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1.
Cytokine profiling during conditioning in haploidentical stem cell transplantation and its prognostic impact on early transplant outcomes
Li, N., Zhao, C., Ma, R., Lou, R., Liu, X. J., Zheng, F. M., Wang, J. Z., Wang, Y., Huang, X. J., Sun, Y. Q.
Transplant immunology. 2023;78:101830
Abstract
Cytokine storm development is a major cause of many transplant-related complications, especially during the conditioning regimen. This study aimed to characterize the cytokine profile and determine its prognostic impact during conditioning in patients undergoing subsequent haploidentical stem cell transplantation. A total of 43 patients were enrolled in this study. Sixteen cytokines associated with cytokine release syndrome (CRS) during anti-thymocyte globulin (ATG) treatment were quantified in patients undergoing haploidentical stem cell transplantation. Thirty-six (83.7%) patients developed CRS during ATG treatment; most of those cases (33/36; 91.7%) were classified as grade 1 CRS, whereas only three (7.0%) developed grade 2 CRS. CRS was observed more frequently on the first (15/43; 34.9%) and second day (30/43; 69.8%) of ATG infusion. No factors were identified that could predict the development of CRS on the first day of ATG treatment. Five of the 16 cytokines (interleukins 6, 8, and 10 (IL-6, IL-8, and IL-10), C-reactive protein (CRP), and procalcitonin (PCT)) were significantly elevated during ATG treatment, although only the level of IL-6, IL-10, and PCT were associated with the severity of CRS. However, neither CRS nor the cytokine levels significantly impacted the development of acute graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection or affected overall survival.
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2.
Thrombopoietin level predicts the response to avatrombopag treatment for persistent thrombocytopenia after haploidentical haematopoietic stem cell transplantation
Fu, H., Lv, M., Liu, H., Sun, Y., Zhang, Y., Mo, X., Han, T., Wang, F., Yan, C., Wang, Y., et al
Bone marrow transplantation. 2023
Abstract
Persistent thrombocytopenia (PT) has an unsatisfactory response to therapy after haploidentical haematopoietic stem cell transplantation (haplo-HSCT). We retrospectively evaluated the safety and efficacy of avatrombopag treatment in 69 patients with PT following haplo-HSCT and assessed whether baseline thrombopoietin (TPO) levels could predict treatment response. Overall response (OR) and complete response (CR) were defined as increased platelet levels to over 20 × 10(9)/L or 50 × 10(9)/L independent of platelet transfusion during or within 7 days of the end of avatrombopag treatment, respectively. The incidences of OR and CR were 72.5% and 58.0%, with a median of 11 and 29 days to OR and CR, respectively. ROC analysis suggested that the optimally discriminant baseline TPO level threshold for both OR and CR to avatrombopag was ≤ 1714 pg/mL. In multivariate analysis, a lower baseline TPO level (P = 0.005) was a significant independent factor of response to avatrombopag. For patients resistant to other TPO receptor agonists (TPO-RAs), 9/16 (56.3%) exhibited a response after switching to avatrombopag. Avatrombopag was well tolerated, and responders achieved improved overall survival (79.0% vs. 91.1%, P = 0.001). In conclusion, avatrombopag is a potential safe and effective treatment for PT after haplo-HSCT, and lower baseline TPO levels predicted a better response.
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3.
Cytokine release syndrome in haploidentical stem cell transplant may impact T-cell recovery and relapse
Shapiro, R. M., Kim, H. T., Ansuinelli, M., Guleria, I., Cutler, C. S., Koreth, J., Gooptu, M., Antin, J. H., Kelkar, A. H., Ritz, J., et al
Blood advances. 2023
Abstract
Cytokine release syndrome (CRS) following haploidentical hematopoietic cell transplantation (HCT) resembles the CRS after chimeric antigen receptor (CAR)-T therapy. We conducted this single-center retrospective study evaluating the association of post-haploidentical HCT CRS with clinical outcomes and immune reconstitution. One hundred sixty-nine patients who underwent haploidentical HCT between 2011 and 2020 were identified. Of these, 98 patients (58%) developed CRS after HCT. CRS was diagnosed based on the presence of fever within the first 5 days after HCT without evidence of infection or infusion reaction, and graded according to established criteria. The development of post-haploidentical HCT CRS was associated with a lower incidence of disease relapse (p=0.024) but with an increased risk of chronic GVHD (p=0.01). The association of CRS with a lower incidence of relapse was not confounded by graft source or disease diagnosis. Neither CD34 nor TNC dose was associated with CRS independently of graft type. In patients developing CRS, CD4+ Treg (p<0.0005), CD4+ Tcon (p<0.005) and CD8+ T-cells (p<0.005) were increased at 1 month following HCT compared to those who did not develop CRS, but not at later time points. The increase in CD4+ regulatory T cells at 1 month post HCT was most notable among patients with CRS who received a bone marrow graft (p<0.005). The development of post haploidentical HCT CRS is associated with a reduced incidence of disease relapse and with a transient effect on post HCT immune reconstitution of T cells and their subsets. Validation of these observations in a multicenter cohort is required.
