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1.
Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis
Gagelmann, N., Hobbs, G. S., Campodonico, E., Helbig, G., Novak, P., Schroeder, T., Schneider, A., Rautenberg, C., Reinhardt, H. C., Bosques, L., et al
American journal of hematology. 2024
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Editor's Choice
Abstract
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.
PICO Summary
Population
Adults with with primary myelofibrosis, post polycythemia vera, and post-essential thrombocythemia myelofibrosis, identified from centres worldwide (n=171)
Intervention
Splenic irradiation within a median of 2 weeks before transplant (n=59)
Comparison
Matched controls receiving immediate transplant without splenic irradiation (n=56), or who had splenectomy (n=56)
Outcome
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, showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy.
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Low dose total body irradiation added to fludarabine and busulfan reduced intensity conditioning reduces graft failure in patients with myelofibrosis
Freyer, C. W., Babushok, D. V., Frey, N. V., Gill, S. I., Loren, A. W., Luger, S. M., Maity, A., Martin, M. E., Plastaras, J. P., Porter, D. L., et al
Transplantation and cellular therapy. 2022
Abstract
INTRODUCTION Allogeneic hematopoietic cell transplantation (alloHCT) is indicated for patients with intermediate or high risk myelofibrosis (MF) and remains the only potential cure. Reduced-intensity conditioning (RIC) is commonly used due to older patient age, comorbidities, and a high incidence of transplant-related mortality. Patients with MF are at increased risk of graft failure (GF), which is more common with RIC regimens, and is associated with shortened overall survival (OS). Due to a high rate of GF with conventional fludarabine (Flu) and busulfan (Bu) RIC, we added low dose total body irradiation (TBI, 200 cGy) for patients with MF. We compared outcomes between RIC with Flu/Bu/TBI and Flu/Bu for patients with MF. METHODS Adults with MF who underwent alloHCT at a single center between 2008-2020 and received Flu/Bu +/- TBI were retrospectively reviewed. The primary endpoint was the incidence of GF. Secondary endpoints included time to engraftment, acute and chronic graft-versus-host disease (GVHD), hepatic sinusoidal obstruction syndrome (SOS), non-relapse mortality (NRM), as well as overall response rate (ORR), progression-free survival (PFS), and OS. RESULTS Of 33 patients who underwent alloHCT, 8 received Flu/Bu and 25 received Flu/Bu/TBI RIC. GF occurred in 50% with Flu/Bu (all secondary GF) and 4% with Flu/Bu/TBI (1 case of primary GF; RR 0.08, 95% CI 0.01-0.62, p = 0.0016). GF incidence was similar with related or unrelated donors and in patients who did and did not receive Janus-associated kinase inhibitors prior to alloHCT. Molecular remission and donor chimerism ≥ 99% were significantly more common with Flu/Bu/TBI. No significant differences in aGVHD, cGVHD, or time to engraftment were observed. SOS occurred in 0/8 patients who received Flu/Bu and 6/25 patients who received Flu/Bu/TBI, but this difference did not reach statistical significance. Progression or relapse at 1 year was less common with Flu/Bu/TBI (0% vs. 63%, p < 0.001). Median OS was 49 and 30.8 months for Flu/Bu/TBI and Flu/Bu, respectively (HR 0.98, 95% CI 0.33-2.88, p = 0.97). CONCLUSION Flu/Bu/TBI resulted in a significant reduction in GF and significant improvement in the frequency of molecular remission and full donor chimerism compared to Flu/Bu. The addition of low dose TBI to Flu/Bu successfully mitigates against GF in patients with MF without increased rates of complications.
