scholarly journals SARS-CoV-2 Infection and Active, Multiorgan, Severe cGVHD After HSCT for Adolescent ALL: More Luck Than Understanding? A Case Report

2022 ◽  
Vol 9 ◽  
Author(s):  
Natalia Zubarovskaya ◽  
Irene Hofer-Popow ◽  
Marco Idzko ◽  
Oskar A. Haas ◽  
Anita Lawitschka
Keyword(s):  
Case Report ◽  
B Cell ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Chronically Ill ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Autoantibody Production ◽  
Computed Tomography Images ◽  
Steroid Sparing

Graft-vs. -host disease (GvHD) is a serious and complex immunological complication of haematopoietic stem cell transplantation (HSCT) and is associated with prolonged immunodeficiency and non-relapse mortality. Standard treatment of chronic GvHD comprises steroids in combination with other immunosuppressive agents. Extracorporeal photopheresis (ECP), with its immunomodulatory mechanism, is applied as part of steroid-sparing regimens for chronic GvHD. Immunocompromised, chronically ill patients are at particular risk of severe disease courses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. T-cell immunity in SARS-CoV-2 infection is well-described but the role of the humoral immune responses is not fully understood. This case report describes a moderate course of SARS-CoV-2 infection in a patient <9 months after HSCT who was suffering from active, severe, chronic GvHD treated with prednisone and ECP. Following HSCT from a matched unrelated donor to cure acute lymphoblastic leukaemia, the 25-year-old male patient experienced multiple infectious complications associated with cytopenia, B-cell dyshomeostasis and autoantibody production followed by development of severe chronic GvHD thereafter at day +212. The steroid-sparing treatment plan consisted of supportive care, topical treatment, prednisone and ECP. He was diagnosed with SARS-CoV-2 infection at day +252, experiencing loss of smell and taste as well as a cough. The patient's oxygen saturation was between 94 and 97% on room air, and computed tomography images showed evolution of typical of SARS-CoV-2 infiltrates. In addition to cytopenia and immune dyshomeostasis, laboratory tests confirmed macrophage activating syndrome, transaminitis and Epstein-Barr virus viraemia. At that time, anti-SARS-CoV-2 monoclonal antibodies were not available in Austria and remdesivir seemed contraindicated. Surprisingly, despite severe lymphopenia the patient developed SARS-CoV-2-specific antibodies within 15 days, which was followed by clearance of SARS-CoV-2 and EBV with resolution of symptoms. Thereafter, parameters of immune dysregulation such as lymphopenia and B-cell dyshomeostasis, the latter characterised by elevated CD21low B cells and autoantibody expression, normalised. Moreover, we observed complete response of active chronic GvHD to treatment.

Unrelated Donor Marrow Transplantation for B-Cell Chronic Lymphocytic Leukemia After Using Myeloablative Conditioning: Results From the Center for International Blood and Marrow Transplant Research

2005 ◽  
Vol 23 (24) ◽  
pp. 5788-5794 ◽  
Author(s):  
Steven Z. Pavletic ◽  
Issa F. Khouri ◽  
Michael Haagenson ◽  
Roberta J. King ◽  
Philip J. Bierman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Marrow Transplantation ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Cell Chronic Lymphocytic Leukemia

Purpose To determine the role of myeloablative conditioning and unrelated donor (URD) bone marrow transplantation in the treatment of patients with advanced B-cell chronic lymphocytic leukemia (CLL). Patients and Methods A total of 38 CLL patients received a matched URD transplant using bone marrow procured by the National Marrow Donor Program. The median age was 45 years (range, 26 to 57 years), the median time from diagnosis was 51 months, and the median number of prior chemotherapy regimens was three. Fifty-five percent of patients were chemotherapy refractory and 89% had received fludarabine. Conditioning included total-body irradiation in 92% of patients. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate with cyclosporine or tacrolimus for 82% of patients. Results Twenty-one patients (58%) achieved complete response and six (17%) achieved partial response. Incidences of grades 2 to 4 acute GVHD were 45% at 100 days and incidences of chronic GVHD were 85% at 5 years. Eleven patients are alive and disease free at a median of 6 years (range, 3.0 to 9.0 years). Five-year overall survival, failure-free survival, disease progression rates, and treatment-related mortality (TRM) were 33%, 30%, 32%, and 38% respectively. Conclusion These data demonstrate that lasting remissions can be achieved after URD transplantation in patients with advanced CLL. High TRM suggest that myeloablative conditioning and HLA-mismatched donors should be avoided in future protocols, and it is mandatory to investigate transplant strategies with a lower morbidity and mortality, including the use of nonmyeloablative regimens.

