-
1.
Age Impacts Risk of Mixed Chimerism Following RIC HCT for Non-SCID Inborn Errors of Immunity
Fitch, T., Lane, A., McDonnell, J., Bleesing, J., Jordan, M., Kumar, A., Khandelwal, P., Khoury, R., Marsh, R., Chandra, S.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Alemtuzumab, fludarabine and melphalan containing reduced intensity conditioning (RIC) is commonly used in patients undergoing allogeneic hematopoietic cell transplantation (HCT) for definitive treatment of high-risk inborn errors of immunity (IEI). Although survival is favorable, there is increased risk of mixed chimerism leading to secondary graft failure. OBJECTIVES Evaluate factors associated with risk of developing mixed chimerism, particularly the influence of age in patients undergoing allogeneic HCT for non-SCID IEI who received a uniform RIC regimen that included intermediate schedule alemtuzumab, fludarabine and melphalan. We hypothesized that age would impact incidence of mixed chimerism. STUDY DESIGN We retrospectively reviewed records of patients who underwent HCT for non-SCID IEIs with a uniform RIC regimen that included intermediate schedule alemtuzumab (1 mg/kg divided over days -14 to - 10), fludarabine (150 mg/m2 or 5 mg/kg if weight <10 kg divided over days -9 to -4), and melphalan (140 mg/m2 or 4.7 mg/kg if weight <10 kg on day-3) between 2010 and 2020 at our institution. Mixed chimerism was defined as <95% donor on 2 or more consecutive occasions on whole blood. RESULTS Ninety-three patients who underwent RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan were evaluated and categorized into 3 groups: <1, 1-5, and > 5 years of age. Forty-nine patients (52.7%) developed mixed chimerism at a median of 34 days post-HCT (range, 10-1396 days). Mixed chimerism developed in 88.9 % (n=16/18) for <1 year, 57.1% (n=20/35) for 1-5 years, and 35% (n=14/40) for those >5 years. Patients <5 years of age were significantly more likely to develop mixed chimerism (X(2) (3, N = 93) = 14.8, p =0.001). We observed a significantly increased cumulative incidence of developing mixed chimerism if < 1 year of age (p=0.0002). Competing risk regression analysis demonstrated an increase in odds of development of mixed chimerism for age <1 (OR 3.72, p = 0.006, 95% CI 1.46-19.46) compared to age >5 years and decrease in odds of mixed chimerism in patients who developed acute GVHD prior to any intervention (OR 0.24, p=0.005, 95% CI 0.09-0.65) There was no significant association between mixed chimerism and graft source, graft type, CD34+ or CD3+ cell dose, HLA match or underlying disease (HLH vs non-HLH). Additionally, the need for secondary intervention was evaluated; 27 patients (29.0%) required one or more secondary intervention(s) (DLI, CD34 Boost, or second HCT). Patients <1 year of age with mixed chimerism were significantly more likely to require secondary intervention for mixed chimerism than patients > 5 years (p =0.004). CONCLUSION Our study demonstrates that young age <5 years, especially age <1 year is associated with an increased risk of developing mixed chimerism in patients undergoing RIC-HCT for non-SCID IEI using intermediate schedule alemtuzumab, fludarabine, and melphalan. Our data suggest tailoring regimen intensity based on age to reduce the incidence of mixed chimerism. Children <5 years, particularly those <1 year of age, require a higher intensity regimen. Possible strategies include adding thiotepa or using a busulfan-based reduced toxicity regimen.
-
2.
Immunosuppression Boost With Mycophenolate Mofetil for Mixed Chimerism in Thalassemia Transplants
Mehta, P., Singh, A., Halder, R., Verma, M., Agrawal, N., Ahmed, R., Bhurani, D.
Transplantation and cellular therapy. 2023;29(2):122.e1-122.e6
Abstract
Declining mixed chimerism (MC) portending impending graft failure is an undesirable outcome. However, for hemoglobinopathies in a stable state of MC, residual host cells persist without rejection in 30% to 40% of patients after hematopoietic stem cell transplantation (HSCT). Early detection and level of MC have been attributed to be significant in predicting the outcome of MC. Common clinical approach on MC is removal of immunosuppression. We retrospectively evaluated MC in transfusion dependent thalassemia patients who underwent HSCT in our institution between September 2013 and January 2022 to determine the outcome of MC on the basis of our approach of immunosuppression boost in comparison to conventional approach of immunosuppression tapering. Among 90 patients, 22 (24.4 %) had MC at some time point after transplantation with a median follow-up of 496 (67-1492) days. Immunosuppression withdrawal was done in 12 (54.5%) patients, whereas immunosuppression boost was given in 8 (36.3%) patients. In the immunosuppression withdrawal group, 2 (16.6%) patients evolved to complete chimerism, 5(41.6%) patients had persistent MC (PMC), whereas 5 (41.6%) patients had secondary rejection. All these rejections were at median of 186 (89-251) days after transplantation. In the immunosuppression boost group, all patients (n = 8) had PMC with no secondary rejection until median follow-up of 255(97-812) days after transplantation. We acknowledge that we need more experience with our unconventional approach of immunosuppression boost to obtain statistical significance in comparison to the conventional approach of tapering of immunosuppression.
