mortality and strategies to mitigate these risks should be developed.

Efficacy and safety of outpatient fludarabine, cyclophosphamide, and rituximab based allogeneic hematopoietic cell transplantation in adults with severe aplastic anemia

The age effect in severe aplastic anemia (SAA) following allogeneic hematopoietic cell transplantation (HCT) favors the use of reduced intensity conditioning (RIC) regimens in older adults. We implemented a non-myeloablative regimen consisting of fludarabine, cyclophosphamide, and rituximab (FCR) to improve HCT outcomes in SAA. Patients who underwent first HCT for SAA utilizing an FCR regimen between January 2016 and May 2022 were included. Outcomes analyzed included time to engraftment, incidence of graft failure, GVHD, viral reactivation, disease recurrence, and GVHD-free, relapse-free survival (GRFS). Among 24 patients included, median age was 43.5 years (22–62) and a variety of donor types and stem cell sources were represented. At median follow-up of 26.9 months (2.4–72.7), no cases of grade III-IV acute (aGVHD) or severe chronic GVHD (cGVHD) were recorded. Viral reactivation was minimal, and there were no cases of graft failure or PTLD, with 100% disease-free and overall survival at last follow up. The estimate of 1-year GRFS was 86.3% (95% CI: 72.8–100%), with moderate cGVHD accounting for all events. The FCR regimen in SAA was well tolerated, even in older adults, with 100% disease-free survival with low GVHD and infection rates. These encouraging findings should be validated in larger prospective trials.

A first-in-human study of CRISPR/Cas9-engineered tumor infiltrating lymphocytes (TILs) product GT316 as monotherapy in advanced solid tumors.

2549 Background: A next-generation TIL product GT316 was engineered with CRISPR/Cas9 to genetically disrupt two key immunoregulatory targets identified from a genome-wide CRISPR screening platform and demonstrated significantly enhanced anti-tumor efficacy and persistence in pre-clinical animal studies with ameliorated TIL exhaustion profile. A first-in-human trial was initiated to evaluate the preliminary safety and efficacy of GT316 in advanced solid tumors. Methods: The first-in-class study is to enroll patients (pts) with advanced treatment-refractory solid tumors, especially gynecological tumors. Once the optimal biological dose (OBD) is identified, a monotherapy expansion phase will be initiated for pts with various solid tumors. Enrolled pts were preconditioned with a nonmyeloablative (NMA) lymphodepletion regimen and treated by infusion of the GMP-grade G316 product followed by IL-2 administration. Results: As of January 22, 2024, the dose escalation study enrolled 4 pts, all of whom were female with a median age of 58 years with 1 to 9 prior lines of systemic treatment. The median number of infused TIL cells was 1.0E+10. All pts experienced TRAEs with the majority being grade 1 or 2. Grade 3/4 TRAEs included lymphocyte count decreased, white blood cell count decreased, monocyte count decreased and neutrophil count decreased, which were related to the NMA regimen. No dose-limiting toxicities (DLTs) or TIL-related grade≥3 TRAEs were observed. Median time on study was 33.4 wks (8–35 wks). One pt with treatment-refractory cervical cancer experienced a confirmed complete response (CR) after 4 wks and the duration of response is 32 wks by now (RECIST 1.1). One ovarian cancer pt with 9 lines of previous systemic therapies experienced a confirmed partial response (PR) after 4 wks and the duration of response is 22 wks by now (RECIST 1.1). Response data will be continuously collected. The other two ovarian cancer pts experienced stable disease (SD) and progressive disease (PD), respectively. Despite varying doses of TILs (3.2E+09 to 1.90E+10) and IL-2 (up to 3.0E+05 IU/kg), all pts receiving GT316 showed robust TIL expansion post-infusion, which is positively correlated with administrated IL-2 doses. Enhanced IFN-γ secretion could be detected in the serum of the CR and PR pts compared to the SD and PD pts, indicating potential tumor antigen-specific response. Conclusions: The first-in-human study of GT316, a CRISPR/Cas9-dual KO anti-exhaustion TIL product, demonstrates good tolerability with encouraging preliminary anti-tumor efficacy as a monotherapy in pts with advanced solid cancers. The infusion of GT316 was associated with robust TIL expansion and IFN-γ secretion. Updated data with additional follow-up will be continuously collected, and OBD will be determined based on the overall data of safety and preliminary efficiency. Clinical trial information: NCT06145802 .

Effect of pre-transplant functional status on length of hospital stay in patients undergoing allogeneic hematopoietic stem cell transplant in an outpatient transplant program.