Thymoglobulin Decreases the Need for Immunosuppression at 12 Months after Myeloablative and Nonmyeloablative Unrelated Donor Transplantation: CBMTG 0801, a Randomized, Controlled Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 38-38 ◽  
Author(s):  
Irwin Walker ◽  
Kirk R. Schultz ◽  
Cynthia L. Toze ◽  
Holly Margaret Kerr ◽  
John Moore ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Peripheral Blood ◽  
Chronic Gvhd ◽  
Immunosuppressive Agents ◽  
Analysis Of Covariance ◽  
Unrelated Donor ◽  
Symptom Scale ◽  
Serious Infections ◽  
Multicenter Rct

Abstract Background: Randomized trials (RCT) have shown that anti-thymocyte globulin (ATG) decreases the incidence and severity of chronic graft-versus-host disease (cGVHD) following unrelated donor transplants, but it is not used universally. We conducted a multicenter RCT to test whether the addition of Thymoglobulin® (TG) to both myeloablative (MA) and nonmyeloablative (NMA) preparative regimens results in a decrease in use of immunosuppression for cGVHD, leading to improvements in quality of life but without an increase in mortality, disease relapse or serious infections. Methods: Multicentric (Canada and Australia, 12 centres), open label RCT, in patients having transplantation from unrelated donors for a hematologic malignancy. Inclusion criteria: age 16-70, MA or NMA preparative regimen, bone marrow or peripheral blood graft, fully major histocompatibility complex (MHC) matched (HLA-A, B, C and DRB1) or 1-antigen/allele mismatched donor. Subjects were allocated by minimization procedure to TG or No Thymoglobulin® (NoTG). The TG arm received 0.5, 2.0, 2.0 mg/kg of TG on days -2, -1 and +1 respectively. Analyses were on a modified intention-to-treat basis for patients actually transplanted. The primary end-point was freedom from cGVHD at 12 months from transplantation defined as withdrawal of all systemic immunosuppressive agents (IST) without resumption up to 12 months after transplantation. Secondary end-points included relapse, serious infections, acute and chronic GVHD, overall survival (OS), and quality of life (QoL). QoL measures included Life Happiness Rating, Affect Balance Scale, FACT-BMT, EuroQol 5D, Center for Epidemiologic Studies-Depression Scale, Chronic GVHD Symptom Scale, and the Illness Intrusiveness Ratings Scale, collected prior to randomization and at 12 months. Treatment group comparisons, adjusted for baseline values, were made using logistic regression, analysis of covariance or the Cox proportional hazards model; in the presence of competing risks the method of Fine and Gray was implemented. Results: Data were locked on July 7, 2014. Two hundred and three (203) subjects consented and were randomized; seven were non-evaluable (6 withdrew before transplant, 3 having relapsed; 1 withdrew consent day 139), leaving 196 subjects for analysis. One subject was later found ineligible but was analyzed. Study populations were balanced for clinical risk factors. Sixty-seven percent (67%) received myeloablative conditioning, and 88% peripheral blood. Eighty-three percent (83%) were 8/8 HLA matched. Overall, freedom from IST at 12 months was twice as high in the TG group 37.4% vs. 16.5%, p=0.0001, even after adjusting for clinical factors: odds ratio 4.25 (95% CI, 1.87 – 9.67); p=0.006 or separately analyzing the MA and NMA groups. Acute GVHD (I-IV) and moderate/severe NIH grades of cGVHD were higher in the NoTG group, while relapse, non-relapse mortality, serious infections and OS were not significantly different. CGVHD (mild/mod/severe) was borderline significant using Fine and Gray (p=0.12; HR=0.65 95% CI (0.38 – 1.11) but the Cox result was significant p=0.01 (HR=0.48 95% CI (0.27 -0.85). Life Happiness was higher and Chronic GVHD Symptoms lower in the TG group as compared to the NoTG group (p=0.014 and 0.017 respectively); no other measure differed significantly. Conclusions: Addition of TG to the conditioning regimen for unrelated donor transplantation results in twice the likelihood of being alive and off immunosuppression at 12 months after transplantation, and is associated with modest improvements in some aspects of QoL. This benefit is seen without an increase in relapse, serious infections or non-relapse mortality. Our data support the use of TG in both MA and NMA preparative regimens before unrelated donor transplantation.TableTG N=97NoTG N=99p-valuePRIMARY ENDPOINTFreedom from IST at 12 mos37.4%16.5%0.001Myeloablative Subanalysis37.9%19.7%0.02Nonmyeloablative Subanalysis36.4%9.7%0.01SECONDARY ENDPOINTSAcute GVHD I-IV58.6%73.2%0.012cGVHD (NIH criteria)22.4%33.4%0.01 (Cox) 0.12 (Fine and Gray)cGVHD (NIH) Mod/Severe4.4%31%0.0001Serious infections38.4%37.1%0.85Relapse10.1%13.4%0.27Non-relapse mortality (12 mo)19.2%24.1%0.45Survival (12 mo)74.7%64.5%0.16Life Happiness Rating (QoL)*7.405.970.014GVHD Symptom Scale (QoL)*14.9520.930.017* Other QoL measures not significant Disclosures Walker: Sanofi: Research Funding. Off Label Use: Thymoglobulin which is the intervention in this randomized trial. Kuruvilla:Sanofi Aventis: Honoraria. Popradi:Sanofi: Honoraria.