-
3.
Association of early donor chimerism status with survival outcomes in post allogeneic haematopoietic stem cell transplant patients of nonmalignant diseases
Sial, N., Ahmed, P., Wattoo, F. H., Ali, N.
JPMA. The Journal of the Pakistan Medical Association. 2022;72(3):464-470
Abstract
OBJECTIVE To highlight the association of early donor chimerism status at 2nd month with various survival outcomes. METHOD The retrospective study was conducted at the Armed Forces Bone Marrow Transplant Centre, Rawalpindi, Pakistan, and comprised patient data from January 2011 to July 2016. Data related to participants who underwent human leukocyte antigen-matched transplants for bone marrow failure syndrome and beta thalassemia major. Short tandem repeat-based polymerase chain reaction was used to assess donor chimerism status. Overall survival, disease-free survival, relapse-free survival, and graft versus host disease-free survival rates were noted. Data was analysed using SPSS 23. RESULTS Of the 106, 64(60.4%) had bone marrow failure syndrome and 42(39.6%) had beta thalassemia major. The overall median follow-up was 13.53 months (range: 1.81-62.73 months). Early donor chimerism status was associated with overall survival (p=0.02) and disease-free survival (p=0.01). Mixed donor chimerism was less hazardous in terms of overall survival (p=0.04) and disease-free survival (p=0.02). CONCLUSIONS Early mixed donor chimerism contributed to optimal survival in nonmalignant disease.
-
4.
Incremental donor lymphocyte infusion to treat mixed chimerism after allogeneic stem cell transplantation in children with non-malignant diseases
Gabelli, M., Stepensky, P., Ottaviano, G., Mullanfiroze, K., Lazareva, A., Zaidman, I., Even-Or, E., Lucchini, G., Chiesa, R., Silva, J., et al
Bone marrow transplantation. 2022
-
5.
Thalassemia-free and graft-versus-host-free survival: outcomes of hematopoietic stem cell transplantation for thalassemia major, Turkish experience
Yesilipek, M. A., Uygun, V., Kupesiz, A., Karasu, G., Ozturk, G., Ertem, M., Şaşmaz, İ, Daloğlu, H., Güler, E., Hazar, V., et al
Bone marrow transplantation. 2022
Abstract
We report the national data on the outcomes of hematopoietic stem cell transplantation (HSCT) for thalassemia major (TM) patients in Turkey on behalf of the Turkish Pediatric Stem Cell Transplantation Group. We retrospectively enrolled 1469 patients with TM who underwent their first HSCT between 1988 and 2020 in 25 pediatric centers in Turkey. The median follow-up duration and transplant ages were 62 months and 7 years, respectively; 113 patients had chronic graft versus host disease (cGVHD) and the cGVHD rate was 8.3% in surviving patients. Upon the last visit, 30 patients still had cGvHD (2.2%). The 5-year overall survival (OS), thalassemia-free survival (TFS) and thalassemia-GVHD-free survival (TGFS) rates were 92.3%, 82.1%, and 80.8%, respectively. cGVHD incidence was significantly lower in the mixed chimerism (MC) group compared to the complete chimerism (CC) group (p < 0.001). In survival analysis, OS, TFS, and TGFS rates were significantly higher for transplants after 2010. TFS and TGFS rates were better for patients under 7 years and at centers that had performed over 100 thalassemia transplants. Transplants from matched unrelated donors had significantly higher TFS rates. We recommend HSCT before 7 years old in thalassemia patients who have a matched donor for improved outcomes.
-
6.
Unmanipulated Stem Cell Boost for Mixed Chimerism in Transfusion Dependent Thalassemia
Garg, A., Shivchhand, A., Shah, S., Shah, K., Patel, K., Panchal, H., Patel, A., Parikh, S.
