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1.
Impact of Iron overload and Iron Chelation with deferasirox on outcomes of patients with severe aplastic anemia after allogeneic hematopoietic stem cell transplantation
Pan, T., Ji, Y., Liu, H., Tang, B., Song, K., Wan, X., Yao, W., Sun, G., Wang, J., Sun, Z.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Patients suffering from severe aplastic anemia (SAA) need frequent blood transfusions during allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, these transfusions can result in an excess of iron in the body tissues, which can negatively impact the success of the transplant. OBJECTIVES This study aimed to examine the impact of pre-transplant iron overload (IO) on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe aplastic anemia (SAA). It also investigated whether iron chelation (IC) therapy was necessary to enhance transplantation outcomes in SAA patients by providing guidelines for determining when excess iron should be chelated. STUDY DESIGN The study consisted of two parts: Cohort 1, which was retrospective and conducted from April 2012 to December 2018, divided SAA patients receiving their first allo-HSCT into two groups based on their pre-transplant serum ferritin (SF) levels: the iron overload (IO) group (SF >1000 ng/ml, n=17) and the non-IO group (SF ≤ 1000 ng/ml, n=48). Cohort 2 was a prospective clinical trial conducted from January 2019 to July 2020. It involved SAA patients diagnosed with IO who were treated with iron chelation (IC) therapy using deferasirox (DFX) at a dose of 10-30 mg/kg. Patients were separated into two groups based on their pre-transplant SF levels: the IC success (IC(success)) group (SF ≤ 1000 ng/ml, n=18) and the IC failure (IC(failure)) group (SF >1000 ng/ml, n=28) groups. All participants were evaluated for the correlation between pre-transplant SF levels and transplantation outcomes. A P-value of less than 0.05 was considered statistically significant. RESULTS There was no significant difference in the speed of engraftment for the three lineages or in the incidence of 100-day grade II-IV acute graft-versus-host disease (aGVHD), grade III-IV aGVHD, or 3-year chronic GVHD between the two groups in both cohorts. However, in cohort 1, it was noteworthy that 1-year OS (83.3% vs. 41.2%, p < 0.001) and 3-year OS (83.3% vs. 35.3%, p < 0.001) were significantly worse in the IO group. Furthermore, 180-day TRM (14.6% vs. 47.1%, p = 0.005) and 1-year TRM (16.7% vs. 52.9%, p = 0.002) were significantly higher in the IO group. The IO group was significantly associated with inferior 3-year OS in both univariate and multivariate analyses. In cohort 2, it was found that 1-year OS (42.9% vs. 88.9%, p = 0.003) and 3-year OS (42.9% vs. 83.3%, p = 0.007) were significantly better in the IC(success) group, while 180-day TRM (11.1% vs. 39.3%, p = 0.040) and 1-year TRM (11.1% vs. 57.1%, p = 0.003) were significantly lower in the IC(success) group. These differences were confirmed in both univariate and multivariate analyses. CONCLUSIONS The study involving two cohorts showed that pre-HSCT iron overload has a negative impact on transplantation outcomes in SAA patients. Chelating excess iron with a serum ferritin level below 1000 ng/ml was found to be necessary and could potentially improve the outcomes.
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2.
Efficacy and Safety of Iron Chelation Therapy After Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Thalassemia Patients: A Retrospective Observational Study
Kupesiz, F. T., Sivrice, C., Akinel, A., Kintrup, G. T., Guler, E., Kupesiz, A.
Journal of pediatric hematology/oncology. 2022;44(1):e26-e34
Abstract
BACKGROUND Studies on the increased body iron load in patients with thalassemia major have thoroughly demonstrated the problems caused by iron overload. In patients who undergo hematopoietic stem cell transplantation (HSCT) as curative therapy, iron overload continues long after transplantation. There are few pediatric studies on chelation therapy in the posttransplant period. In this study, we present the outcomes of our patients who received posttransplant oral chelation therapy. PATIENTS AND METHODS This retrospective observational study evaluated the outcomes of pediatric patients with thalassemia major who used oral chelation therapy after allogeneic HSCT at the Akdeniz University Pediatric Bone Marrow Unit between January 2008 and October 2019. RESULTS Deferasirox therapy was initiated in 58 pediatric patients who underwent HSCT for thalassemia. Pretreatment mean serum ferritin was 2166±1038 ng/mL. Treatment was initiated at a mean of 12±6.7 months after transplantation and continued for a mean of 15.7±11.5 months. At treatment discontinuation, the mean serum ferritin was 693±405 ng/mL and the mean reduction was -1472.75±1121.09 ng/mL (P<0.001 vs. posttreatment). Serum ferritin was below 500 ng/mL in 52% of the patients at treatment discontinuation. Manageable side effects such as nausea, vomiting, liver enzyme elevation, and proteinuria were observed in 17% of the patients, while one patient developed ototoxicity. CONCLUSIONS Deferasirox therapy effectively reduces iron overload in the posttransplant period. Studies evaluating the effects of early treatment on the graft may help to establish guidelines for posttransplant chelation therapy. Clear guidelines are needed regarding when to initiate and discontinue treatment.