scholarly journals Unrelated Transplants for High-risk Adult Acute Lymphoblastic Leukaemia

2009 ◽  
Vol 03 (01) ◽  
pp. 45
Author(s):  
Christelle Ferrà ◽  
Josep-Maria Ribera ◽  
◽  
Keyword(s):  
High Risk ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Adult Patients ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
High Incidence

Standard chemotherapy has a poor outcome in adult patients with high-risk acute lymphoblastic leukaemia (ALL). Allogeneic haematopoietic stem cell transplant (alloSCT) is the treatment of choice, and SCT with alternative progenitors should be considered in the absence of a matched sibling donor. There is great heterogeneity in the data on unrelated SCT for adult patients with high-risk ALL. Many studies include both paediatric and adult patients, or provide combined data from ALL and acute myeloid leukaemia (AML) patients. Moreover, the follow-up of the reported series is highly variable, and the definition of high-risk criteria varies from one study to another. The reported disease-free survival (DFS) for adult ALL patients ranges from 30 to 70%, and leukaemia relapse (14–47%) is an important cause of treatment failure. Despite great improvements in recent years, transplant-related mortality (TRM) from unrelated SCT (USCT) remains unacceptably high (29–36%). The human leukocyte antigen (HLA) disparity in the unrelated donor setting with a high incidence of graft-versus-host disease (GvHD) and delayed immunological reconstitution with a high incidence of infectious events in the unrelated cord blood SCT are the most important causes of morbidity and mortality in unrelated transplants. Disease status at transplant and the presence of acute and/or chronic GvHD are the most important factors determining relapse in high-risk ALL adult patients undergoing USCT.

scholarly journals Tissue-Resident PSGL1loCD4+ T Cells Interact with B Cells Via PD-1 and PD-L2 in Gvhd Target Tissues to Augment Autoimmune-like Chronic Gvhd

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5607-5607
Author(s):  
Xiaohui Kong ◽  
Deye Zeng ◽  
Xiwei Wu ◽  
Shijie Yang ◽  
Bixin Wang ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Research Funding ◽  
Cellular Therapy ◽  
Chronic Gvhd ◽  
Advisory Board ◽  
Murine Models ◽  
B Cell Differentiation ◽  
Autoantibody Production