6560 Background: The use of reduced intensity conditioning regimens including non-myeloablative regimens in allogeneic hematopoietic stem cell transplant (allo SCT), has expanded the pool of transplant candidates in the United States. Nonetheless, allo SCT, is associated with significant morbidity and mortality especially in patients 65 and older. In our outpatient transplant program, allo SCT patients undergo a comprehensive physical and occupational therapy (PT/OT) evaluation pre-transplant. Methods: We retrospectively reviewed all patients undergoing an allo SCT between January 2019 and December 2022 who had a PT/OT evaluation pre-transplant. We analyzed lower extremity functional scale (LEFS) and fatigue score (FACIT). The FACIT score is a patient reported outcome tool where the lower the score, the less fatigue impacts a patient’s performance. Results: We identified 218 patients who had at least one variable reported. Eighty-one patients were 65 years of age or older. All patients in the 65 and older group had a RIC or NMA conditioning regimen. In the 65 and older group, 72.8% had an HCTCI score of 3 or more compared to 59.1% in the group younger than 65. In patients younger than 65, those who had a lower LEFS (ie less lower extremity strength), had a statistically significant longer hospital stay of 15.5 days compared to 9 days (p=0.003). In patients 65 and older, lower FACIT scores (ie less patient reported fatigue), resulted in a statistically significant shorter hospital stay of 7.5 days compared to 13 days (p=0.019). In addition, there was a trend towards shorter hospital stays in patient 65 and older who had a higher LEFS of 5 days compared to 12.5 days (p=0.07). There was no difference in survival outcomes but there was a trend towards better overall survival in patients 65 and older with high LEFS (p=0.08) and a trend towards better NRM in this group (p=0.11). Conclusions: Our study highlights the need for comprehensive assessments in patients undergoing allo SCT. Geriatric functional status assessments are necessary to determine patients at risk for complications and to optimize such patients with exercise and cognitive rehabilitation programs prior to allo SCT. [Table: see text]

Long term outcomes of nonmyeloablative allogeneic stem cell transplantation with TSEB TLI and ATG for Mycosis Fungoides and Sezary Syndrome

Advanced stage (IIB-IVB) Mycosis Fungoides (MF) and Sezary Syndrome (SS) have a poor prognosis with median survival <5 years. We report long-term outcomes of a non-myeloablative allogeneic stem cell transplantation regimen consisting of total skin electron beam therapy, total lymphoid irradiation and antithymocyte globulin. Our prospective cohort consisted of 41 patients with a higher proportion of MF (34MF, 7SS). Acute GVHD Grade 2 to 4 was seen in 31.7% and chronic GVHD Grade 2 to 4 in 24%. The cumulative incidence of non-relapse mortality was 9.8% at 1 year and 12.6% at 2 years. At Day +90 post-transplant 66% of patients had a complete response (CR). With a median post-transplant follow up of 5.27 years, the 5-year overall survival rate was 37.7% (MF 36.7%, SS 57.1%). The 5-year cumulative incidence of progressive disease or relapse was 52.7% in all patients but only 20.8% in those with CR at transplant compared to 70.6% in those not in CR at transplant (p = 0.006). Long term survival is possible in advanced MF and SS with non-myeloablative transplantation and outcomes are improved in patients with CR at transplant.

Excellent Outcomes of HLA Matched Related Donor Transplant for Adults with Severe Sickle Cell Disease Using a Non-Myeloablative Conditioning with Thiotepa and Post-Transplant Cyclophosphamide: Multi-Center International Experience