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3.
Long-term effect of hematopoietic stem cell transplantation on the quality of life of patients with β-thalassemia major in Guangxi, China--A cross-sectional study
Zhai, L., Liu, Y., Huo, R., Pan, Z., Zhang, Y., Li, Z., Li, F., Fan, J., Wei, W.
Current stem cell research & therapy. 2022
Abstract
OBJECTIVE The purpose of our study was to compare the quality of life (QOL) of patients with hematopoietic stem cell transplantation (HSCT) for more than 2 years for β-thalassemia major (β-TM) with that of β-TM patients with conventional therapy (blood infusion and iron chelation) and that of the general population. METHODS This was a cross-sectional comparative study on the QOL of 225 β-TM patients treated with blood transfusion and iron-chelation therapy, 133 β-TM patients who had undergone HSCT or 270 age- and sex-matched healthy individuals from Guangxi, China. Child-self and parent-proxy reports of the PedsQL 4.0 Generic Core Scales were used to prospectively evaluate QOL. RESULTS The incidence of acute GVHD was 14.3% (grade III-IV in 4.5% of patients), and that of chronic GVHD was 3.8%. This was lower than that of previous studies since the inclusion of anti-thymocyte globulin(ATG)ATG. Patients who underwent transplantation from a voluntary donor had higher QOL scores and lower rates of acute GVHD, chronic GVHD and comorbidities than those receiving stem cell sources from an HLA mismatched related donor (haploidentical donor). Transplants with PBSCs or UCBT, PBSCT+BMT, BMT, or BMT+UCBT as stem cell sources did not have any impact on QOL. The QOL of β-TM patients was very similar to that of the general population. More complications (P<0.001), shorter posttransplantation time (P<0.001) and older age at HSCT (P=0.01) were associated with poorer child QOL (P=0.020). Additional analyses investigating QOL β-TM patients receiving conventional treatment with β-TM revealed poorer outcomes than the cohort of transplanted patients. CONCLUSION β-TM patients can be cured by HSCT and regain QOL as good as that of the general population. β-TM patients are suggested to undergo HSCT as soon as possible to avoid complications related to iron overload and blood infusion.
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4.
Outcome of allogeneic hematopoietic stem cell transplantation in adult patients with paroxysmal nocturnal hemoglobinuria
Nakamura, Y., Takenaka, K., Yamazaki, H., Onishi, Y., Ozawa, Y., Ikegame, K., Matsuoka, K. I., Toubai, T., Ueda, Y., Kanda, Y., et al
International Journal of Hematology. 2021;113(1):122-127
Abstract
The safety and efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) remain unclear. Therefore, we retrospectively analyzed the outcomes of 42 adult patients with PNH who underwent allogeneic HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median patient age was 32.5 years. The number of packed red cell (PRC) transfusions was < 20 times in 19 patients and ≥ 20 times in 16; 7 patients had missing data. Stem cell sources were bone marrow (N = 15) or peripheral blood (N = 13) from a related donor or bone marrow (N = 11) and cord blood (N = 3) from an unrelated donor. The cumulative incidence of neutrophil engraftment at day 40 was 81%. Six patients died before engraftment, and the 6-year overall survival (OS) was 74%. The OS of patients with < 20 pretransplant PRC transfusions was significantly higher than that of patients with ≥ 20 pretransplant PRC transfusions (95% vs. 63%; P < 0.05). Moreover, the OS of patients aged < 30 years was significantly higher than that of patients aged ≥ 30 years (90% vs. 59%; P < 0.05). Allogeneic HSCT for PNH could provide favorable survival; however, pretransplant transfusion burden and patient age should be considered when deciding the timing of allogeneic HSCT.
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5.
