Splenic Irradiation Research Articles

Magnetic Resonance Imaging Guided Radiation Therapy for Splenomegaly: Clinical Experiences and Technical Tips

IntroductionSplenomegaly is a common manifestation in chronic lymphoid and myeloid malignancies. While splenectomy is the preferred treatment for symptomatic splenomegaly, it carries significant risks. Radiotherapy (RT) has traditionally been considered a palliative option. This study explores the use of Magnetic Resonance-Guided Radiotherapy (MRgRT) for splenic irradiation (SI) in patients with myelofibrosis (MFI) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). MethodsThis single-center retrospective analysis includes patients with MFI and MDS/MPN who underwent MRgRT SI between 2018 and 2022. Ten 1 Gy fractions were delivered to the PTV (spleen+3/5mm margin). An adaptive online/offline strategy has been used to reduce the dose to healthy organs. Dosimetric data and clinical outcomes, including pain relief, gastrointestinal symptoms, and hematological values, were assessed. ResultsTwelve patients completed SI without interruption, with supportive transfusions as needed for cytopenias. Pain and gastrointestinal symptoms relief was observed in most cases. The mean percentage reduction in spleen volume was 53.61%, with an average cranio-caudal extension reduction of 77.78%. Twenty-nine (24.2%) out of 120 fractions were online adapted and 14 (11.7%) were replanned offline. Non-hematological toxicities were not reported. At a median follow-up of 12.9 months, 6 patients died, while 9 patients underwent hematopoietic cell transplantation, with 6 of them surviving. ConclusionThis study demonstrates MRgRT SI feasibility in MFI and MDS/MPN patients, offering symptom relief and significant spleen volume reduction. Real-time setup verification and adaptive planning allowed for tailored treatment with reduced margins, minimizing healthy tissue exposure. Larger prospective studies with longer follow-up are needed to further validate its efficacy and safety.

Spleen Volume Reduction Is a Reliable and Independent Biomarker for Long-Term Risk of Leukopenia Development in Peptide Receptor Radionuclide Therapy.

177Lu-DOTATATE therapy is an effective treatment for advanced neuroendocrine tumors, despite its dose-limiting hematotoxicity. Herein, the significance of off-target splenic irradiation is unknown. Our study aims to identify predictive markers of peptide receptor radionuclide therapy-induced leukopenia. Methods: We retrospectively analyzed blood counts and imaging data of 88 patients with histologically confirmed, unresectable metastatic neuroendocrine tumors who received 177Lu-DOTATATE treatment at our institution from February 2009 to July 2021. Inclusion criterium was a tumor uptake equivalent to or greater than that in the liver on baseline receptor imaging. We excluded patients with less than 24 mo of follow-up and those patients who received fewer than 4 treatment cycles, additional therapies, or blood transfusions during follow-up. Results: Our study revealed absolute and relative white blood cell counts and relative spleen volume reduction as independent predictors of radiation-induced leukopenia at 24 mo. However, a 30% decline in spleen volume 12 mo after treatment most accurately predicted patients proceeding to leukopenia at 24 mo (receiver operating characteristic area under the curve of 0.91, sensitivity of 0.93, and specificity of 0.90), outperforming all other parameters by far. Conclusion: Automated splenic volume assessments demonstrated superior predictive capabilities for the development of leukopenia in patients undergoing 177Lu-DOTATATE treatment compared with conventional laboratory parameters. The reduction in spleen size proves to be a valuable, routinely available, and quantitative imaging-based biomarker for predicting radiation-induced leukopenia. This suggests potential clinical applications for risk assessment and management.

Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

The senomorphic impact of astaxanthin on irradiated rat spleen: STING, TLR4 and mTOR contributed pathway.

Exposure of spleen tissues to ionizing radiation during radiotherapy can induce cellular stress and immune-dysfunction leading to cellular senescence. The process of a cancerous development is facilitated by the accumulation of senescent cells. This justifies the incorporation of anti-senescent medications during splenic irradiation (SI). In this study senescence was induced in the spleen of male albino rats by radiation exposure (5Gy-single whole body gamma-irradiation) then after 2weeks, oral astaxanthin regimen was started once daily in a dose of 25mg/kg for 7 consecutive days. Concurrent control groups were carried out. the present data reflected that irradiation provoked an increase in the oxidative stress biomarkers (nitric oxide, lipid peroxidation and total reactive oxygen species levels)and the inflammatory biomarkers (Myeloperoxidase and interleukin-6). In addition irradiation led to the over expression of stimulator of interferon genes (cGAS-STING), mammalian target of rapamycin (mTOR) and Toll-like receptor 4 (TLR4) along with the lactate dehydrogenase (LDH), cyclin-dependent kinase inhibitor 1 (p21) cyclin-dependent kinase inhibitor 2A (p16) increment with elevation of tumor suppressor protein (p53) level. However, reduced glutathione contents and catalase activity were reduced post irradiation in spleen tissues, all these changes reflecting induction of cellular senescence. Astaxanthin treatment showed an improvement in the antioxidant/oxidative stress balance, inflammatory biomarkers, histopathological examination and immunohistochemical expressions of the tested proteins in the irradiated rats. the current findings offer a new insight into the senomorphic effect of astaxanthin following radiation-induced spleen senescence via STING, mTOR, and TLR4 signalling pathways.