Chronic graft versus host disease (cGVHD) is a systemic autoimmune-like syndrome, and donor-type CD4+ T interaction with B cells plays an important role in its pathogenesis. Our recent publication has demonstrated that cGVHD pathogenesis does not require germinal center formation and is associated with expansion of extrafollicular CD44hiCD62LloPSGL1loCD4+ (PSGL1loCD4+) T cells in the spleen and GVHD target tissues. The causal role of PSGL1loCD4+ T cells in cGVHD pathogenesis remains unclear. With murine and humanized murine models, we show that both murine and human PSGL1loCD4+ T cells reside in tissues and do not circulate in the blood, and their high expression of PD-1 and ICOS and production of IL-21 suggest that they provide B cell help. In murine models, PSGL1loCD4+ T cells augment plasma cell expansion and autoantibody production via their PD-1 interaction with PD-L2 on B. In humanized mouse models, human PSGL1loCD4+ T cells from GVHD target tissues augment memory B cell differentiation into plasma cells and antibody production via their production of IL-21.These results indicate that tissue-resident PSGL1loCD4+ T cells augment autoantibody production and cGVHD pathogenesis. Targeting tissue-resident T cells may represent a novel approach for treating cGVHD. Disclosures Nakamura: Alexion: Other: support to a lecture at a Japan Society of Transfusion/Cellular Therapy meeting ; Kirin Kyowa: Other: support for an academic seminar in a university in Japan; Celgene: Other: support for an academic seminar in a university in Japan; Merck: Membership on an entity's Board of Directors or advisory committees. Martin:Abgenomics: Research Funding; Enlivex Therapeutics: Consultancy; Genentech: Consultancy, Other: One-time advisory board; Neovii: Other: One-time advisory board; Pfizer: Other: Data and Safety Monitoring Committee; Pharmacyclics LLC: Other: One-time advisory board; Procter and Gamble: Equity Ownership; Xenikos: Research Funding.

Non–myeloablative Allogeneic Hematopoietic Stem Cell Transplantation with Low-Dose Total Body Irradiation and Peri-Transplant Rituximab for B Cell Non-Hodgkin Lymphoma: Favorable Disease Control in Chemosensitive Patients,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4160-4160
Author(s):  
Craig S Sauter ◽  
Esperanza B Papadopoulos ◽  
Miguel-Angel Perales ◽  
Ann A Jakubowski ◽  
Jenna D Goldberg ◽  
...  
Keyword(s):  
Stem Cell ◽  
Disease Control ◽  
B Cell ◽  
Low Dose ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Total Body ◽  
Grade 3 ◽  
Related Mortality