Introduction: The validated curative treatment for sickle cell disease (SCD) is allogeneic hematopoietic stem-cell transplantation (HSCT). Despite paucity of available matched sibling donors (10-14%), they are preferred due to less immunogenic complications like graft versus host disease (GVHD) and graft failure (GF) using alternative donors. In-vivo T-cell depletion by post-transplant cyclophosphamide (PTCy) has been shown to be most effective in GVHD control and a non-myeloablative regimen minimizes the toxicity associated with HSCT in this vulnerable population. In 2013, the multi-institutional Vanderbilt Haploidentical Learning Collaborative showed the improved outcomes of their non-myeloablative regimen for related haploidentical BMT for SCD (ClinicalTrials.gov identifier NCT01850108). We used a similar non-myeloablative approach to improve donor engraftment rates, while minimizing GVHD. Material and methods: This study was conducted at three international centers using similar conditioning from our experience in multi-institutional Vanderbilt Global Haploidentical Learning Collaborative to optimize haploBMT for SCD. The conditioning regimen included ( Figure3): rabbit anti-thymoglobulin (ATG) 4.5 mg/kg, thiotepa 10 mg/kg, fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and total body irradiation (TBI) 200 cGy. GVHD prophylaxis included PTCy 100 mg/kg, mycophenolate mofetil (MMF), and sirolimus. Stem cell source included bone marrow (BM) mobilized with filgrastim (5-10 μg/kg/d x 3-5 days) and peripheral blood (PB). Primary graft failure (GF) was defined as &amp;lt;5% donor myeloid/lymphoid chimerism or &amp;lt;5% donor cells by whole blood (WB) chimerism by day+28 posttransplant. Secondary graft rejection was defined &amp;lt;5% donor myeloid/lymphoid chimerism or &amp;lt;5% donor cells by whole blood (WB) chimerism with prior documentation of &amp;gt;5% donor cells by day +28. The Event free survival (EFS) was defined by survival with no GF, no death and/or no chronic GVHD. This cohort includes 4/22 patients (18.2%) had prior graft failure from a previous bone marrow transplants. Results: Here we report the outcome of 22 SCD patients (100% HbSS genotype), with a median age of 26.5 (15-41), transplanted from 10/10 MRD 86.4 % (n= 19) or single antigen mismatch related donor (MMRD) (9/10) 13.6% (n=3). The stem cell source was PB in 54.5% (12/22), and BM in 45.5% (10/22). Median CD34 stem cells dose was 6 X 10 6/Kg (1.2 - 10.25). Neutrophils and platelets engrafted at a median of 21.0 (15 - 26) and 25.0 (12 - 45) days, respectively. Demographic and clinical characteristics of participants summarized in Table 1. No primary or secondary graft failure was observed in the participants based on the last follow-up and time of analysis of this report. For participants with durable engraftment, the median WB chimerism values for D+28 and D+365 engraftment was 99.25% (n=14; IQR: 52 - 100) and 96.5% (n=16; IQR: 52 - 100), respectively. The median follow-up time was 14.6 months (n=22; IQR: 0.5-45.44). The overall incidence of acute GVHD grade III-IV was 4.5% (n= 1/22), and no incidence of chronic GVHD. There was no transplant related mortality. A Kaplan-Meier based probability of overall survival (OS) was 100%, Figure 1. All patients were off immunosuppression at 1-year post transplant. EFS as defined in the method was 100%, Figure 2. The EFS of free acute GVHD grade III-IV was 95.5%. Conclusion: This result shows the superiority of Thiotepa based non-myeloablative conditioning and PTCy for MRD transplants in adults with severe SCD. It not only minimizes the toxicity and GVHD but provides optimal donor engraftment mitigating against risk of secondary myeloid neoplasms from mixed chimerism. This needs further validation in a larger cohort.

Myeloablative or reduced-intensity/non-myeloablative hematopoietic cell transplantation for Philadelphia-positive acute lymphoblastic leukemia in adults older than 40years old - a secondary analysis of a CIBMTR database.

Few studies have addressed the role of reduced-intensity conditioning (RIC) and non-myeloablative (NMA) regimens in older adults with Philadelphia acute lymphoblastic leukemia (Ph + ALL). The objective of this current study was to compare the outcomes of RIC/NMA versus TBI-based myeloablative (MAC) regimens in Ph + ALL patients older than 40years old who underwent hematopoietic cell transplantation (HCT) in CR1. We used a freely available database from the CIBMTR. Transplants were performed between 2013 and 2017. With a median follow-up of 37.6months, we have included 629 patients. We used propensity score weighting. Three-year OSs were 64% in the TBI-MAC group and 66% in the RIC/NMA group. OS was not different (HR = 0.92; p = 0.69). Three-year relapse incidences were 21.6% and 27.6% in the TBI-MAC and RIC/NMA groups. RIC/NMA was not associated with an increase in relapse rate (HR 1.02; p = 0.91). Three-year NRMs were 24.3% in the TBI-MAC group and 20.3% in the RIC/NMA group. RIC/NMA was not associated with superior NRM (HR 0.88; p = 0.57). In summary, we have shown that RIC/NMA regimens achieve outcomes comparable to TBI-based MACin Ph+ ALL older patients in CR1 who may tolerate a TBI-based MAC regimen.