Incidental splenic irradiation in patients receiving radical radiotherapy for oesophageal cancer

Incidental splenic irradiation in patients receiving radical radiotherapy for oesophageal cancer

Role of Splenic Irradiation Prior to Transplant for Myelofibrosis: A Global Collaboration

JAK inhibitors and novel agents have shown promising reduction of spleen size in newly diagnosed myelofibrosis. However, not all patients will respond or they eventually progress at some point. Despite hematopoietic cell transplantation (HCT) being the only curative treatment option to date, splenomegaly prior to HCT remains a particular challenge. On the other hand, numbers of patients eligible for HCT continue to increase worldwide, and thus management of splenomegaly becomes more and more relevant. One approach to reduce spleen size prior to HCT could be splenic irradiation. However, evidence on its role remains scarce. We took advantage of a global collaboration between European, US, and Latin American centers to investigate the role of splenic irradiation as part of the HCT platform for patients with myelofibrosis. Radiation therapy had to be given within 3 months prior to or be part of conditioning therapy for HSCT. Detailed information on irradiation as well as post-HCT safety profiles was collected in addition to usual patient-, disease-, and transplant-related variables. This global collaborative study included 52 patients, of whom 71% had primary myelofibrosis, 17% post polycythemia vera and 12% post essential thrombocythemia myelofibrosis. Median age at HCT was 60 years (range, 32-76). Risk category according to DIPSS prior to irradiation was intermediate-1 in 20%, intermediate-2 in 52%, and high in 28%. Driver mutation status was JAK2 in 44%, CALR in 40%, MPL in 4%, and triple negative in 12%. Four patients had portal vein thrombosis before irradiation. Ruxolitinib before irradiation was received by 76% and 4% received fedratinib. Reduced intensity conditioning HCT was received by 73% and 85% were matched related or matched unrelated donor transplants. Median time from irradiation to HCT was 2 weeks (range, 0.9-12 weeks) and median spleen size prior to irradiation was 23 cm (range, 14-35). Spleen size was measured by ultrasound in 70%, CT scan in 20%, and physical examination in 10%. Median total irradiation dose was 7 Gy (range, 3-12), fractionated in a median of 5 administrations (range, 2-12). Splenic irradiation resulted in a significant spleen reduction prior to HCT but was also associated with significant reduction in platelet and leukocyte counts ( Table). Spleen size did not correlate with blood counts prior or after irradiation. Higher platelet count prior to irradiation correlated with higher counts after irradiation (r=0.83; P<0.001). There was no correlation between irradiation dose and post-irradiation hematological toxicities. Only 1 patient had non-hematological adverse events (tumor lysis syndrome). Neutrophil engraftment was achieved by 90% within a median of 18 days after HCT and platelet engraftment was achieved by 81% within a median of 38 days. Median follow-up of the total cohort was 2.7 years and 3-year overall survival was 66% (95% CI, 52-80%; Figure). Non-relapse mortality was 27% (95% CI, 15-39%) and cumulative incidence of relapse was 11% (95% CI, 2-20%; Figure). Incidence of acute GVHD grade II-IV and chronic GVHD was 25% and 38%, respectively. Increased spleen size (as continuous variable) prior to irradiation was associated with worse outcome (P=0.05), showing 3-year survival of 73% for spleen ≤25cm vs 42% for >25cm, and non-relapse mortality of 58% vs 14%, respectively (P=0.02). No effect of spleen size after irradiation on outcomes was observed. All 4 patients with portal vein thrombosis died (2-year survival 25%). A multivariable model showed that larger spleen size before irradiation, lower hemoglobin levels, CALR/MPL-unmuated driver mutation genotype, and presence of portal vein thrombosis were significantly associated with worse survival ( Table). This first international and largest study to date on splenic irradiation as part of the HCT algorithm for patients with myelofibrosis and splenomegaly showed a significant impact of spleen size on overall survival and non-relapse mortality, while relapse rates were low. In addition, lower hemoglobin levels and presence of portal vein thrombosis at time of irradiation predicted worse outcomes.

Impact of Clinical and Genetic Factors on Myelofibrosis Outcomes after Allogeneic Transplantation