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Total body irradiation-containing conditioning regimens without antithymocyte globulin in adults with aplastic anemia undergoing umbilical cord blood transplantation
Hiramoto, N., Yamazaki, H., Nakamura, Y., Uchida, N., Murata, M., Kondo, T., Yoshioka, S., Eto, T., Nishikawa, A., Kimura, T., et al
Annals of hematology. 2021
Abstract
Thus far, there have been no large cohort studies on total body irradiation (TBI)-containing conditioning regimens without antithymocyte globulin (ATG) in adults with aplastic anemia (AA) undergoing umbilical cord blood (UCB) transplantation (UCBT). We retrospectively analyzed 115 adults with idiopathic AA undergoing UCBT using TBI-containing reduced-intensity conditioning (RIC) regimens without ATG between 2000 and 2018 on behalf of the Adult Aplastic Anemia Working Group of the Japanese Society for Hematopoietic Cell Transplantation. We then compared transplantation outcomes between a fludarabine (Flu)- and melphalan (Mel)-based regimen (FM) and a Flu- and cyclophosphamide (Cy)-based regimen (FC). The median patient age at UCBT was 41 years. The median total nucleated cell and total CD34(+) cell doses in a UCB unit at cryopreservation were 2.5?×?10(7)/kg and 0.7?×?10(5)/kg, respectively. The median follow-up period for survivors was 47 months. The cumulative incidence rate of neutrophil engraftment was 76.5%, and the 4-year overall survival (OS) rate was 64.3%. In multivariate analysis, the covariates that were significantly associated with a higher neutrophil engraftment were total CD34(+) cell dose in an UCB unit (=?0.7?×?10(5)/kg; hazard ratio, 0.57, P?=?0.01) and total dose of TBI (4 Gy of TBI; hazard ratio, 0.32, P?=?0.01). There was no significant difference in the cumulative incidence of neutrophil engraftment and the 4-year OS between the FM and FC groups. In conclusion, TBI-containing RIC regimens without ATG are suitable for adults with AA undergoing UCBT. There were no significant differences in transplantation outcomes between the FM and FC groups.
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Comparison of the Kinetics of Hematologic Recovery in Aplastic Anemia After Total Nodal Irradiation Between Helical Tomotherapy and Conventional Radiotherapy
Hong, J. H., Jang, H., Choi, B. O., Kang, Y. N., Song, J. H.
International journal of radiation oncology, biology, physics. 2021;111(3s):e310
Abstract
PURPOSE/OBJECTIVE(S): Total nodal irradiation (TNI) followed by antithymocyte globulin (ATG) has been using as the conditioning regimen before allogeneic hematopoietic stem cell transplantation (HSCT) in aplastic, severe aplastic, and very sever aplastic anemia. As technology developed in radiotherapy, helical tomotherapy has been applied to TNI. This study compares the kinetics of hematologic changes after TNI between helical tomotherapy and 3D conformal radiotherapy (3DRT) in aplastic anemia patients. MATERIALS/METHODS Between January 2010 and December 2020, 34 patients underwent TNI before HSCT. According to different radiotherapy methods, patients were divided into two groups: 16 patients (3DRT) and 18 patients (Tomotherapy). For one month after TNI, hematologic values including absolute neutrophil counts (ANC), absolute lymphocyte counts (ALC), platelet counts, and hemoglobin counts were reviewed and analyzed. RESULTS All but one patient achieved engraftment successfully with neutrophils (median 12 days, range 4 ~ 19) and platelets (median 14 days, range 7 ~ 66). Median age at TNI was 37.3 years (range, 19.4 ~ 64.6). TNI dose was 750cGY in single fraction while two patients were treated with 700cGY. 15 patients were treated as second allogenic HSCT after graft failure. All hematologic value changes including ANC, ALC, platelet and hemoglobin didn't show significant difference between two groups (P?=?0.185, P?=?0.287, P?=?0.127, and P?=?0.244). ANC showed lowest value at nine days after TNI in both group and recovered afterwards, while ALC showed lowest value at three days after TNI. Platelet showed lowest value at nine days after TNI in 3DRT, and 12 days after in tomotherapy. Successful engraftment of ANC between two groups weren't significantly different (P?=?0.320), though, successful engraftment of platelet between two groups showed significant difference (P?=?0.003), CONCLUSION The kinetics of hematologic values after TNI using tomotherapy and 3DRT didn't show significant difference. The method of radiotherapy needs to be decided carefully, considering other factors including economic evaluation, side effects, and outcomes. It needs further studies.