Comparison of Non-Myeloablative Conditioning Regimens Flu/Bu2, Flu/Mel 100 and Flu/TBI in Patients with AML and MDS

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment modality for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Non-myeloablative (NMA) conditioning regimens are used to decrease toxicity, making HSCT more tolerable and available to older patients or patients with co-morbidities. It remains unclear as to which NMA regimen leads to superior outcomes. Methods: We retrospectively compared outcomes of 3 NMA regimens in 98 patients with AML or MDS undergoing allogeneic HSCT from January 2017 to December 2021. The 3 regimens were: Flu/Mel 100: fludarabine 40 mg/m2 days -5 to -2, melphalan 100 mg/m2 day -2; Flu/Bu2: fludarabine 30 mg/m2 days -6 to -2, busulfan 130 mg/m2 days -3 to -2; Flu/TBI: fludarabine 30 mg/m2 days -4 to -2, total body irradiation 200-300 cGY on day-1. Patients conditioned with Flu/Mel 100 or Flu/Bu2 also received rabbit anti-thymocyte globulin 4-6 mg/kg. Graft versus host disease (GVHD) prophylaxis consisted of tacrolimus and low dose methotrexate for patients receiving Flu/Mel 100 or Flu/Bu2, and sirolimus, cyclosporine and mycophenolate mofetil for patients conditioned with Flu/TBI. Continuous variables were compared between conditioning regimens using Pearson's Chi-squared test or Fisher's exact test. PFS and OS survival probability and survival times were estimated with Kaplan-Meyer(K-M) procedure. To compare survival distributions between conditioning regimens, a log-rank test was used. We report 24-month survival probabilities in months with corresponding 95% confidence intervals. Results: Patient demographics were balanced between the 3 groups including age (range 54-80), gender, disease risk and cell source (Table 1). 24-month progression free survival (PFS) was not different between the groups: Flu/Mel 100 was 70% (47%-100%), Flu/Bu2 was 49% (39%-63%), and Flu/TBI was 33% (18%-61%) (p=0.3). For Flu/Mel 100 the 24-month overall survival (OS) was 70% (47%-100%), Flu/Bu2 was 53% (42%-66%), Flu/TBI was 32% (17%-61%) which was not statistically different ( p=0.3) (Figure 1). There was no difference between the 3 groups for non-relapse mortality (NRM) ( p=0.46). The incidence of all grade acute GVHD was 70% for Flu/Mel 100, 66% for Flu/Bu2 and 76% for Flu/TBI ( p=0.70). There was no difference in the incidence of chronic GVHD between the groups; Flu/Mel 100 50%, Flu/Bu2 55%, Flu/TBI 57% (p&amp;gt;0.99). Conclusions: All three NMA regimens were found to be statistically equivalent. NRM, PFS, OS and the incidence of acute and chronic GVHD was not statistically different between the groups. A limitation of the study is the relatively small number of patients in the Flu/Mel 100 group. Further study with a larger sample size is needed to evaluate for small differences between the regimens.

Characteristics and Clinical Outcomes of Patients with Acute Myeloid Leukemia with TP53 Mutations - a Single Center Experience

Introduction TP53-mutated acute myeloid leukemia (AML) carries a dismal prognosis. Optimal induction therapy is uncertain, and it remains unclear whether allogeneic stem cell transplant (allo-SCT) improves survival. Methods We investigated 89 cases of TP53-mutated AML diagnosed at or referred to Thomas Jefferson Hospital between April 2016 and May 2023 and reviewed clinical characteristics and outcomes. Remission status was determined by bone marrow biopsy and aspiration after at least 1 cycle of anti-leukemic therapy (ALT). ALT was classified into high- or low-intensity treatment. High-intensity treatment was defined as regimens containing high-dose cytarabine (≥ 200 mg/m 2/day) for at least five consecutive days in combination with an anthracycline. Low-intensity treatment was defined as hypomethylating agent (HMA)-based therapy containing either azacitidine or decitabine with or without venetoclax. Results Median age at diagnosis was 66 (range, 23-91). Forty-nine percent had de novo AML, and the rest had secondary AML. Ninety-one percent had newly diagnosed AML and 9% were found to have a TP53 mutation at relapse. Median somatic mutation count as detected by next-generation sequencing (NGS) was 2 (range, 1-9). Thirty percent were treated with high-intensity treatment, 46% with low-intensity treatment, and 22% received supportive care only. Detailed patient characteristics are in Table 1. Median overall survival (OS) for the entire group was 3.17 months [95% confidence interval (CI) 1.90-5.13 months], and 5.13 months (95% CI 3.83-8.00 months) for patients who received any ALT. Of 69 patients who received ALT, composite complete remission (CRc) rates were 26% with high-intensity treatment and 34% with low-intensity treatment ( p = 0.56). Fifty-six percent did not achieve a remission, and 12% were not able to be assessed due to early mortality. The 30-day mortality was 15% and 7% with high- and low-intensity treatments, respectively. OS was not different between patients who received high- and low-intensity treatments (5.13 months vs 5.27 months, p = 0.65). Twenty-four percent underwent allo-SCT with a median follow-up of 15.2 months. The median time to transplant was 180 days from time of diagnosis (range, 119-341). Median hematopoietic cell transplantation-specific comorbidity index was 3 (range, 1-7). The majority of patients (69%) received a reduced intensity or non-myeloablative regimen, and 63% received a haploidentical transplant. Eighty-one percent of transplant recipients were in CR or CR with incomplete count recovery at the time of transplant; the remaining had either primary induction failure or relapsed disease. Median OS was significantly longer for patients who received allo-SCT compared to those who received chemotherapy only (18.0 months vs 3.7 months, p &amp;lt;0.0001) (Figure 1). Cumulative incidence of relapse post-transplant was 36% at 1 year and 79% at 2 years. Conclusions TP53-mutated AML is associated with a dismal outcome. In our single-center analysis, approximately one-third of patients achieved remission after initial ALT. Consolidation with allo-SCT is associated with improved survival, however relapse risk remains high. Treatment strategies aimed at reducing disease relapse post-transplant are warranted.