Abstract Abstract 4160 Background: Allogeneic stem cell transplantation (allo-SCT) remains the only curative therapy for patients with indolent B cell Non-Hodgkin's Lymphoma (B-NHL) as well as patients with aggressive B-NHL that have failed prior autologous stem cell transplants (ASCT). Myeloablative conditioning is associated with a high incidence of early transplant related mortality (TRM) particularly in patients with extensive prior therapy and advanced age. Non-myeloablative conditioning (NMA) provides less TRM and the opportunity to exploit graft-versus-lymphoma (GVL) effects at the expense of conditioning intensity for disease control. The addition of rituximab to these regimens provides both anti-lymphoma and potential immunomodulatory benefit in terms of decreasing the incidence of graft-versus-host disease (GVHD). The aim of this phase 2 trial was to determine the safety and efficacy of low-dose total body irradiation (TBI), cyclophosphamide, fludarabine and peri-transplant rituximab in patients with CD20+ B cell malignancies. Patients and Methods: This analysis includes 35 B-NHL patients with a median age of 54 years (range 33–67) at the time of allo-SCT. Diagnoses included: 15 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 9 follicular lymphoma (FL), 6 diffuse large B cell lymphoma (DLBCL)/ transformed lymphoma (B-tNHL), 3 mantle cell lymphoma (MCL) and 2 other. Patients were previously treated with a median of 3 prior chemotherapy regimens (range 1–5) and 6 patients had a previous ASCT. Twenty-five patients were chemosensitive at the time of allo-SCT by International Criteria (Cheson et al JCO 1999, Hallek et al Blood 2008 for CLL/SLL). Patients with DLBCL, B-tNHL and MCL were required to have chemosensitivity prior to allo-SCT. Patients with FL and CLL/SLL were not required to achieve chemosensitivity, but did require stable disease, prior to allo-SCT. Conditioning consisted of cyclophosphamide 50 mg/kg, fludarabine 25 mg/m2 daily over 5 days and 200 cGy TBI. Rituximab 375 mg/m2 was administered 1–2 days prior to the initiation of conditioning and weekly for 4 doses beginning d+21. Graft rejection prophylaxis with equine anti-thymocyte globulin (ATG), 30 mg/kg daily d-3 and d-2, was given to recipients of unrelated grafts. All patients received a G-CSF mobilized peripheral blood stem cell graft. GVHD prophylaxis consisted of tacrolimus and sirolimus beginning d-3 and methotrexate 5 mg/m2on d+1, d+3 and d+6. Twelve patients received a graft from a 10/10 HLA matched related donor, 19 from a 10/10 HLA matched unrelated donor and 4 from a 9/10 HLA mismatched unrelated donor. A survival event was defined as progression of disease (PD) or death from any cause, including transplant-related mortality (TRM). Results: All patients engrafted and full donor chimerism in neutrophils and T cells was documented at 3 months posttransplant in 30 evaluable patients. This regimen was well tolerated and no grade 3–4 oral mucositis was observed. Acute GvHD, grades 2 to 4, developed prior to d+100 in 20% of evaluable patients (8% grade 3–4). The 2-year incidence of chronic GVHD (CIBMTR criteria) in 32 patients at risk was 65% (23% mild, 34% moderate and 9% severe). Twenty six patients are alive with a median of 23 months (range 6–41). Of the 9 events, 6 were TRM (5 from GVHD) and 3 PD (all of which died of lymphoma). No events have occurred beyond 15 months. The 2-year EFS for all patients is 72%. No difference in EFS or OS was demonstrated according to: histology, graft source, number of previous lines of therapy, previous autologous transplant or age. The only variable associated with EFS was pre-allo-SCT chemosensitivity. The 2-year EFS for chemosensitive patients was 83% compared to 44% for patients without chemosensitivity pre-allo-SCT (see figure, p=0.02). Conclusions: This NMA regimen with peri-transplant rituximab is effective and safe allowing full donor myeloid and T cell chimerism with minimal toxicities and with notable anti-lymphoma effect, however chronic GvHD developed in a significant number of patients. In this trial, peri-transplant rituximab may provide disease control but its role on cGvHD prevention is not clear. These data confirm chemosensitivity as a significant prognostic factor to survival in B-NHL with NMA allo-SCT. Disclosures: No relevant conflicts of interest to declare.

Autoimmune hemolytic anemia in a patient with myelodysplastic syndrome: Responding to 5-azacitidine therapy

2021 ◽  
pp. 107815522098761
Author(s):  
Jaspreet Kaur ◽  
Shahaf Tuler ◽  
Constantin A Dasanu
Keyword(s):  
Case Report ◽  
Myelodysplastic Syndrome ◽  
B Cell ◽  
Hemolytic Anemia ◽  
Autoimmune Hemolytic Anemia ◽  
Scientific Literature ◽  
Cell Clone ◽  
Autoimmune Disorders ◽  
Autoantibody Production ◽  
Autoimmune Cytopenias

Introduction Autoimmune disorders, including autoimmune cytopenias, are more common in patients with myelodysplastic syndrome (MDS) and may share with MDS the same steps of pathogenesis. Some patients with MDS have antibodies against red cells. Case report We describe herein a 79-year-old patient who presented with fatigue, jaundice and pancytopenia. She was diagnosed with warm-antibody autoimmune hemolytic anemia (AIHA) and synchronous MDS. Management and outcome: In our patient, AIHA responded to the hypomethylating agent 5-azacitidine used for the treatment of MDS. Six months later, the patient remains in clinico-laboratory remission for both MDS and AIHA. Discussion/conclusions Our case indirectly suggests that 5-azacitidine led to a decrease in autoantibody production by the auto-reactive B-cell clone in MDS leading in turn to a diminished rate of autoimmune hemolysis. If our observation is accurate, we believe that similar reports will populate the scientific literature in the future years.