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4.
"Incidence and significance of donor-specific antibodies in haploidentical stem cell transplantation"
Altareb, M., Al-Awwami, M., Alfraih, F., Alhayli, S., Ahmed, S. O., Shaheen, M., Chaudhri, N., Alsharif, F., Alkhabbaz, H., Albabtain, A. A., et al
Bone marrow transplantation. 2023
Abstract
PGF is a devastating complication after allogeneic transplant. We retrospectively analyzed our haploidentical transplant registry to report the incidence and impact of DSA and anti-HLA on engraftment. 107 patients were identified. Median recipient-age of 22, median donor-age of 31. Sixty-two patients had AML (58%), 29 had ALL (27%), 16 (15%) had other malignancies. Sixty-one recipients (57%) had positive anti-HLA, 56 of them had the DSA results available, of these 17 patients had DSAs (15% of the total number of patients, or 28% of patients who have anti-HLA antibodies). The median cumulative MFI was 2062. Sixty-three percent of the DSA were against class-II HLA antigens. The OS, CIR, aGvHD, and cGvHD did not differ between patients with and without anti-HLA antibodies, nor between patients with and without DSA. The gender of the recipient and donor, as well as the gender mismatch between recipient and donor, were statistically associated with the incidence of anti-HLA antibodies. Three patients only developed GF (2.8%), one was primary (0.9%) and the other two secondary GF (1.9%). None of the GF cases was in patients with anti-HLA antibodies or DSA. The presence of anti-HLA or DSAs did not affect the outcomes including the incidence of PGF.
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5.
Incidence of late-onset hemorrhagic cystitis and its effect on PFS in acute leukemia patients after haplo-PBSCT: The 5-year single-center data
Yuan, H., Chen, G., Xu, J., Yang, R., Muhashi, M., Aizezi, G., Jiang, M.
Frontiers in oncology. 2022;12:913802
Abstract
We conducted a single-center 5-year retrospective study on the occurrence of hemorrhagic cystitis (HC) and its effect on survival after haploid high-dose peripheral blood stem cell transplantation (haplo-PBSCT) in patients with acute leukemia. We retrospectively analyzed 153 patients with acute leukemia who were treated with non-in vitro T-cell depleted haplo-PBSCT and myeloablative conditioning regimen. All patients were followed up for more than 180 days after transplantation. HC occurrence and its effect on long-term progression free survival (PFS) were retrospectively analyzed. Totally, 64 out of 153 patients had late onset HC (LOHC). No early onset HC occurred. The median onset time was 38.5 (17-163) days after transplantation. The cumulative incidence of LOHC was 41.8%. The cumulative incidence of LOHC in patients under 27 years old (50.0%) and in ALL patients (54.1%) was significantly higher than that in patients over 27 years old (34.5%) and in AML patients (36.9%), respectively. The cumulative incidence of mild LOHC was 44.2% and that of severe LOHC was 28.6%. However, urine copies of BK virus were not related to LOHC duration. There was no significant difference in 3-year expected PFS between AML and ALL patients with and without LOHC, or between LOHC duration more than and less than 38.5 days (P>0.05). Conclusively, LOHC incidence is higher in patients under 27 years old and in ALL patients. LOHC occurrence is related to urine BK virus copy, but not blood BK virus load. LOHC duration and severity has no significant effect on PFS.
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6.