Introduction: The reported impact of gene mutations, including JAK2-V617F, other MPN phenotypic drivers and additional cooccurring mutations on outcomes after allogeneic transplantation (HCT) in myelofibrosis (MF) has been inconsistent. While the MTSS score incorporated ASXL1 and JAK2 (non MPL/CALR mutations) as unfavorable predictors after HCT, other studies reported JAK2 mutations to be favorable (Blood 2010). Further, in some studies, mutations known to affect disease progression in MF pre-HCT (high-molecular risk or HMR mutations) have not been predictors of post-HCT outcomes. Here we present outcomes in all MF patients undergoing HCT at Dana-Farber Cancer Institute (DFCI) from 2000-2020 and examine clinical and genetic predictors of outcomes, stratified by year of HCT (<2011 or pre-2011 and >2011 or post-2011). Of note, ruxolitinib was available for use post-2011 only, following its FDA approval that year. Methods: Patients with MF who underwent HCT from 2000-2020 at DFCI (n=166) were included in this retrospective cohort analysis. Outcomes were analyzed for the whole cohort as well as sub-group analyses in the pre-2011 (n=39) and post-2011 era (n=127). Mutational analysis was performed by targeted next-generation sequencing of available pre-HCT samples in 115/127 patients in the post-2011 era. Results: Median age was 61 years and follow up 56.2 months. 25% had massive splenomegaly. DIPSS-plus scores were high in 45.2% and 45.1% received rux. HCT and patient characteristics (including KPS and median time from diagnosis to HCT) were similar pre and post 2011, with differences in conditioning regimens. Majority (77.1%) had HLA-matched donors, underwent reduced intensity (69.3%) HCT with peripheral blood stem-cells (92.2%) and received tacrolimus/methotrexate based GVHD prophylaxis (90.1%). FluMel100/140 (n=65), FluBu4 (n=34) and FluBu2 (n=11) were commonly used in the post-2011 era, while Flu/Bu1 (n= 34), ablative Bu/Cy (n=5) and Cy/TBI (n=12) were predominant pre-2011. Few patients underwent pre-HCT splenectomy (10.2%) or splenic irradiation (9%). Median D100 donor chimerism was 68% for Flu/Bu1, 86% for Flu/Bu2, 98% for Flu/Bu4, and 100% for Flu/Mel100-140. At 4 years, overall survival (OS) for the whole cohort was 58% (50,66), progression-free survival (PFS) 55% (47,63), non-relapse mortality (NRM) 23% (17,30) and relapse rate 21%. 4 year OS was significantly better in the post-2011 era compared to pre-2011 (69% vs 26%, p<0.0001), as was PFS, driven by lower relapse rates in the post-2011 era (15% vs 41%, p<0.0001). 4-yr NRM was also marginally better (20% vs 33%, p= 0.17). In the post-2011 era, 115/127 patients had NGS panel-based genetic analysis prior to HCT (Fig 1), demonstrating 91.3% of patients had at least one driver mutation (JAK2 62.6%, CAL-R 13.9%, MPL 14.8%) while 8.7% patients were triple negative. The most frequent cooccurring mutations were ASXL1 (40%), TET2 (28.7%) and U2AF1 (17.4%).In univariable analysis (UVA), the presence of JAK2 mutations (JAK2+) was associated with superior PFS (HR 0.5, 95% CI 0.27,0.94, p= 0.03) while CALR (HR 1.86, p=0.12) and MPL (HR:1.21, p=0.65) mutations were not significant for PFS. Triple negative patients showed a trend towards poorer PFS (HR 2.27, p=0.05). OS results mirrored those of PFS. No cooccurring myeloid gene mutations were associated with PFS or OS. Superior 4-year OS for JAK2+ versus JAK2- recipients (80% versus 58%, p=0.01) is shown in Figure 2. TP53 (p=0.03), TET2 (p=0.015) and EZH2 (p=0.002) mutations were associated with higher relapse rates in UVA. Patients with JAK2+ and cooccurring ASXL1 mutations had poorer OS compared to those with JAK2+/no cooccurring ASXL1 mutations (HR=2.69, p=0.031). Combining clinical and molecular features in the post-2011 era, in MVA, only DIPSS high (HR=4.76, p=0.03) and KPS < 90% (HR=2.66, p=0.024) were significantly associated with poorer OS/PFS while JAK2+ (HR=0.32, 95% CI 0.14,0.75,p=0.009) was significantly associated with better OS/PFS; JAK inhibitor use spleen size/management, conditioning regimen or other mutations including HMR mutations and TP53 were not significantly associated with OS/PFS. Conclusions: In this single-institution retrospective analysis, the presence of a JAK2-V617F mutation was associated with better OS and PFS following HCT in MF in the post-2011 era. Survival outcomes are significantly better in the post-2011 era compared to pre-2011, in our cohort.

The Effect of Splenic Irradiation on Mean Fluorescence Intensity Values of HLA Antibody in Presensitized Patients Waiting for Kidney Transplantation

To explore the desensitization treatment of patients waiting for kidney transplantation, this article comparative analysis of the effect of splenic irradiation on mean fluorescence intensity (MFI) values of HLA antibodies of 4 presensitized patients. After splenic irradiation, the mean MFI values of HLA-I antibody in 4 patients all decreased (P ≤ .001, P ≤ .001, P ≤ .001, P ≤ .001), and 3 patients had a decrease in intensity level (P ≤ .001, P=.001, P ≤ .001); as for HLA-II antibody, the mean MFI values in 3 patients also decreased (P ≤ .001, P=.025, P=.016), 1 patient had a decrease in intensity level (P ≤ .001) and the other 2 cases had no significant changes (P=1.000, P=.564). On the other hand, splenic irradiation reduces MFI values in different levels of HLA antibody. So, splenic irradiation can reduce the MFI values of HLA antibodies.

Low Dose Splenic Radiotherapy for Myeloproliferative Neoplasms prior to Allogeneic Hematopoietic Stem Cell Transplant.