T-Cell Depleted Unrelated Donor Stem Cell Transplants Appear to Be of Value for Adult Philadelphia Chromosome Negative ALL Patients and Should Be Evaluated Prospectively in New Large Group Studies

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4413-4413
Author(s):  
B. R Patel ◽  
Keiren Kirkland ◽  
R. Pearce ◽  
Richard E Clark ◽  
Charles F. Craddock ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Acute Lymphoblastic Leukaemia ◽  
Lymphoblastic Leukaemia ◽  
Chronic Gvhd ◽  
Philadelphia Chromosome ◽  
Disease Free Survival ◽  
British Society ◽  
Haematopoietic Stem Cell ◽  
Unrelated Donor

Abstract Matched sibling allogeneic haematopoietic stem cell transplantations (HSCT) in first complete remission (CR1) result in superior survival compared to standard chemotherapy in adult patients with acute lymphoblastic leukaemia (ALL). However, application is limited by donor availability. The role of unrelated donor (URD) transplantation in ALL in CR1 is not clearly delineated. We report a retrospective series of URD transplants in 55 adults with Philadelphia chromosome (Ph) negative acute lymphoblastic leukaemia (ALL) in CR1 reported to the British Society of Blood and Marrow Transplantation registry from 1993 to 2005. Median follow-up of survivors was 55.2 months (range 17–160). Median age was 25.5 years (range 15.7–50). Eighty nine percent of patients had at least one adverse prognostic feature. Sixty six percent of transplants were matched at 10 of 10 loci and 34% were mis-matched. T cell depletion (TCD) was carried out by in-vivo Campath administration in 96% of recipients with additional ex-vivo TCD in 21% of these patients. The estimated actuarial Overall survival (OS), Disease free survival (DFS) and non relapse mortality (NRM) were 59%, 57% and 19% at 5 years respectively. The overall incidence of Grade II–IV and III–IV GVHD was 25% and 7% respectively. The actuarial estimate of extensive chronic GVHD was 22 % at 5 years. HLA mismatching at 2 alleles or antigens was associated with poorer survival (RR=3.22, (1.08–9.64). T depleted URD HSCT can result in good OS and low TRM for adults with high risk ALL in CR1 and merits prospective comparison with other methods of GVHD prophylaxis.

scholarly journals Low Numbers of CD27- IgD- 'Double Negative' Senescent B-Cells Early after Reduced Intensity T Cell Depleted Haematopoietic Stem Cell Transplantation Are Predictive of Subsequent Chronic GvHD

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4529-4529
Author(s):  
Francesca Kinsella ◽  
Harriet Protheroe ◽  
Hayden Pearce ◽  
Charlotte F Inman ◽  
Suzy A Eldershaw ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Gvhd ◽  
Subsequent Development ◽  
Haematopoietic Stem Cell ◽  
Cell Repertoire ◽  
Graft Versus Host ◽  
Post Transplant ◽  
B Cell Repertoire ◽  
B Cell Subsets