Risk factors and outcomes of diffuse alveolar haemorrhage after allogeneic haematopoietic stem cell transplantation
Wu, J., Fu, H. X., He, Y., Mo, X. D., Liu, X., Cai, X., Gui, R. Y., Liu, H. X., Yan, C. H., Chen, Y. H., et al
Bone marrow transplantation. 2021;:1-11
Abstract
Diffuse alveolar haemorrhage (DAH) is a life-threatening pulmonary complication occurring after allogeneic haematopoietic stem cell transplantation (allo-HSCT) without an explicit aetiology or a standard treatment. This study aimed to explore the occurrence and prognosis of DAH after allo-HSCT, in addition to comparing discrepancies in the incidence, clinical characteristics and outcomes of DAH between patients undergoing haploidentical HSCT (HID-HSCT) and matched related donor HSCT (MRD-HSCT). We retrospectively evaluated 92 consecutive patients among 3987 patients with a confirmed diagnosis of DAH following allo-HSCT (HID: 71 patients, MRD: 21 patients). The incidence of DAH after allo-HSCT was 2.3%, 2.4% after HID-HSCT and 2.0% after MRD-HSCT (P?=?0.501). The prognosis of patients with DAH after transplantation is extremely poor. The duration of DAH was 7.5 days (range, 1-48 days). The probabilities of overall survival (OS) were significantly different between patients with and without DAH within 2 years after transplantation (P?0.001). According to the Cox regression analysis, a significant independent risk factor for the occurrence of DAH was delayed platelet engraftment (P?0.001), and a high D-dimer level (>500?ng/ml) was a significant risk factor for the poor prognosis of DAH. HID-HSCT is similar to MRD-HSCT in terms of the outcomes of DAH.
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7.
Timing of Initiation of Calcineurin Inhibitors in Pediatric Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: Effects on Survival, Relapse, and Cytokine Release Syndrome
Uygun, V., Karasu, G., Yalçin, K., Ozturkmen, S., Daloglu, H., Çelen, S. S., Hazar, V., Yesilipek, A.
Acta haematologica. 2021
Abstract
BACKGROUND The use of unmanipulated haploidentical stem cell transplantations (haplo-HSCT) with post-transplant cyclophosphamide (PTCY) in children has emerged as an acceptable alternative to the patients without a matched donor. However, the timing of calcineurin inhibitors (CNI) used in combination with PTCY is increasingly becoming a topic of controversy. METHOD We evaluated 49 children with acute leukemia who underwent unmanipulated haplo-HSCT with PTCY according to the initiation day of CNIs (pre- or post-CY). RESULTS There were no significant differences in the overall survival analysis between the two groups. The cumulative incidence of relapse at 2 years was 21.2% in the pre-CY group and 38.9% in the post-CY group (p=0.33). Cytokine release syndrome (CRS) was observed more frequently in the post-CY group (p=0.04). The OS and EFS at 2 years in patients with and without CRS in the pre-Cy group were 42.9% vs 87.5% (p=0.04) and 38.1% vs 87.5% (p=0.04), respectively. CONCLUSION Our study shows that the argument for starting CNI administration after CY is tenuous, and the rationale for not starting CNI before CY needs to be reconsidered.
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8.
Grade 3-4 cytokine release syndrome is associated with poor survival in haploidentical peripheral blood stem cell transplantation
Modi, D., Albanyan, O., Kim, S., Deol, A., Ayash, L., Ratanatharathorn, V., Uberti, J. P.
Leukemia & lymphoma. 2021;:1-11
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Editor's Choice
Abstract
The information on the impact of cytokine release syndrome (CRS) on haploidentical donor peripheral blood stem cell transplant (haploPBSCT) outcomes is limited. We retrospectively evaluated 98 patients who underwent haploPBSCT between June 2012 and June 2019 for the onset and severity of CRS per the ASTCT guidelines. The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%, p<.001), inferior relapse-free survival (64.0% vs. 20%, p<.001), and higher non-relapse mortality (NRM) (16.4% vs. 60%, p<.001) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71, p=.04), and higher NRM (SHR 4.51, p=.006) with grade 3-4 CRS. Our study shows that grade 3-4 CRS was adversely associated with survival. Therefore, early identification and preventive strategies are warranted.
PICO Summary
Population
Patients who underwent haploidentical peripheral blood stem cell transplantation (haploPBSCT) between June 2012 and June 2019 (n=98)
Intervention
Evaluation of the onset and severity of cytokine release syndrome (CRS)
Comparison
None
Outcome
The incidence of CRS was 93% (91/98). Outcomes were compared between grade 1-2 and 3-4 CRS. Eighty-one patients developed grade 1-2 CRS (89%) and 10 (11%) developed grade 3-4 CRS. Compared to grade 1-2 CRS, grade 3-4 CRS experienced adverse survival (73.7% vs. 30%), inferior relapse-free survival (64.0% vs. 20%), and higher non-relapse mortality (NRM) (16.4% vs. 60%) at 1-year. Propensity score-based multivariable analyses revealed worse survival (HR 2.71), and higher NRM (SHR 4.51) with grade 3-4 CRS.