Myeloproliferative neoplasms including primary and secondary myelofibrosis (MF) are a rare spectrum of chronic myeloproliferative disorders in which nearly 90% of patients experience splenomegaly. Importantly, splenic radiotherapy (SRT) may be used in combination with allogeneic stem cell transplant (alloSCT) to improve symptoms related to splenomegaly, though there currently is no consensus SRT dose/fractionation protocol reported in the literature for use in combination with alloSCT. We sought to report our institutional experience utilizing low dose SRT prior to alloSCT in the post-Jakafi era. We performed a retrospective review of all patients diagnosed with MF at our institution from 2017-2022 who received reduced intensity alloHCT. Patients who underwent total lymphoid or body irradiation were excluded. Descriptive demographic and clinical characteristics of patients were summarized by means, medians, standard deviations, ranges and proportions as appropriate. We identified 39 patients with MF who underwent reduced intensity conditioning (RIC) consisting of fludarabine/melphalan in preparation for alloHCT (median age 64.5, 12/16 males, median follow up 21 months). 16 patients with Jakafi-resistant splenomegaly completed low dose SRT prior to transplant (median spleen size: 24.5cm) with a median dose of 5Gy delivered in 5 fractions. 3D conformal therapy was used for all patients. All patients completed the planned total radiation course without treatment break or dose limiting acute toxicity. Thrombocytopenia was the most reported toxicity (CTCAE v5.0; 2 patients experienced grade 1, 1 patient experienced grade 2). No patients experienced grade 3 or higher acute cytopenias nor required transfusion during radiotherapy. All patients successfully received alloHCT a median of 7 days (range: 2-11) after the completion of SRT with a 94% (15/16) engraftment rate. Median neutrophil recovery (ANC > 500 × 3 days) time was 18 days (range: 13-31); median length of hospital stay was 23 days (range: 20-129). Overall survival was 75% in the SRT cohort (12/16, 2 with persistent disease, 2 due to other causes). Symptom burden data was available for 14/16 patients; 79% (11/14) of patients reported improvement in symptoms associated with splenomegaly or reduction in splenic size on physical examination. In the largest reported experience of a low dose SRT only cohort to date, we observe low dose SRT is feasible, safe in combination with alloHCT with high engraftment rates, and may reduce symptoms related to splenomegaly thereby improving patient quality of life without compromising transplant related outcomes. A prospective study validating this protocol is currently underway.

Splenic Irradiation and Late Volume Changes Following Stereotactic Ablative Radiotherapy (SABR) for Adrenal Tumors

Splenic irradiation may increase the risk of life-threatening infections. New guidelines recommend limiting mean spleen doses (MSD) to <10Gy, based on data derived after chemoradiotherapy and conventional radiotherapy. Splenic changes after abdominal SABR are not well characterized. We studied splenic doses during MR-guided SABR for adrenal tumors, and evaluated late changes in splenic volumes (SV). AnEthics approved institutional database was accessed for details of patients treated using MR-SABR on a 0.35T unit for adrenal metastases between 2016-2023. No splenic planning constraints were routinely applied during this period. The spleen was delineated on treatment planning breath-hold CT and MR-scans and MSD, relative V5-10-20-30 values derived. On follow-up CT scans, SV was measured at 6, 12 and 24 months. Intergroup comparisons were performed with Wilcoxon rank-sum and Fisher exact tests; linear and logistic regression analyses computed to assess variables associated with the MSD and SV reduction >20% respectively. Of 113 adrenal tumors treated, 56% were left-sided. MR-SABR was mostly delivered in 5 fractions to 50 Gy (53%), in 3 fractions to 45 Gy (13%) or 16-24 Gy single-fraction (14%). The median MSD and V10 were 9.7 Gy (range, 1.5-28.4) and 46.3% (range, 0-100%) for left-sided treatments, 1.5 Gy (range, 0.2-5.9) and 0% (range, 0-6.2%) for right-sided treatments. Systemic therapy was administered in 51% of patients, either during or after MR-SABR. Baseline SV, GTV and use of systemic treatment did not significantly differ between right and left-sided tumors. MSD>10Gy was only seen in 44% of left-sided tumors, accounting for 25% of all patients. Multivariable linear analysis revealed treatment laterality (p<0.001), PTV dose (p = 0.02) and larger GTV size (p<0.001) to be significantly associated with MSD. Repeat imaging was available at 6 months (n = 59, 56% left-sided), 12 months (n = 47, 57% left-sided) and 24 months (n = 31, 65% left-sided). In the overall population, MSD >10Gy correlated with greater decreases in SV at 6 months (-19.5% vs -1.7%, p = 0.003), 12 months (-17.0% vs -3.9%, p = 0.03) and 24 months (-24.6% vs -9.3%, p = 0.06). For patients with an MSD >10Gy, a >20% decrease in SV was observed in 46% at 6 months, and 40% at 12 months. SV reduction >20% was associated with the MSD, V5 and V10 in multivariable logistic regression analysis. An MSD>10Gy was seen in 44% of all left adrenal SABR plans, with late SV reductions observed in 40% of them. The functional implications are unclear, but suggest a need to give more priority to splenic doses during abdominal SABR.