Transfusions in aplastic anemia patients cause HLA alloimmunization Comparisons of current and past cohorts demonstrate progress
Julen, K., Volken, T., Holbro, A., Infanti, L., Halter, J. P., Schaub, S., Wehmeier, C., Diesch, T., Rovó, A., Passweg, J. R., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Transfusions are the mainstay of supportive therapy in patients with aplastic anemia (AA) and may lead to anti-human leukocyte antigen (HLA) alloimmunization, thereby also increasing the risk for donor-specific antibodies in the setting of HLA-mismatched transplantation. Historically, AA patients were thought to be at particularly high risk for HLA alloimmunization. OBJECTIVE In the past decades, blood product manufacturing (leukoreduction), but also HLA antibody testing has improved significantly by single antigen bead (SAB) technology. It is currently unknown how those developments have impacted HLA-alloimmunization and treatment outcome in patients with AA. STUDY DESIGN We retrospectively investigated 54 AA patients treated by immunosuppressive therapy and/or allogeneic hematopoietic cell transplantation after the introduction of the SAB assay at our center. We compared the HLA antibody results to a historical AA cohort (n=26), treated prior to introduction of leukoreduced blood products from 1975 to 1995. RESULTS HLA alloimmunization was detected in 43 of 54 (80%) patients in recently treated patient. Past pregnancy, female gender, disease severity, age and a history of more transfusions were significantly associated with a larger number and/or higher intensity (mean fluorescence intensity) of HLA antibodies. Treatment outcome including bleeding episodes, response to treatment, engraftment, GvHD and overall survival was not associated with HLA alloimmunization. In the historical cohort a significantly higher number of HLA antibodies (p<0.01) with a higher MFI (p<0.01) was observed. CONCLUSION HLA alloimmunization remains frequent in AA tested by current techniques but it has significantly decreased since prior decades and does not affect treatment outcome.
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6.
Pre-transplant red blood cell and platelet transfusion burden in de novo myelodysplastic syndrome undergoing allogeneic transplantation: Pre-transplant red blood cell and platelet transfusion burden in de novo MDS after allogeneic transplantation
Konuma, T., Aoki, J., Ozawa, Y., Uchida, N., Kobayashi, T., Onizuka, M., Katayama, Y., Ohta, T., Nakano, N., Ota, S., et al
Transplantation and cellular therapy. 2021
Abstract
BACKGROUND Most patients of myelodysplastic syndrome (MDS) require red blood cell (RBC) and/or platelet transfusion during their disease courses, which could cause an increased risk of iron overload and alloimmunization. However, it remains less clear whether pre-transplant RBC or platelet transfusion burden affects transplant outcomes in patients with MDS. OBJECTIVE The objective was to examine the significance of pre-transplant RBC and platelet transfusion burden on transplant outcomes after allogeneic HCT for adults with de novo MDS. STUDY DESIGN We retrospectively evaluated the effect of pre-transplant RBC or platelet transfusion burden on transplant outcomes in a cohort of 1007 adult patients with de novo MDS treated by upfront allogeneic hematopoietic cell transplantation (HCT) between 2006 and 2018. RESULTS Both higher pre-transplant RBC and platelet transfusion burdens were significantly associated with higher overall mortality and relapse-related mortality, but not non-relapse mortality in the multivariate analysis. Higher pre-transplant RBC transfusion burden was also significantly associated with lower neutrophil, platelet, and reticulocyte recovery in the multivariate analysis. CONCLUSION In summary, our study clearly demonstrated that a higher pre-transplant RBC and platelet transfusion burden was independently associated with higher overall mortality, relapse-related mortality, and lower hematopoietic recovery after allogeneic HCT for de novo MDS. Early allogeneic HCT should be considered for patients with de novo MDS who require RBC and platelet transfusion repeatedly.
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7.
Outcome of iron reduction therapy in ex-thalassemics
Aboobacker, F. N., Dixit, G., Lakshmi, K. M., Korula, A., Abraham, A., George, B., Mathews, V., Srivastava, A.
PloS one. 2021;16(1):e0238793
Abstract
There is limited data on iron reduction therapy (IRT) after successful allogeneic haematopoietic stem cell transplantation (aHSCT) for patients with thalassemia major (TM). We present the long term outcome of IRT in 149 patients with TM who underwent aHSCT during January, 2001-December, 2012. The median age was 7 years (range:1-18) and 92 (61.7%) belonged to Pesaro class 3 with a median ferritin at aHSCT of 2480ng/ml (range:866-8921). IRT was reinitiated post-aHSCT at a median of 14 months (range:5-53) post aHSCT with phlebotomy alone in 10 (6.7%) patients or iron chelation alone in 60 (40.3%) patients while 79 (53%) were treated with the combination. Reduction in serum ferritin/month [absolute quantity (ng/ml/month) was as follows: 87 (range:33-195), 130 (range:17-1012) and 147 (range:27.7-1427) in the phlebotomy, chelation and combination therapy groups, respectively (p = 0.038). With a median follow up of 80 months (range:37-182), target ferritin level of <300ng/ml was achieved in 59(40%) while a level <500ng/ml was achieved in 88 patients (59%) in a median duration of 41 months of IRT (range: 3-136). Patients in class III risk category and higher starting serum ferritin levels (>2500ng/ml) were associated with delayed responses to IRT. Our data shows that IRT may be needed for very long periods in ex-thalassaemics to achieve target ferritin levels and should therefore be carefully planned and initiated as soon as possible after aHSCT. A combination of phlebotomy and iron chelators is more effective in reducing iron overload.