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9.
Clinical Utility of the Detection of the Loss of the Mismatched HLA in Relapsed Hematological Patients After Haploidentical Stem Cell Transplantation With High-Dose Cyclophosphamide
Muñiz, P., Kwon, M., Carbonell, D., Chicano, M., Bailén, R., Oarbeascoa, G., Suárez-González, J., Andrés-Zayas, C., Menárguez, J., Dorado, N., et al
Frontiers in immunology. 2021;12:642087
Abstract
Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients. Unraveling the mechanisms of relapse is therefore crucial for designing effective relapse treatment strategies. One of these mechanisms is the loss of the mismatched HLA on the recipient's leukemic cells. To study the incidence and clinical relevance of this phenomenon, we analyzed 181 patients treated with Haplo-HSCT with PTCy (2007-2019), of which 37 relapsed patients after transplantation. According to the kit employed for HLA-loss analysis, among 22 relapsed patients, we identified HLA loss at relapse in 6 of the 22 patients (27%) studied. Based on the results obtained, the genomic loss of HLA was more common in females than males (66 vs. 33%) and HLA-loss relapses occurred later than classical relapses (345 vs. 166 days). Moreover, the patients with HLA-loss had a greater presence of active disease at the time of transplantation and had undergone a larger number of treatment lines than the group with classical relapses (66 vs. 43% and 66 vs. 18%, respectively). Four of these relapses were studied retrospectively, while two were studied prospectively, the results of which could be considered for patient management. Additionally, two relapsed patients analyzed retrospectively had myeloid neoplasms. One patient had not undergone any treatment, and three had undergone donor lymphocyte infusions (DLIs) and chemotherapy. All presented severe GVHD and disease progression. In contrast, the two patients studied prospectively had a lymphoid neoplasm and were not treated with DLIs. One of them was treated with chemotherapy but died from disease progression, and the other patient underwent a second Haplo-HSCT from a different donor and is still alive. We can conclude that the detection of HLA-loss at the onset of relapse after Haplo-HSCT with PTCy could help in clinical practice to select appropriate rescue treatment, thereby avoiding the use of DLIs or a second transplantation from the same donor.
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10.
Risk-adapted therapy for the management of cytokine release syndrome in children undergoing unmanipulated haploidentical stem cell transplantation
Jayakumar, I., Uppuluri, R., Lakshmanan, C., Kumar Gowdhaman, A., Vellaichamy Swaminathan, V., Raj, R.
Pediatric transplantation. 2020;:e13964
Abstract
BACKGROUND We aimed to describe an algorithm for the management of cytokine release syndrome (CRS) associated with haploidentical hematopoietic stem cell transplantation (haploSCT). PATIENTS AND METHODS We performed a prospective study where children up to 18 years of age undergoing haploSCT with post-transplant cyclophosphamide from September 2014 to March 2020 were included. Supportive care included low-dose adrenaline, high-flow nasal cannula, and N-acetylcysteine (NAC). Methylprednisolone and tocilizumab were administered in the peri-engraftment phase for grade 2 CRS or one-log increase and grade 3 CRS or a two-log increase in ferritin, respectively. RESULTS Data were analyzed in 135/148 children as 13 children died before engraftment due to sepsis. CRS was noted in 97% transplants (grade 1-74.1%, grade 2-15.6%, grade 3-6.7%, grade 4-1.4%). Grade 2 and above CRS was higher in non-malignant conditions (33% vs 13%, P-value .009). The percentage median rise in ferritin was 129%-grade 1, 171%-grade 2, and 344%-grade 3. Seven children received tocilizumab, and two of whom had ferritin values greater than 100 000 ng/mL with no mortality in this group. Low-dose adrenaline, high-flow nasal cannula, and ventilator support were needed in 13%, 10%, and 4%, respectively. Mortality in our cohort was 3/135 (2.2%), with two deaths due to sepsis and one due to grade 4 CRS. CONCLUSIONS A risk-stratified approach using steroids in grade 2 and tocilizumab in grade 3/4 in the setting of haploSCT with NAC infusion and early use of low-dose adrenaline and HFNC can help provide adequate control of CRS, thereby ensuring optimal outcomes and survival.