scholarly journals Successful outcome of pre-engraftment COVID-19 in an HCT patient: impact of targeted therapies and cellular immunity

2022 ◽  
Author(s):  
Hoda Pourhassan ◽  
CORINNA LA ROSA ◽  
Flavia Chiuppesi ◽  
Alfredo Puing ◽  
Ibrahim Aldoss ◽  
...  
Keyword(s):  
T Cell ◽  
Cellular Immunity ◽  
Cellular Therapy ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Humoral Response ◽  
Successful Outcome ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
The Impact

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has emerged as a global pandemic that upended existing protocols and practices, including those for allogeneic hematopoietic stem cell transplantation (HCT). Here we describe the successful clinical course and multiple key interventions administered to an acute lymphoblastic leukemia patient, who tested SARS-CoV-2 positive by RT-PCR on day -1 of matched unrelated donor (SARS-CoV-2 IgG negative) T-cell-replete HCT. This experience allowed for implementing a virologic and immunomonitoring panel to characterize the impact of SARS-CoV-2 on the recipient's nascent humoral and cellular immune response. The finding of robust, functional, and persistent levels of SARS-CoV-2 specific T-cells, starting early after transplant was unexpected, and in combination with the clinical strategy may have contributed to the favorable outcome. Additionally, it is plausible that pre-existing cross-reactive endemic coronavirus immunity in the allogeneic graft reduced recipient susceptibility to COVID-19 disease. This case supports the critical role that T-cell responses may play in mitigating SARS-CoV-2 infection, even in the context of transplant immunosuppression, in which reconstitution of humoral response is commonly delayed. Interventional approaches to transfer SARS-CoV-2-specific cellular immunity such as HCT donor vaccination and adaptive cellular therapy could be of benefit.

scholarly journals Impact of Different T Cell Depletion Protocols on Immune Reconstitution Following Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 43-44
Author(s):  
Amandine Pradier ◽  
Adrien Petitpas ◽  
Anne-Claire Mamez ◽  
Federica Giannotti ◽  
Sarah Morin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Reconstitution ◽  
Cell Depletion ◽  
Unrelated Donor ◽  
T Cell Depletion ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
The Impact