Indian journal of hematology & blood transfusion : an official journal of Indian Society of Hematology and Blood Transfusion. 2021;37(3):458-462
Abstract
Early mixed chimerism (MC) can lead to secondary graft rejection post allogeneic hematopoietic stem cell transplantation in transfusion dependent thalassemia (TDT) patients. Reduction of immunosuppression and donor lymphocyte infusions is the mainstay for treating MC. We report our experience of administering unmanipulated stem cell boost (SCB) in reversing progressive early MC. There were 70 transplants done for 69 TDT patients at our center between September 2005 and January 2020. Mixed chimerism was defined by >?5% recipient cells and the severity was assigned according to the proportion of recipient cells as level 1?=??10%, level 2?=?10-25%, level 3?=??>?25%. For patients developing MC level 2 and 3, we administered unmanipulated SCB and analyzed its safety and efficacy. Out of 70 transplants 7 (10%) had MC level 2 (3/7) and 3 (4/7). These patients received unmanipulated SCB at a median CD34 cell dose of 4.5?×?10(6)/kg (range-3.5?×?10(6)/kg-5.5?×?10(6)/kg). Overall Response (stable MC and/or transfusion independency) to unmanipulated SCB was seen in 5 patients (71.4%). Five patients (71.4%) developed acute graft versus host disease (GVHD) of which 1 patient expired due to severe GVHD. SCB infusion was well tolerated by majority of our patients. The 3 year overall survival and thalassemia free survival was 85.7% (6/7) and 57.1% (4/7) respectively. Timely monitoring of chimerism is important for detecting early MC. Development of acute GVHD is common after administration of unmanipulated SCB and requires vigilance and prompt management. Unmanipulated SCB is a feasible modality for treating progressive MC and salvaging the graft especially in resource-constrained settings.
-
7.
The Relationship Between Busulfan Exposure and Achievement of Sustained Donor Myeloid Chimerism in Patients with Non-Malignant Disorders
Apsel Winger, B., Shukla, P., Kharbanda, S., Keizer, R. J., Goswami, S., Cowan, M. J., Dvorak, C. C., Long-Boyle, J.
Transplantation and cellular therapy. 2021;27(3):258.e1-258.e6
Abstract
The overall objective of allogeneic hematopoietic cell transplantation (HCT) in patients with non-malignant conditions involves replacing a dysfunctional or absent cell or gene product for disease correction. It is unclear whether lower busulfan exposure may be sufficient in this population to facilitate durable myeloid engraftment and limit toxicity. Given that neither the ideal level of mixed myeloid chimerism for specific non-malignant diseases nor how to condition a patient to achieve stable mixed myeloid chimerism is fully known, we sought to analyze the relationships among busulfan exposure, myeloid chimerism, and outcomes in patients with non-malignant conditions receiving busulfan as a part of combination pretransplant conditioning at our institution. This was a single-center, retrospective study including pediatric patients with a variety of non-malignant disorders who underwent allogeneic HCT at the University of California San Francisco Benioff Children's Hospital from March 2007 to June 2018. The busulfan cumulative area under the curve (cAUC) was estimated using a validated population pharmacokinetic model and nonlinear mixed effects modeling. Median busulfan cAUC for all patients was 70 mg·h/L (range, 53 to 108). All of the 29 patients with a busulfan cAUC of =70 mg·h/L achieved long-term disease correction with full or stable mixed (>20%) myeloid chimerism, compared to 78.5% (22/28) of patients with a cAUC of <70 mg·h/L (P = .01). Overall ksurvival was evaluated up to 3 years and was identical in patients with busulfan cAUC < 70 mg·h/L and patients with busulfan cAUC =70 mg·h/L (96% versus 93%; P = .92). Only three patients died, at days 65, 164 and 980 days post-HCT. Severe busulfan-related toxicities and graft-versus-host-disease (GVHD) were rare, with veno-occlusive disease occurring in four patients (7%), acute respiratory distress syndrome in three patients (5%), and GVHD in five patients (9%). These results demonstrate excellent outcomes and extremely low rates of toxicity across our entire cohort. Based on the results of this study, we recommend a busulfan exposure target of 75 mg·h/L (range, 70 to 80) in all non-malignant patients receiving allogeneic HCT to ensure optimal exposure for achievement of high-level stable myeloid chimerism.
-
8.
Does Mixed Chimerism After Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients With Fanconi Anemia Impact on Outcome?
Ayas, M., Siddiqui, K., Al-Jefri, A., Al-Ahmari, A., Ghemlas, I., Al-Saedi, H., Al-Anazi, A., Khan, S., El-Solh, H., Al-Seraihi, A.