Thyroid and Adrenal Dysfunction in Hemoglobinopathies Before and After Allogeneic Hematopoietic Cell Transplant.

To determine the rate and clinical characteristics associated with abnormal thyroid and adrenal function in recipients of nonmyeloablative hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) and beta-thalassemia. We retrospectively reviewed patients who enrolled in 4 nonmyeloablative HCT regimens with alemtuzumab and total body irradiation (TBI). Baseline and annual post-HCT data were compared, which included age, sex, sickle phenotype, thyroid panel (total T3, free T4, thyroid stimulating hormone, antithyroid antibodies), cortisol level, ACTH stimulation testing, ferritin, medications, and other relevant medical history. Among 43 patients in haploidentical transplant and 84 patients in the matched related donor protocols with mostly SCD, the rate of any thyroid disorder pre-HCT was 3.1% (all subclinical hypothyroidism) and post-HCT was 29% (10 hypothyroidism, 4 Grave's disease, and 22 subclinical hypothyroidism). Ninety-two (72%) patients had ferritin >1000 ng/dL, of which 33 patients (35.8%) had thyroid dysfunction. Iron overload was noted in 6 of 10 patients with hypothyroidism and 12 of 22 patients with subclinical hypothyroidism.Sixty-one percent were on narcotics for pain control. With respect to adrenal insufficiency (AI) pre-HCT, 2 patients were maintained on corticosteroids for underlying rheumatologic disorder and 8 had AI diagnosed during pre-HCT ACTH stimulation testing (total 10, 7.9%). Post-HCT, an additional 4 (3%) developed AI from corticosteroid use for acute graft vs host disease, Evans syndrome, or hemolytic anemia. Although iron overload was common in SCD, thyroid dysfunction pre-HCT related to excess iron was less common. Exposure to alemtuzumab or TBI increased the rates of thyroid dysfunction post-HCT. In contrast, AI was more common pre-HCT, but no risk factor was identified. AI post-HCT was infrequent and associated with corticosteroid use for HCT-related complications.

Reduced-Intensity Compared to Nonmyeloablative Conditioning in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P=.1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P=.24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P=.5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P=.039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P=.002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.

Acute Pulmonary Toxicity after Allogeneic Stem Cell Transplantation Using Total Body Irradiation-Based Conditioning- Myeloablative vs. Non-Myeloablative Regimens