Splenic irradiation prior to allogeneic transplant conditioning in myelofibrosis: A pilot experience

IntroductionIn the era of JAK inhibitors, allogeneic stem cell transplantation (HSCT) remains the only curative treatment for patients with Myelofibrosis (MF). Splenic irradiation (SI) may be used to reduce spleen size and related symptoms. MethodsWe conducted a retrospective analysis on 14 patients with MF who underwent HSCT with SI from any donor source at our center between June 2016 and March 2021. All patients received a conditioning backbone based on treosulfan and fludarabine, with post-transplant cyclophosphamide (PTCy) and sirolimus as graft-versus-host disease (GvHD) prophylaxis. Patients received SI with 10 Gy involved-field radiotherapy in five 2-Gy fractions over the course of a week prior to the beginning of conditioning. ResultsAt transplant all patients were transfusion-dependent and had splenomegaly (median bipolar diameter by ultrasound: 20.75 cm). Overall, 12 patients had received ruxolitinib prior to transplant. Re-evaluation of spleen dimensions was available for 13 patients: median splenic bipolar diameter after at least 3 months from transplant decreased by a median of 25%. With a median post-transplant follow-up of 25 months, 6 patients remain in CR with full-donor chimerism, 3 patients died due to NRM. Overall, 4 patients relapsed. At last follow-up, nine patients are currently alive and achieved transfusion-independence. ConclusionsIn a small cohort of mostly ruxolitinib pre-treated patients, SI and treosulfan-based conditioning appeared a safe and effective tool to reduce spleen dimensions and ameliorate symptoms. Future prospective studies with adequate sample size are warranted to further investigate the usefulness and safety of this approach in MF.

Splenic Irradiation Prior to Allogeneic Hematopoietic Cell Transplantation for Patients with Myelofibrosis

Background: Myelofibrosis (MF) is a clonal stem cell neoplasm characterized by excess fibrous tissue formation in the bone marrow. Allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment for MF. Patients with MF often have compensatory splenic extramedullary hematopoiesis leading to splenomegaly, which is associated with delayed engraftment and decreased survival post-HCT. Several Janus kinase (JAK) inhibitors are approved to treat splenomegaly and systemic symptoms in MF patients. However, JAK inhibitor therapy does not always lead to complete resolution of splenomegaly. Therefore, splenic irradiation (RT) prior to HCT may benefit patients with persistent splenomegaly, yet research investigating outcomes of this therapeutic approach is limited. Methods: We conducted a single-center, retrospective cohort study of MF patients to characterize the feasibility of splenic RT and assess engraftment rates and post-transplant outcomes with this approach. Forty-eight MF patients who underwent HCT at Massachusetts General Hospital between 2011 to 2021 were identified using an institutional transplant database. Patient disease- and transplant-related characteristics were summarized according to splenic RT within 3 months prior to transplant. Results: Baseline disease- and transplant-related characteristics are displayed in Table 1. Among all patients, twenty-nine (60%) were male, and the median age was 67 years (range, 53-77). All patients received reduced intensity conditioning, with a majority (81%) receiving fludarabine with melphalan. Seventy-three percent of patients had a JAK2 mutation and 46% received ruxolitinib (RUX) prior to HCT. A total of 17 (35%) patients received splenic RT prior to transplant. Splenic RT ranged from 2 daily doses of 1 Gy to 5 daily doses of 1.5 Gy, with total radiation ranging from 2 Gy to 7.5 Gy. Splenic RT was administered at a median of 13 days prior to transplant (range, 7-69 days). All splenic RT patients had splenomegaly prior to transplant, and 11 (65%) were treated with RUX prior to HCT. Patients receiving splenic RT had significantly larger spleen sizes prior to transplant (23.1 v. 17.3 cm, p<0.01), and were more likely to have at least one high molecular risk (HMR) mutation than patients in the no RT group (83% v. 33%, p=0.01). For the entire cohort, the median days to neutrophil engraftment and platelet engraftment was 14 and 23, respectively. Among splenic RT patients, there was one case of primary graft failure and one case of secondary graft failure. The median days to neutrophil engraftment was 15 (IQR, 13-19) for the RT group and 13 (IQR, 12-14) for the no RT group (p=0.07). The median days to platelet engraftment was 32 (IQR, 25-108) for the RT group and 22 (IQR, 18-25) for the no RT group (p<0.01). Three splenic RT patients (18%) died early without platelet engraftment. When RUX was accounted, patients with RT and RUX had a substantially delayed platelet engraftment compared to no RT and/or no RUX (69.5 days vs 19.5-22.5 days, p=0.03) [Figure 1]. For the entire cohort, the 3-year overall survival (OS) and progression-free survival (PFS) was 67% (95%CI: 50%-79%) and 61% (95%CI: 45%-74%), respectively. The cumulative incidence of non-relapse mortality (NRM) and relapse was 26% (95%CI: 13%-40%) and 13% (95%CI: 5%-24%), respectively. Despite delayed platelet engraftment, survival outcomes were not different between RT and no RT, regardless of pre-HCT RUX exposure. Conclusion: Splenic RT administration prior to HCT appears feasible and associated with acceptable engraftment and clinical outcomes for MF patients with splenomegaly at the time of transplant. The persistence of massive splenomegaly at transplant following pre-transplant RUX is likely indicative of higher risk disease and remains associated with longer time to platelet engraftment, despite the addition of splenic RT. Larger prospective studies are required to fully assess the clinical impact of splenic RT in the transplant setting, especially in combination with other therapeutic strategies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Safety and Efficacy of Splenic Irradiation for Non-Hodgkin Lymphoma