Chronic graft versus host disease (cGvHD) is an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). It is now believed that B cells play a major role in the development of cGvHD as evidenced by the efficacy of B-cell directed therapies, and the disturbances in B cell subsets found in patients. This is characterised by a relative lack of naive B cells and increase in CD27+ (antigen experienced) mature B cells that can mediate host directed responses. Despite this the cellular mechanisms underlying the pathogenesis of cGvHD remain unclear. We investigated the phenotype and function of CD19+ B-cell subsets in a cohort of 46 patients undergoing reduced intensity-conditioned allo-HSCT with alemtuzumab. 76% of patients had myeloid disease and 24% lymphoid disease. All patients received PBMC grafts, fludarabine and melphalan conditioning and 10mg/day alemtuzumab from day -5 for 5 days. Overall survival at 3 years was 65% and relapse free survival was 62%. 16% patients experienced acute GvHD (grade 2+) and 29% developed chronic GvHD. B cell subsets were examined at 6 weeks post-transplant and CD27-IgD- 'double negative' (DN) B-cells were seen to dominate the B cell repertoire (mean 55% of B-cells). DN B-cells are an ill-defined memory B cell subset associated with immune senescence, auto-immune inflammatory conditions and cancer but their role in allo-HSCT has not been described. The frequency of DN B-cells decreased over time, as the naive B cell compartment regenerated, but still represented 31% of B cells at 1 year. However the mean number of DN B cells remained remarkably stable (0.033x109/L at 6 weeks v 0.037x109/L at 1 year). 14% of DN B-cells early post-transplant were transitional (CD24high CD38high) whilst 10% were plasma cells (CD24- CD38high). The remaining 76% had increased CD86 expression compared to memory B-cells (16% v 9.6%; *p=0.039) and lower levels of surface immunoglobulin. DN B-cells were less functional than other B cell subsets with decreased proportions of cells producing IL-2 (20%), IL-6 (17%), IFN-γ (6.2%), and IL-10 (6.2%) compared to naive or memory B cells. They also demonstrated reduced proliferation to in vitro stimulation (Ki-67 5.3%). Importantly, the proportion of DN B cells early post transplant was then studied in relation to transplant outcome and a lower frequency of cells was found to be correlated with subsequent development of cGvHD (38% v 62%; *p=0.04). These data show that senescent CD27-IgD- DN B-cells dominate the B cell repertoire in the early period after lymphocyte-depleted allo-HSCT. Furthermore, they are significantly reduced in patients who subsequently develop cGvHD. These data suggest that early B cell senescence can directly regulate the subsequent development of chronic graft versus host disease and indicate that the composition of the B cell repertoire at an early time-point post-transplant may be used to predict subsequent clinical outcome. Disclosures No relevant conflicts of interest to declare.

scholarly journals Unrelated donor vs HLA-haploidentical α/β T-cell– and B-cell–depleted HSCT in children with acute leukemia

Blood ◽  
2018 ◽  
Vol 132 (24) ◽  
pp. 2594-2607 ◽  
Author(s):  
Alice Bertaina ◽  
Marco Zecca ◽  
Barbara Buldini ◽  
Nicoletta Sacchi ◽  
Mattia Algeri ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Leukemia ◽  
B Cell ◽  
Cumulative Incidence ◽  
Therapeutic Option ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Probability Of Survival

Abstract Traditionally, hematopoietic stem cell transplantation (HSCT) from both HLA-matched related and unrelated donors (UD) has been used for treating children with acute leukemia (AL) in need of an allograft. Recently, HLA-haploidentical HSCT after αβ T-cell/B-cell depletion (αβhaplo-HSCT) was shown to be effective in single-center studies. Here, we report the first multicenter retrospective analysis of 127 matched UD (MUD), 118 mismatched UD (MMUD), and 98 αβhaplo-HSCT recipients, transplanted between 2010 and 2015, in 13 Italian centers. All these AL children were transplanted in morphological remission after a myeloablative conditioning regimen. Graft failure occurred in 2% each of UD-HSCT and αβhaplo-HSCT groups. In MUD vs MMUD-HSCT recipients, the cumulative incidence of grade II to IV and grade III to IV acute graft-versus-host disease (GVHD) was 35% vs 44% and 6% vs 18%, respectively, compared with 16% and 0% in αβhaplo-HSCT recipients (P < .001). Children treated with αβhaplo-HSCT also had a significantly lower incidence of overall and extensive chronic GVHD (P < .01). Eight (6%) MUD, 32 (28%) MMUD, and 9 (9%) αβhaplo-HSCT patients died of transplant-related complications. With a median follow-up of 3.3 years, the 5-year probability of leukemia-free survival in the 3 groups was 67%, 55%, and 62%, respectively. In the 3 groups, chronic GVHD-free/relapse-free (GRFS) probability of survival was 61%, 34%, and 58%, respectively (P < .001). When compared with patients given MMUD-HSCT, αβhaplo-HSCT recipients had a lower cumulative incidence of nonrelapse mortality and a better GRFS (P < .001). These data indicate that αβhaplo-HSCT is a suitable therapeutic option for children with AL in need of transplantation, especially when an allele-matched UD is not available.