Allogeneic hematopoietic stem cell transplantation (HSCT) is associated with a high risk of acute pulmonary toxicity, especially with total body irradiation-based (TBI) conditioning regimens. High-grade acute pulmonary toxicity occurs in ∼30% of patients when a myeloablative regimen is utilized (∼12-14 Gy). The risk of pulmonary toxicity with non-myeloablative regimens (∼2 Gy) is not well described. We evaluated the incidence and predictors of acute pulmonary toxicity after HSCT comparing myeloablative and non-myeloablative TBI-based conditioning regimens. All adult (≥ 18 y/o) patients undergoing allogeneic HSCT with TBI (1995-2020) at our institution were evaluated. The dose to the lungs was attenuated to 7-10 Gy in all patients undergoing myeloablative TBI. Acute pulmonary toxicity, occurring within 6 months of HSCT, was scored using CTCAE v5.0. The incidence of acute pulmonary toxicity was calculated using the Kaplan-Meier method, and logistic regression was performed to assess for independent risk factors. Five hundred fifty-two patients were included the analysis (myeloablative- 378; non-myeloablative- 174). Myeloablative TBI was most commonly 13.5 Gy/9Fx (335/378), while non-myeloablative TBI was delivered most often as 2 Gy/1Fx (165/174). Patients undergoing myeloablative TBI were younger than non-myeloablative patients (43 vs 58 years, p<0.001), but baseline pulmonary function parameters were similar. At 6 months after transplant, the cumulative incidences of any acute pulmonary toxicity for patients receiving myeloablative and non-myeloablative TBI were 39% and 33%, respectively (p = 0.11). The risk of low-grade (1-2) and high grade (3-5) pulmonary toxicity was 10% vs 12% (p = 0.59) and 28% vs 21% (p = 0.05), respectively, comparing myeloablative and non-myeloablative TBI. Proportions of high-grade toxicities among the myeloablative and non-myeloablative cohorts were as follows: infectious pneumonia (31% and 49%), bronchopulmonary hemorrhage (25% and 3%), respiratory failure NOS (17% and 10%), pleural effusion (5% and 1%), and pneumonitis (4% and 0%). Female sex (OR 1.52, p = 0.05) and refractory disease at the time of transplant (OR 2.25, p = 0.03) were associated with a higher risk of severe pulmonary toxicity on logistic regression. Younger age (OR 0.99, p = 0.35) and non-myeloablative TBI (OR 0.21, p = 0.60) were not significantly associated with a lower risk. The risk of acute pulmonary toxicity was high with both myeloablative and non-myeloablative TBI-based regimens, though high-grade toxicity was modestly higher in the myeloablative cohort. A better understanding of pulmonary toxicity in the setting of non-myeloablative TBI (∼2 Gy) is needed.

Long-Term Toxicity after Total Body Irradiation-Based Conditioning Regimens for Allogeneic Stem Cell Transplantation

Total body irradiation (TBI) is an integral component of many conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT). Few studies have investigated long-term sequelae. A large series of patients undergoing myeloablative and non-myeloablative regimens was studied. Adult patients undergoing allogeneic HSCT utilizing TBI-based conditioning regimens from 1995-2020 at our institution were included. Baseline treatment-related factors and long-term toxicities (developing, or persisting beyond, 6 months after HSCT) were collected. The cumulative incidence of long-term toxicities and overall survival (OS) were calculated. Cox regression was used to assess for predictors of toxicity. Five hundred fifty-two patients were analyzed: 378 myeloablative (typically 13.5 Gy/9fx) and 174 non-myeloablative (typically 2 Gy/1fx) TBI recipients. Median follow-up was 7.4 years for surviving patients. Cumulative incidences of long-term toxicities at 5 and 10 years are included in the Table. The most common toxicities were: pulmonary- infectious pneumonia and respiratory failure NOS; cardiac- heart failure and myocardial infarction; other endocrine- adrenal insufficiency and testosterone deficiency. The most common secondary malignancy was non-melanoma skin cancer. The proportion of all toxicities that were high-grade (3-5) for myeloablative and non-myeloablative regimens, respectively, were: pulmonary (65%, 52%), cardiac (66%, 39%), renal (23%, 27%), and other endocrine (3%, 18%). Increasing number of chemotherapy regimens (p = 0.05) and umbilical cord donor (p = 0.02) were associated with long-term pulmonary toxicity. Male sex (p = 0.03), increasing number of chemotherapy regimens (p<0.01), and elevated creatinine after transplant (p<0.01) were associated with long-term renal toxicity. Cataract development was associated with increasing age at transplant (p = 0.02). OS (5 years) was 40% (42% -myeloablative; 33%-non-myeloablative). Allogeneic HSCT, often preceded by TBI-based conditioning regimens, has significant survivorship challenges. Recipients of non-myeloablative regimens are still at risk of significant long-term multisystem toxicity despite much lower doses of TBI and chemotherapy. Pre-transplant factors such as cumulative chemotherapy exposure and age at transplant were associated with some toxicities.