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8.
Pre-transplant donor-type red cell transfusion is a safe and effective strategy to reduce isohemagglutinin titers and prevent donor marrow infusion reactions in major ABO-mismatched transplants
Mehta, P., Ramprakash, S., Raghuram, C. P., Trivedi, D., Dhanya, R., Agarwal, R. K., Faulkner, L.
Annals of hematology. 2021
Abstract
ABO incompatibility is not a barrier to allogeneic stem cell transplant but may result in acute hemolytic reactions. As stem cell product manipulation is cumbersome, we are reporting the effectiveness and safety of donor-type red cell infusion as a method of reducing acute hemolytic reaction while using marrow as stem cell source. In major ABO-mismatched bone marrow transplants, manipulation of marrow product requires expertise and expensive equipment, which may not be readily available to transplant centers in low- and middle-income regions. The aim behind our study is to report a safe and effective strategy to reduce isohemagglutinin titers and prevent donor marrow infusion reactions in major ABO-mismatched transplants. We retrospectively analyzed 303 consecutive allogeneic bone marrow transplants (BMTs) for beta thalassemia major, between August 2015 and March 2020, with either major (n = 41) or bidirectional (n = 14) mismatches. When isohemagglutinin titers were 1:32 or higher, donor-type packed red blood cell was divided into 4 aliquots, irradiated and administered over 4 days at incremental volumes. Patients were observed for hemolytic reaction, and if no reaction, bone marrow was infused without manipulation. Out of 55 patients, 20 received donor-type blood infusion. Twelve patients showed evidence of mild hemolysis. None developed severe hemolytic or anaphylactic reaction. Titers were rechecked in 14 patients and all had reduction in titers, except for one. Our experience demonstrated that donor-type PRBC infusion is safe and effective in preventing acute hemolysis in major ABO-mismatched stem cell transplants even with bone marrow as graft source.
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9.
Quantification of Liver Iron Overload: Correlation of MRI and Liver Tissue Biopsy in Pediatric Thalassemia Major Patients Undergoing Bone Marrow Transplant
Bafna, V., Bhat, S., Raj, V., Badiger, S., Annapandian, V. M., Nataraj, K. S., Damodar, S.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2020;36(4):667-673
Abstract
Determination of the magnitude of body iron stores helps to identify individuals at risk of iron-induced organ damage in Thalassemia patients. The most direct clinical method of measuring liver iron concentration (LIC) is through chemical analysis of needle biopsy specimens. Here we present a noninvasive method for the measurement of LIC in vivo using magnetic resonance imaging (MRI). Twenty-three pediatric Thalassemia major patients undergoing bone marrow transplantation at our centre were studied. All 23 patients had MRI T2* and R2* decay time for evaluation of LIC on a 1.5 Tesla MRI system followed by liver tissue biopsy for the assessment of iron concentration using an atomic absorption spectrometry. Simultaneously, serum ferritin levels were measured by enzymatic assay. We have correlated biopsy LIC with liver T2* and serum ferritin values with liver R2*. Of the 23 patients 11 were males, the mean age was 8.3 ± 3.7 years. The study results showed a significant correlation between biopsy LIC and liver T2* MRI (r = 0.768; p < 0.001). Also, there was a significant correlation between serum ferritin levels and liver R2* MRI (r = 0.5647; p < 0.01). Two patients had high variance in serum ferritin levels (2100 and 4100 mg/g) while their LIC was around 24 mg/g, whereas the difference was not seen in T2* MRI. Hence, the liver T2* MRI is a better modality for assessing LIC. Serum ferritin is less reliable than quantitative MRI. The liver T2* MRI is a safe, reliable, feasible and cost-effective method compared to liver tissue biopsy for LIC assessment.
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10.
Blood transfusion support for sickle cell patients during haematopoietic stem cell transplantation: a single-institution experience
De Santis, G. C., Costa, T. C. M., Santos, F. L. S., da Silva-Pinto, A. C., Stracieri, Abpl, Pieroni, F., Darrigo-Junior, L. G., de Faria, J. T. B., Grecco, C. E. S., de Moraes, D. A., et al
British journal of haematology. 2020