Transplantation and cellular therapy. 2021;27(3):257.e1-257.e6
Abstract
Fanconi anemia (FA) cells are characterized by genomic instability, which places FA patients at risk for malignancies such as leukemia and oropharyngeal/urogenital cancers. The risk of development of leukemia is theoretically eliminated after hematopoietic cell transplantation (HCT). Mixed chimerism (MC) in FA patients might have a unique implication because the persistent existence of FA cells might give rise to a malignant clone. We have studied a large population of FA patients who underwent allogeneic HCT at our institution and report here the outcome according to chimerism status. Patients with FA who had evidence of progressive bone marrow failure and were blood products-transfusion dependent (packed red blood cells, platelets, or both) were included in the study. Those who had myelodysplasia (MDS) or an abnormal clone or evidence of leukemia were excluded. All but 3 patients had normal renal and cardiac function at the time of transplantation. In total, 160 patients with FA underwent allogeneic HCT at our center from January 1995 to December 2017; mean age at HCT was 8.4. Chimerism data at last follow-up visit were available on 97 patients who are the subjects of this analysis (no day +100 chimerism data on one of them). On day +100, 46 patients (47.9%) had full chimerism (FC) and 50 (52.1%) had MC, whereas at last follow-up 50 (51.5%) exhibited FC and the remaining 47 (48.5%) had MC. Cumulative incidence of all grades acute graft-versus-host disease (GVHD) was 13.4% and that of grade III to IV GVHD was 4.1%. Chronic GVHD was seen in eight (8.0%) patients. Incidence of severe acute GVHD (grade = III) and that of chronic GVHD were not significantly associated with FC or MC measured at day +100 (P values = .347 and .254, respectively), nor at the last follow-up. Graft failure occurred in 2 patients; both from the MC at day +100 group. No graft failures occurred in the FC at day +100 group (P value = 1.00). At a median follow-up of 83.8 months (95% confidence interval, 51.0-116.6; range, 19.3-181.1 months) the cumulative probability of overall survival (OS) at 5 years was 95.7% ± 2.1%. Mean follow-up time in our cohort was 90.7 months. Five-year overall survival was not significantly associated with FC or MC evaluated at day +100 (95.7% ± 3.0% versus 95.6% ± 3.1%, P value = .908) nor at the last follow-up (96.0% ± 2.8% versus 95.4% ± 3.2%, P value = .925). No patient in either group developed MDS/leukemia during the follow-up period. We conclude that mixed chimerism in patients with FA appears to have no adverse effect on outcome in our follow-up period. A longer follow-up period is needed, however, to confirm the validity of this statement.
-
9.
Impact of the human leucocyte antigen (HLA)-B leader peptide dimorphism and HLA-A expression on outcomes of stem cell transplantation for sickle cell disease
Cappelli, B., Scigliuolo, G. M., Boukouaci, W., Rafii, H., Volt, F., Kenzey, C., Maio, K. T., Chabannon, C., Corbacioglu, S., Rocha, V., et al
British journal of haematology. 2021
-
10.
Mixed chimerism after allogeneic hematopoietic stem cell transplantation for severe aplastic anemia
Zhang, Y., Li, Y., Wu, L., Zhou, M., Wang, C., Mo, W., Chen, X., Xu, S., Zhou, R., Wang, S., et al
Hematology (Amsterdam, Netherlands). 2021;26(1):435-443
Abstract
A retrospective study on 287 patients with SAA who underwent allo-HSCT between October 2012 and January 2020 was conducted to explore the outcomes, risk factors and treatment options for MC. Among 287 AA patients who excluded Fanconi anemia (FA), Congenital dyskeratosis (DKC), Paroxysmal nocturnal hemoglobinuria (PNH), etc.112 underwent matched sibling donor (MSD)-HSCT, 91 matched unrelated donor-HSCT and 84 haploidentical-HSCT. Patients were divided into the following 4 groups: group 1: Donor chimerism (DC); group 2: MC without cytopenia; group 3: MC with cytopenia; group 4: secondary graft failure (SGF). Compared with the other three groups, SGF predicted a poor prognosis of SAA (P< 0.001). In addition, SGF was associated with the early (within 3 months after transplantation) presence of MC and the high levels of MC. Uni- and multivariate logistic regression analysis showed that donor/recipient sex-mismatching and CTX?+?ATG regimen were high-risk factors for MC. Of note, in MC patients with cytopenia (group 3), the effective response rate reached 55% (6/11) following enhanced immunosuppression combined with cellular therapy, while only one of the four was effective who received enhanced immunosuppression alone. SGF was associated with poor prognosis, early presence of MC and increased levels of recipient chimerism. The donor/recipient sex-mismatching and CTX?+?ATG regimen based MSD-HSCT were risk factors for MC. Cellular therapy could improve the effective response rate of patients with progressive MC.