VMAT TBI Technique Using Autoplanning Scripts

Evident by the Children's Oncology Group (COG) survey of pediatric total body irradiation (TBI) practice, 100% of physicians were open to refining the conventional TBI technique to lower the lung dose and 75% of respondents were interested in implementing VMAT or a 3-D CRT and IMRT system TBI. Unfortunately, only a handful of COG institutions have implemented VMAT or Tomo TBI. We created the autoplanning scripts and shared them with the public to make the VMAT TBI more wide-spread. Here, we report on our initial experience of treating Stanford VMAT TBI technique using the scripts. From October 2019 to February 2023, 75 patients were treated with VMAT TBI at our institution. Organ sparing depended on the regimen: myeloablative (lungs, kidneys, and lenses); non-myeloablative (lungs, kidneys, lenses, gonads, brain, and thyroid). Treatment planning was performed using Eclipse Scripting Application Programming Interface (ESAPI) auto-planning scripts. Data on patient, treatment details, and dosimetric indices were collected. Treatment was delivered using IGRT for every isocenter and every fraction. In-vivo measurements were performed on the matchline between the VMAT and AP/PA fields and on the testes for the first fraction. Median patient age was 13 years (range, 1 - 64). The patient height and width range were 83.6-197.3 cm and 24.9-60.3 cm, respectively. Forty-eight percent of patients were treated using myeloablative and 52% nonmyeloablative regimens. For all patients the lungs, lungs-1cm, and kidneys Dmean were consistently spared to 59.8±4.7%, 43.0±6.5%, and 70.9±7.7% of the prescription dose, respectively. Gonadal sparing (Dmean = 31.5±5.9%) was achieved for all patients with benign disease. In addition, brain and thyroid was spared for these patients. For nine patients, VMAT TBI offered additional organ sparing (liver, heart, and previously irradiated areas) and possibility to perform the simultaneously integrated boost. The average PTV D1cc was 120.3±6.6% for all patients. PTV D1cc correlated with patient height and width (R2 = 0.62 and 0.53). Sixteen patients (21.3%) with height <116cm were treated with 3-isocenter VMAT only plans, 59 patients (78.6%) were treated with 3-4 isocenter VMAT plans in head-first-supine position and 1-3 AP/PA plan in feet-first-supine position. Rotational platform was used to change the patient orientation. The average matchline dose measurement indicated patient setup was reproducible (96.1±4.5% relative to planned dose). For the first 35 patients, treatment time, including patient setup and beam-on, was 47.5±9.5 min. VMAT TBI is a modern alternative to conventional 2D TBI treatment offering the possibility of organ sparing, dose painting, and accurate treatment using IGRT. The automated scripts enable streamline planning with consistent plan quality.

Harnessing the power of tumor-infiltrating lymphocytes: A first-in-human study of GT201 as monotherapy in advanced solid tumors.

2551 Background: Genetically engineered TIL has shown features such as prolonged memory that can improve therapeutic efficacy in tumor mouse models. GT201 is an engineered TIL that expresses a membrane-bound IL-15 (mbIL-15), and preclinical studies have demonstrated enhanced antitumor reactivity. A phase 1 study was initiated to evaluate the preliminary safety of GT201 and to identify Optimal Biological Dose (OBD) suitable for monotherapy expansion. Methods: The dose-escalation study (using TITE-BOIN design) intended to enroll patients (pts) with advanced treatment-refractory solid tumors. Once the OBD is identified, a monotherapy expansion phase will be opened for patients with various solid tumors. Enrolled patients were preconditioned with a nonmyeloablative (NMA) lymphodepletion regimen and treated by autologous infusion of the GMP-grade G201 cell product, followed with supportive low dose IL-2 administration. Results: As of January 17, 2023, the dose-escalation study enrolled 4 pts, all of whom were female with a median age of 52.6 years. The median number of infused TIL cells was 5.3E+09. All pts experienced TRAEs, with the majority being grade 1 or 2. The most common grade 3/4 TRAEs were lymphopenia (100%), leukopenia (25%) and neutropenia (25%), which were related to the NMA regimen. No dose-limiting toxicities (DLTs) or TIL-related grade ≥3 TRAEs were observed. Median time on study was 17 wks (6–30 wks). One pt with highly treatment-refractory cervical cancer experienced a confirmed partial response (PR) after 16 wks that was durable for 30 wks (RECIST 1.1). Two pts (cervical cancer and melanoma) experienced disease stabilization, while another malignant melanoma pt experienced progressive disease. Despite varying doses of TILs (5.0E+09 to 1.40E+10) and IL-2 (up to 3.0E+05 IU/kg), all patients receiving GT201 therapy showed robust T cell expansion post-infusion, with higher doses of IL-2 leading to more rapid TIL expansion. GT201 TILs could be detected in patients after one month post-infusion, indicating promising activation and long-term persistence of the infused TILs. Based on safety, tolerability, PKs, and preliminary efficacy, a TIL dose of 1.0E+10 and an IL-2 dose of 3.0E+05IU/kg was selected as the OBD for the study. Conclusions: The results of the first-in-human study of GT201, a mIL-15 expressed on TILs, demonstrate promising preliminary findings as a monotherapy in pts with advanced cancers. The administration of GT201 was associated with robust T cell expansion, as well as prolonged persistence of infused TILs. Results of mbIL-15 expressed TIL demonstrates that GT201 has good tolerability with encouraging preliminary antitumor activity as a monotherapy. Further investigations, including correlative biomarker analyses and updated safety and clinical outcome data, will be presented at the meeting. Clinical trial information: NCT05430360 .