Background: Splenic infiltration and associated splenomegaly is a challenging complication of non-Hodgkin lymphoma (NHL). The choice between splenectomy and splenic radiation (RT) is controversial, with little data to provide guidance in NHL. We aim to assess the tolerability and efficacy of splenic RT in NHL. Methods: We reviewed NHL patients treated from 2002 to 2021 with RT to the spleen alone. Splenomegaly was defined as vertical length >13cm. Splenic volume was obtained by manual contouring in MIM PACS 6.9.7 on the baseline pre-RT CT scan and the CT scan at best splenic response post-RT. PET response was evaluated by Lugano criteria. Adverse events (AEs) were retrospectively graded by clinicians using CTCAE v5.0. Cell counts were collected at baseline pre-RT and through 90 days post-RT completion; cell counts were censored at initiation of cytotoxic chemo post-RT if received. Significance was assessed with the Kruskal Wallis test. Results: 21 patients (11 diffuse large B-cell lymphoma (DLBCL), 5 marginal zone lymphoma (MZL), 4 mantle cell lymphoma (MCL), 1 follicular lymphoma) were identified with 23 courses of splenic RT. Median age was 75 (42-94); median KPS was 80 (50-90). Most patients (57%) had splenic only disease. Median splenic height pre-RT was 13.6 cm (6.4-26.6); 13 patients (57%) had baseline splenomegaly. Median splenic volume was 682cc (104-3355). 11 patients (48%) were symptomatic pre-RT (most frequently with pain: n=7, dyspnea: n=4, or nausea: n=4). 91% had any cytopenia before RT with median baseline absolute neutrophil count (ANC) 2.3 (0.2-10.6), hemoglobin 9.8 (7.1-13.8), and platelets 93 (9-221). RT was performed with definitive (n=11) or palliative (n=9) intent, or as bridging to chimeric antigen receptor T cells (n=3). Median dose was 30Gy for DLBCL (10.8-45), and 4Gy for MCL/MZL/FL (0.6-20); 10 patients received ≥20Gy. RT was well tolerated with 43% of courses without AEs and 57% with G1-2 AEs. AEs with frequency >10% were G1 fatigue (n=6), G1 anorexia (n=5), G1 nausea (n=5), G1 diarrhea (n=4), and G2 fatigue (n=4). There were no G3-4 AEs. One patient died from respiratory failure secondary to fungal pneumonia which was not felt to be attributable to splenic RT. Median nadirs in the 19 patients with cell count data: ANC 1.6 (0.2-3.8), hemoglobin 10.1 (6-13.4), platelets 70 (6-182) with 8, 6, and 15 median days from RT start to nadir (Table 1). ANC and platelets were disproportionately affected (median reduction: 26% and 28% for ANC and platelets, respectively vs. 5% for hemoglobin; p=0.006). There were no significant differences in reductions in ANC, platelets, or hemoglobin by RT dose (≥20Gy vs. <20Gy; p>0.1). In 3 patients (14%) cytopenias completely normalized post-RT. In most patients, cell counts normalized to pre-RT baseline (see Table 1). 4/13 symptomatic patients (31%) experienced complete relief. Median reduction in splenic volume was 34% (0-90%) with no significant difference in cytoreduction between low and high dose RT groups (median 27% reduction in <20Gy and 46% in ≥20Gy; p=0.2), see Figure 1. Overall response rate (ORR) by PET was 85% (35% complete response, 50% partial response, 10% stable disease, 5% progressive disease). With a median follow up of 12mo, median duration of radiographic response was 8mo (0.5-103) with more durable response at ≥20Gy (median 35 vs. 4mo, p=0.01). Conclusion: Splenic RT was well tolerated and had a high ORR of 85%. Radiographic response was more durable at doses ≥20Gy. Larger sample sizes with homogenous histology are needed to further evaluate the impact of dose on cell counts, clinical toxicity, and symptomatic relief. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Effects of Low-dose Splenic Irradiation on T lymphocyte Immune Function.

Relevant studies have confirmed that the stimulation of spleen function caused by low-dose splenic irradiation can have positive effects on tumors and other diseases. This study aimed to determine radiation-induced changes in spleen index, lymphocyte subsets, spleen cell apoptosis, and pathological features of the spleen in mice. The mouse model was established by irradiating the spleen at different doses. The mice were divided into the following groups: blank control, low-dose, low-dose fractionated irradiation, and challenge dose irradiation. The mice were sacrificed under humanitarian conditions, and spleen tissue and peripheral blood were collected. The spleen index was calculated, and flow cytometry was used to analyze spleen T lymphocyte subsets and spleen apoptosis. The pathological changes in the spleen were determined by hematoxylin and eosin (H&E) staining. The spleen index of mice in the low-dose fractionated irradiation group was significantly increased compared with that in the blank control group. The spleen indexes of the low-dose irradiation and low-dose fractionated irradiation groups were much higher than that of the challenge dose irradiation group. Compared with the blank control group, the percentage of CD3+ and CD4+ T lymphocytes in the peripheral blood and spleen tissues in the low-dose irradiation and low-dose fractionated irradiation groups was significantly increased, whereas that from the challenge dose irradiation group was obviously decreased. CD8+ T lymphocytes in the peripheral blood and spleen tissues in the low-dose irradiation, low-dose fractionated irradiation, and challenge dose irradiation groups were significantly lower than those in the blank control group. The apoptosis rate of the spleen in the challenge dose irradiation group was significantly higher than that in the blank control, low-dose irradiation, and low-dose fractionated irradiation groups. H&E staining analysis of the spleen showed pathological changes in the different irradiation groups compared with the blank control group. Low-dose irradiation and low-dose fractionated irradiation can change the T lymphocyte subsets in the peripheral blood and spleen of mice, which can promote immune excitation and improve immune effects.