Outcome of Children with All Given HSCT from Unrelated Volunteers Has Significantly Improved over Time and Now Is Comparable to That of Children Transplanted from an HLA-Identical Sibling.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2156-2156 ◽  
Author(s):  
Franco Locatelli ◽  
Marco Zecca ◽  
Andrea Pession ◽  
Cornelio Uderzo ◽  
Giorgio Dini ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Significant Proportion ◽  
Disease Free Survival ◽  
Haematopoietic Stem Cell ◽  
Recurrence Time ◽  
Unrelated Donor ◽  
Immune Phenotype

Abstract Leukemia recurrence is the most common cause of treatment failure in children with ALL. The prognosis relapsed ALL mainly depends on the site of recurrence, time between diagnosis and relapse and immune-phenotype, children with bone marrow relapse occurring within the first 30 months after diagnosis or with T-ALL being those with the worst prognosis. Allogeneic haematopoietic stem cell transplantation (HSCT) is considered the treatment of choice for many children with relapsed ALL. We report the outcome of 175 children with ALL in second complete remission given HSCT from either a relative or an unrelated donor (UD) in one of the Italian AIEOP Centers from1998 to 2002. Less than 10% of these patients had an isolated extra-medullary relapse. TBI was employed in the preparative regimen in 92% of patients. GVHD prophylaxis consisted of Cs-A alone in the vast majority of children transplanted from a relative, whereas the combination of Cs-A, short-term MTX and either ALG, or Campath-1G in a minority of cases, was used in children transplanted from an UD. The source of stem cells was bone marrow, cord blood and peripheral blood in 150, 20 and 5 children respectively. We used the Berlin-Frankfurt-Munster (BFM) classification of ALL relapses in childhood to subdivide patients according to site of relapse, time from diagnosis to relapse and immune-phenotype. This classification identifies 4 different groups of risk (S1, S2, S3 and S4), the latter being those including patients with the worst prognosis. The 5-year probability of disease-free survival (DFS) of patients transplanted from either a relative or an unrelated donor was 56% and 44% (P=0.05). However, the outcome of the 86 children transplanted from an HLA-identical sibling or an UD beyond 1998 was comparable, the 3-year Kaplan-Meier estimate of DFS being 62% and 59%, respectively. The cumulative incidence of transplant-related mortality (TRM) for patients transplanted either from a relative or from an UD was 15% and 33%, respectively. For children transplanted beyond 1998 we found a reduction in TRM, irrespectively of the type of donor employed. The 5-year cumulative incidence of relapse for patients transplanted either from a relative or from an UD was 30% and 23%, respectively (P=NS). The occurrence of grade I-III acute GVHD was associated with a reduction in the risk of leukemia recurrence, which translated into a significantly better probability of DFS as compared to children with absent or grade IV acute GVHD. Also chronic GVHD was associated with a significantly lower risk of disease recurrence and with a better DFS. Irrespectively of the type of donor emlpoyed, S1 and S2 patients had a significantly better outcome in comparison to those S3 and S4 groups. These data indicate that allogeneic HSCT is able to rescue a significant proportion of patients with ALL in 2nd CR. DFS of unrelated donor HSCT in children with ALL in 2nd CR has improved in the last few years, being comparable to that of patients transplanted from a matched family donor. This information, together with that on the prognostic relevance of BFM classification, is of value for counselling of patients with relapsed ALL. The GVHD-related graft-versus-leukemia effect is important for the eradication of the malignant clone.

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