Abstract OT2-10-04: Treatment of advanced or metastatic triple-negative breast cancer with adoptive therapy of PD1+ tumor-infiltrating lymphocytes (TILS001 trial)

Abstract Background Metastatic triple-negative breast cancer (mTNBC) exhibits a particularly poor clinical outcome, generally with rapid progression and worse overall survival (OS) than other BC subtypes. Among the few therapeutic options, chemotherapy-based combinations are associated with increased toxicity and limited survival benefit, being treatment with sequential single agents, such as paclitaxel considered an appropriate first-line regimen for the metastatic setting for PDL-1 negative patients. Herein, there is an urgent need for clinically active agents for the mTNBC. Adoptive cell transfer (ACT)-based immunotherapy using ex vivo activated and expanded tumor-infiltrating lymphocytes (TILs) has shown promising therapeutic outcomes in some patients with metastatic tumors. The identification, selection, and enrichment of tumor-reactive lymphocytes at the early stages of the ACT generation could enhance their clinical activity. Thus, the selection of reactive T cells, such as PD1-positive (PD1+) TILs, could improve the responses achieved in those settings. TILS001 trial aims to explore the safety, tolerability and efficacy of selected PD1+ T-cell infusion with a previous pre-selection of mRNA PD1-high expression in patients with mTNBC. Study design: TILs001 trial is an open-label, single-arm, multicenter phase I/II prospective study with a two-stage design evaluating treatment with PD1+ TILs infusion in advanced or mTNBC, defined as HER2 negative and Hormonal Receptor &amp;lt; 10%. The study involves three different parts before PD1+TILs treatment. Tumor samples evaluable for PD1 mRNA expression and life expectancy ≥6 months are mandatory for part 1. Patients with high levels of PD1 mRNA, defined by the pre-specified cutoff, candidates for receiving a first-line taxane-based containing regimen and with at least 1 accessible target lesion to generate TILs are eligible for part 2. Finally, once the complete expansion of PD1+TILs is reached, patients will receive the non-myeloablative lymphodepleting chemotherapy regimen followed by PD1+TIL infusion and IL-2 treatment. Allogeneic hematopoietic stem cell transplantation, immune system-related disease or clinically active cerebral metastasis are not allowed. The primary objectives are to evaluate the safety and tolerability of the PD1+ TIL product, as per incidence of grade 3-5 adverse events (AE) or any grade AE that leads to treatment discontinuation and to assess the efficacy of ACT therapy with selected PD1+ TILs in mTNBC in terms of progression-free survival (PFS) at 6 months. The secondary endpoints are clinical benefit rate at 6 months (CBR6), overall response rate, duration of response (DoR), PFS and OS. Further translational research including immunophenotyping, TCR sequencing and mutational analysis will also be performed. The first 3 patients will be included in a safety run-in phase where safety will be evaluated 24h after PD1+/TILs infusion (before IL-2 treatment) and a phase II stage where efficacy will be evaluated, which will include up to 20 patients. Patients will be enrolled in 4 sites in Spain. Recruitment is expected to start by July 2022 and to be completed within 24 months. This study is financially supported by the Asociación Española Contra el Cáncer (GCAEC19010PRAT). NCT05451784 Citation Format: Nuria Chic, Eva Ciruelos, Cristina Saura, Europa-Azucena Gonzalez, Luís Álvarez-Vallina, Juan José Lasarte, Alena Gros, Lorea Villanueva, Jordi Canes, Laura Angelats, Aleix Prat, Tomás Pascual, Marta Santisteban, Manel Juan. Treatment of advanced or metastatic triple-negative breast cancer with adoptive therapy of PD1+ tumor-infiltrating lymphocytes (TILS001 trial). [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-10-04.

Secondary Neoplasms After Hematopoietic Cell Transplant for Sickle Cell Disease.

To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study

BackgroundPatients with advanced melanoma have limited treatment options after progression on immune checkpoint inhibitors (ICI). Lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, demonstrated an investigator-assessed objective response rate...