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Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres
Alzahrani, M., Damlaj, M., Jeffries, N., Alahmari, B., Singh, A., Rondelli, D., Tisdale, J. F., Saraf, S. L., Hsieh, M. M.
British journal of haematology. 2021
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Free full text
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Abstract
Non-myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim-mobilized peripheral blood HPC and sirolimus. The median follow-up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle-free survival at one and five years were 93% and 85% respectively. Age, sex, pre-HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft-versus-host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle-related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well-tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.
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Outcomes of haploidentical stem cell transplantation using total body irradiation (600 cGy) and fludarabine with ATG in adult patients with severe aplastic anemia: A prospective phase II study
Lee, S. E., Min, G. J., Park, S. S., Park, S., Yoon, J. H., Shin, S. H., Cho, B. S., Eom, K. S., Kim, Y. J., Lee, S., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The aim of this study is to verify the feasibility of rabbit ATG (Thymoglobulin(R)) (5 mg/kg) in combination with 600 cGy fractionated total body irradiation (fTBI; 200cGy, 3 times) and fludarabine (Flu, 150 mg/m(2)) as a conditioning regimen for haploidentical stem cell transplantation from a related mismatched donor (Haplo-SCT) in adult patients with severe aplastic anemia (SAA). We analyzed 47 consecutive patients who underwent Haplo-SCT, including 24 patients from our previous pilot report. The median age was 36.0 years (17-61) and 25 (53%) patients had very SAA (VSAA) at transplantation. All patients achieved primary engraftment. The cumulative incidence of acute GVHD (grade ≥2) and chronic GVHD (≥ moderate) was 27.7% at 100 days and 13.5% at 3 years, respectively. With a median follow-up of 32.3 months, the 3-year probability of overall survival and failure-free survival was 91.0% and 88.6%, respectively. The 3-year GVHD- and failure-free survival (GFFS) was 71.6%. Offspring donor and lower comorbidity index were independent factors correlated with higher GFFS in multivariate analysis. In conclusion, the outcomes of Haplo-SCT with fTBI 600 cGy/Flu/ATG-5 indicate that Haplo-SCT can be an effective alternative option when fully matched donors are not available, or for patients with VSAA who need an urgent transplant.
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7.
Splenic irradiation before allogeneic stem cell transplantation for myelofibrosis
Helbig, G., Wieczorkiewicz-Kabut, A., Markiewicz, M., Krzemien, H., Wojciak, M., Bialas, K., Kopera, M., Rzenno, E., Wozniczka, K., Kopinska, A., et al
Medical oncology (Northwood, London, England). 2019;36(2):16
Abstract
Splenectomy before allogeneic stem cell transplantation (ASCT) for patients with myelofibrosis (MF) remains a matter of debate, and conflicting results have been reported to date. The procedure seems to fasten post-transplant hematological recovery, but it does not have an impact on survival. The role of pre-transplant splenic irradiation (SI) is much more difficult to evaluate. Forty-four patients (25 males and 19 females) with MF at median age of 49 years at diagnosis (range 14-67) underwent ASCT. The post-transplant outcome was compared between irradiated and non-irradiated patients. Eleven patients received irradiation before transplantation. Median dose of radiation was 1000 cGy (range 600-2400). There was no difference in median time to engraftment between patients with and without previous radiotherapy. Acute and chronic graft versus host disease (GVHD) occurred in 47% and 36% of patients, respectively. There was no difference in GVHD incidence between groups. Eight patients relapsed/progressed in irradiated group versus 17 in non-irradiated (70% vs. 51%; p = 0.3). Transformation to acute myeloid leukemia was observed in 3 patients: 2 in irradiated and 1 in non-irradiated group. In total, 22 patients died with no statistical difference in death rate between irradiated and non-irradiated subjects. The probability of overall survival after transplant for the entire cohort at 2 years was 54% (72% for irradiated and 48% for non-irradiated patients; p = 0.25). Splenic irradiation prior to ASCT for myelofibrosis has not beneficial effect on post-transplant outcome.