Abstract 7 Reduced Intensity Conditioning Umbilical Cord Blood Transplantation in Combination with Splenic Irradiation in a Patient with Secondary Myelofibrosis and Massive Splenomegaly

IntroductionMyelofibrosis (MF) is a bone marrow neoplasm characterized by marrow fibrosis/failure and splenomegaly, causing pain, early satiety, and cytopenia. The only curative option is allogeneic hematopoietic stem cell transplant (allo-HSCT); however, its use is limited due to donor availability and patient age, functional status, and comorbidities. Umbilical cord blood (UCB) has been explored in this population for this reason with variable success, partly related to splenomegaly, which might influence engraftment in MF patients.ObjectiveThe objective was to report the successful use of UCB transplantation in conjunction with splenic irradiation to treat a patient with advanced MF and massive splenomegaly.MethodsA 71-year-old male with post-essential thrombocythemia MF was treated with ruxolitinib for 2 years but developed worsening cytopenia and transfusion dependence. Splenomegaly (19.1×7.1×20.8 cm) was identified. Allo-HSCT was recommended on the basis of high-risk disease (DIPSS Plus score: 4) and few alternative options. Although suitable HLA-matched donors were unattainable, two cord blood units were available. A reduced intensity conditioning regimen of fludarabine, cyclophosphamide, and TBI 300 was chosen. Given the primary resistance to ruxolitinib, the spleen was irradiated with 450 cGy prior to transplant.ResultsNeutrophil and platelet engraftment occurred on days +30 and +49, respectively. The patient developed engraftment syndrome and acute graft versus host disease (GVHD) that resolved with methylprednisolone and early introduction of ruxolitinib. His immunosuppressive medications were discontinued by 6-months without evidence of chronic GVHD thereafter. He is now 1 year post-transplant with 100% donor chimerism and no clinical evidence of MF or GVHD.DiscussionWe present a novel therapeutic approach combining the use of splenic irradiation and a double unit UCB HSCT in a patient with MF and massive splenomegaly. UCB transplant should be considered in patients with MF who do not have an HLA-matched donor with the additional benefit of less chronic GvHD. Massive splenomegaly can negatively impact transplant outcomes due to entrapment of donor stem cells, delayed engraftment, and prolonged cytopenia. Splenic irradiation before UCB transplant can potentially reduce these complications, as it did in this case, and in turn decrease transplant-related mortality. Our future aim is to develop a clinical trial to study this approach.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

A Phase Ib Dose-finding Study of Panobinostat and Ruxolitinib in Myelofibrosis.

Pretransplant Splenic Irradiation in Patients With Myeloproliferative Neoplasms

PurposeAllogeneic hematopoietic cell transplantation (HCT) serves as the only curative treatment option for patients with myelofibrosis and other myeloproliferative neoplasms. Splenomegaly commonly manifests in patients with myeloproliferative neoplasms and can lead to delayed or poor engraftment, increased transfusion burden, and worse survival. Methods to decrease the effect of splenomegaly include splenectomy and splenic irradiation. We sought to report on clinical outcomes for patients treated with splenic irradiation as part of their transplant conditioning. Methods and MaterialsPatients with splenomegaly measuring greater than 22 cm were referred for splenic irradiation. They received radiation to the entire spleen to 10 Gy in 5 fractions using 3-dimensional conformal radiation with anteroposterior/posteroanterior or opposed tangent fields. Blood counts were monitored closely on treatment. Changes in splenic size were measured using first and last treatment image guided radiation therapy and pre- and posttransplant diagnostic imaging. ResultsSeventeen patients completed pretransplant splenic irradiation between 2012 and 2021. Median platelet, white blood cell, and hemoglobin levels decreased on treatment. One patient required platelet transfusion and 3 required packed red blood cell transfusions. Mean decrease in spleen size during radiation was -8.5% in the craniocaudal dimension. Prolonged decreases, measured 2 to 12 months after transplant, averaged 14.64%. All patients engrafted. Fourteen (82.4%) were alive at time of analysis with median follow-up of 4.2 years from hematopoietic cell transplantation. ConclusionsSplenic irradiation offers a safe method of managing significant splenomegaly as part of transplant conditioning. Transplant outcomes in this series were excellent. Prospective data may be beneficial to determine the absolute benefit of this addition to pretransplant conditioning in this patient population.

Creating a Standardised Pathway for Patients at Risk of Radiotherapy (RT) Induced Hyposplenism in a Single Cancer Centre

Background: The spleen has not routinely been included as an organ at risk in upper-gastrointestinal radiotherapy (RT) planning. However, there is evidence that splenic irradiation is associated with increased risk of late infection-related mortality with a mean dose >10 Gray (Gy), and particularly for a dose >40 Gy (Weil et al, 2018).

Vertebral body and splenic irradiation are associated with lymphopenia in localized pancreatic cancer treated with stereotactic body radiation therapy

ObjectivesThe purpose of this study was to determine if vertebral body and splenic dosimetry was associated with the development of lymphopenia in patients with borderline resectable (BRPC) and locally advanced pancreatic cancer (LAPC) treated with stereotactic body radiation therapy (SBRT).MethodsPatients with BRPC/LAPC who were treated with SBRT and who had lymphocyte counts and radiation treatment plans available for review were included in the study. Vertebral body levels T11-L3 and the spleen were retrospectively contoured for each patient. Univariate (UVA) and multivariable analyses (MVA) were performed to identify associations between vertebral body and splenic dosimetric parameters with absolute lymphocyte count (ALC) and grade ≥ 2 lymphopenia. Receiver operator characteristic curves were generated to identify dose-volume thresholds in predicting grade ≥ 2 lymphopenia.ResultsA total of 132 patients were included in the study. On UVA and MVA, vertebral V15 (regression coefficient [β]: − 0.026, 95% CI − 0.044 to − 0.009, p = 0.003), vertebral V2.5 (β: − 0.011, 95% CI − 0.020 to − 0.002, p = 0.015), and log10PTV (β: − 0.15, 95% CI − 0.30 to − 0.005, p = 0.042) were associated with post-SBRT ALC. On UVA and MVA, vertebral V15 (odds ratio [OR]: 3.98, 95% CI 1.09–14.51, p = 0.027), vertebral V2.5 (OR: 1.04, 95% CI 1.00–1.09, p = 0.032), and spleen V10 (OR: 1.05, 95% CI 1.09–1.95, p = 0.004) were associated with development of grade ≥ 2 lymphopenia. Development of grade ≥ 2 lymphopenia was more likely in patients with vertebral V15 ≥ 5.84% (65.5% vs 34.0%, p = 0.002), vertebral V2.5 ≥ 48.36% (48.9% vs 23.8%, p = 0.005), and spleen V10 ≥ 4.17% (56.2% vs 26.9%, p < 0.001).ConclusionsIncreasing radiation dose to vertebral bodies and spleen were associated with the development of lymphopenia in BRPC/LAPC treated with SBRT. Optimization of vertebral body and splenic dosimetry may reduce the risk of developing lymphopenia and improve clinical outcomes in this population.

Low Dose Splenic Irradiation as Adjunct Therapy for Patients With High Level of Anti-Human Leukocyte Antigen Donor-Specific Antibodies (Anti-HLA DSAs) Prior to Haploidentical Hematopoietic Stem Cell Transplantation (Haplo-HSCT)

With the increasing numbers of haploidentical hematopoietic stem cell transplants (Haplo-HSCT), the roles affecting transplant outcomes of anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are currently being evaluated. Patients with high levels of DSAs were desensitized with plasmapheresis, immunoglobulin and rituximab prior to transplantation. However, the therapies were not very effective, probably because the source of DSA production was not controlled effectively. Rescue splenectomy has been used with short-term success by establishing source control for the DSA-producing plasmablasts in renal transplantation patients. Splenic irradiation was also proved to be effective in these patients. Herein, we describe the first reported use of splenic irradiation as adjunct therapy for patients with high level of DSAs prior to haplo-HSCT.14 haplo-HSCT patients were involved, including 3 males and 11 females. The median age was 45 years (26-55). Before transplantation, 9 patients were tested positive of HLA-I DSA, and 6 patients were positive of HLA-II DSA, including 1 patient which was tested positive for both HLA-I and II. 12 patients were diagnosed with acute patients and were in complete remission before transplantation, and the other 2 patients with myelodysplastic syndrome received no treatment before transplantation. Modified busulfan/ cyclophosphamide (BU/CY) protocol was processed in all 14 patients. All patients received DSA desensitization treatments as below: spleen irradiation (before transplant, 200cGY in total, 50cGY/d × 4 days), plasmapheresis (before transplant, 40ml/kg × 2 doses), rituximab (before transplant, 375mg/m2 × 1 dose), immunoglobulin (before transplant, transplant day, 0.4g/kg).The average of median fluorescence intensity (MFI) were tested significantly decreased after transplantation (15628 vs 6889, P < 0.05). During the median follow-up of 132 days (42-243), 14 patients (100.0%) achieved HSCT successfully and 13 patients (92.9%) were alive with disease remission, except one death because of transplantation associated thrombotic microangiopathy on +200 days after transplant. The average engraftment time of neutrophils and platelet was 13 days (10-22) and 23 days (10-76), respectively. 4 patients (28.6%) developed acute GVHD (skin, digestive tract), and all improved after treatment. 7 patients (50.0%) developed cytomegaloviremia, all of which was controlled after treatment. 4 cases (28.6%) developed chronic GVHD (skin and liver), which were stable after treatment.Spleen irradiation combined with plasmapheresis, rituximab and immunoglobulin therapy can reduce the levels of anti-HLA DSAs, improving engraftment and survival after haplo-HSCT. No excess toxicity is observed. This protocol can help to improve the prognosis of DSA-positive haplo-HSCT patients, but further study proving the efficacy is still needed.