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Total body irradiation dose escalation decreases risk of progression and graft rejection after hematopoietic cell transplantation for myelodysplastic syndromes or myeloproliferative neoplasms
Monaco, F., Scott, B. L., Chauncey, T. R., Petersen, F. B., Storer, B. E., Baron, F., Flowers, M. E., Deeg, H. J., Maloney, D. G., Storb, R., et al
Haematologica. 2019
Abstract
A nonmyeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive nonmyeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low-risk (n=36) and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 x3 days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary endpoint was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. Primary endpoint was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with nonmyeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease nonrelapse mortality, especially among patients with high-risk disease. Trial registered under ClinicalTrials.gov No. NCT00397813 .
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Excellent outcomes of hematopoietic stem cell transplantation with total nodal irradiation and antithymocyte globulin conditioning in severe aplastic anemia with advanced age and/or severe comorbidity
Park, S. S., Min, G. J., Park, S., Lee, S. E., Yoon, J. H., Cho, B. S., Eom, K. S., Kim, Y. J., Lee, S., Min, C. K., et al
Bone marrow transplantation. 2019
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10.
Allogenic peripheral stem cell transplantation from HLA-matched related donors for adult sickle cell disease: remarkable outcomes from a single-center trial
Ozdogu, H., Boga, C., Yeral, M., Kozanoglu, I., Gereklioglu, C., Aytan, P., Kasar, M., Asma, S., Buyukkurt, N., Solmaz, S., et al
Bone marrow transplantation. 2018
Abstract
Adult patients with sickle cell disease (SCD) are highly susceptible to stem cell transplant complications, including drug toxicity, graft versus host disease (GVHD), and graft rejection due to SCD-related tissue damage, endothelial activation, and inflammation. The scarcity of compatible stem cells for transplantation further limits treatment options, with only 43 cases of adult allogeneic peripheral blood stem cell transplantation (allo-PSCT) from human leukocyte antigen (HLA)-identical sibling donors reported in the international registry for the period 1986-2013. Herein we report remarkable outcomes in a cohort of adult SCD patients who underwent allo-PSCT using a fludarabine (Flu), busulfan (Bu), and anti-T-cell lymphocyte globulin (ATG)-based conditioning regimen in combination with very low dose total body irradiation (TBI), followed by post-transplant cyclophosphamide (Cy) and sirolimus as GVHD prophylaxis. We performed a single-center, retrospective study consisting of 20 consecutive patients (mean age 33.4 years) who underwent allo-PSCT from HLA-matched related donors with a conditioning regimen of Flu 150/Bu 3.2/Cy 29/ATG 30 (Fresenius)/TBI 200 between September 2013 and September 2017. Data were validated by an independent data audit group of the affiliated JACIE-accredited transplantation center. All patients experienced a sustained donor cell engraftment. Full donor chimerism (total cell) occurred within 180 days in all patients. Mean duration of follow-up was 13.8 months (range: 0.3-50 months), with 12 (60%) patients completing 12 months. No non-relapse mortality or graft rejection occurred. Successful treatment was achieved without the presence of graft loss, grade III-IV acute GVHD, extensive chronic GVHD, or other major complications. Allo-PSCT in combination with Flu 150/Bu 3.2/Cy 29/ATG 30(Fresenius)/TBI 200- Cy/Sirolimus therapy yielded encouraging outcomes with no mortality and low incidence of GVHD. Further controlled studies will be necessary to compare transplant protocols and long-term outcomes.