Introduction Allogeneic hematopoietic stem cell transplantation (HSCT) is a well-established therapeutic modality for a variety of hematological malignancies and congenital disorders. One of the major complications of the procedure is graft-versus-host-disease (GVHD) initiated by T cells co-administered with the graft. Removal of donor T cells from the graft is a widely employed and effective strategy to prevent GVHD, although its impact on post-transplant immune reconstitution might significantly affect anti-tumor and anti-infectious responses. Several approaches of T cell depletion (TCD) exist, including in vivo depletion using anti-thymocyte globulin (ATG) and/or post-transplant cyclophosphamide (PTCy) as well as in vitro manipulation of the graft. In this work, we analyzed the impact of different T cell depletion strategies on immune reconstitution after allogeneic HSCT. Methods We retrospectively analysed data from 168 patients transplanted between 2015 and 2019 at Geneva University Hospitals. In our center, several methods for TCD are being used, alone or in combination: 1) In vivo T cell depletion using ATG (ATG-Thymoglobulin 7.5 mg/kg or ATG-Fresenius 25 mg/kg); 2) in vitro partial T cell depletion (pTCD) of the graft obtained through in vitro incubation with alemtuzumab (Campath [Genzyme Corporation, Cambridge, MA]), washed before infusion and administered at day 0, followed on day +1 by an add-back of unmanipulated grafts containing about 100 × 106/kg donor T cells. The procedure is followed by donor lymphocyte infusions at incremental doses starting with 1 × 106 CD3/kg at 3 months to all patients who had received pTCD grafts with RIC in the absence of GVHD; 3) post-transplant cyclophosphamide (PTCy; 50 mg/kg) on days 3 and 4 post-HSCT. Absolute counts of CD3, CD4, CD8, CD19 and NK cells measured by flow cytometry during the first year after allogeneic HSCT were analyzed. Measures obtained from patients with mixed donor chimerism or after therapeutic DLI were excluded from the analysis. Cell numbers during time were compared using mixed-effects linear models depending on the TCD. Multivariable analysis was performed taking into account the impact of clinical factors differing between patients groups (patient's age, donor type and conditioning). Results ATG was administered to 77 (46%) patients, 15 (9%) patients received a pTCD graft and 26 (15%) patients received a combination of both ATG and pTCD graft. 24 (14%) patients were treated with PTCy and 26 (15%) patients received a T replete graft. 60% of patients had a reduced intensity conditioning (RIC). 48 (29%) patients received grafts from a sibling identical donor, 94 (56%) from a matched unrelated donor, 13 (8%) from mismatched unrelated donor and 13 (8%) received haploidentical grafts. TCD protocols had no significant impact on CD3 or CD8 T cell reconstitution during the first year post-HSCT (Figure 1). Conversely, CD4 T cells recovery was affected by the ATG/pTCD combination (coefficient ± SE: -67±28, p=0.019) when compared to the T cell replete group (Figure 1). Analysis of data censored for acute or chronic GVHD requiring treatment or relapse revealed a delay of CD4 T cell reconstitution in the ATG and/or pTCD treated groups on (ATG:-79±27, p=0.004; pTCD:-100±43, p=0.022; ATG/pTCD:-110±33, p<0.001). Interestingly, pTCD alone or in combination with ATG resulted in a better reconstitution of NK cells compared to T replete group (pTCD: 152±45, p<0.001; ATG/pTCD: 94±36, p=0.009; Figure 1). A similar effect of pTCD was also observed for B cells (pTCD: 170±48, p<.001; ATG/pTCD: 127±38, p<.001). The effect of pTCD on NK was confirmed when data were censored for GVHD and relapse (pTCD: 132±60, p=0.028; ATG/pTCD: 106±47, p=0.023) while only ATG/pTCD retained a significant impact on B cells (102±49, p=0.037). The use of PTCy did not affect T, NK or B cell reconstitution when compared to the T cell replete group. Conclusion Our results indicate that all TCD protocols with the only exception of PTCy are associated with a delayed recovery of CD4 T cells whereas pTCD of the graft, alone or in combination with ATG, significantly improves NK and B cell reconstitution. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Sars-Cov-2 T-Cell Response in Allogeneic Hematopoietic Stem Cell Recipients Following Two Doses of BNT162b2 Vaccine

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2895-2895
Author(s):  
Beatrice Clemenceau ◽  
Thierry Guillaume ◽  
Marianne Coste-Burel ◽  
Pierre Peterlin ◽  
Alice Garnier ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cellular Immunity ◽  
Cell Response ◽  
Humoral Response ◽  
T Cell Response ◽  
Healthy Controls ◽  
Hematopoietic Stem ◽  
Hla Dr

Abstract Introduction: Virus-specific humoral and cellular immune responses act synergistically to protect from viral infection. In our recent observational monocentric study of 117 hematopoietic stem cell adult recipients, we found that 54% and 83 % patients achieved a humoral response after two doses of BNT162b2 anti-SARS-CoV-2 messenger RNA vaccine (Pfizer BioNTech), respectively. Here, we evaluated the T-cell response against the SARS-Cov-2 spike protein after two doses of BNT162b2 vaccine in some allografted patients from the same cohort and compared these results to those from healthy controls. Methods: To quantify SARS-CoV-2 specific T-cells, we used an INFg ELISpot assay that detects these cells after activation of peripheral blood mononuclear cells (PBMC) with 3 peptide pools covering the whole protein sequence of the spike glycoprotein (Prot _S1; _S+ and _S PepTivator peptide pools, Miltenyi Biotec, Bergisch Gladbach, Germany). EBV and CMV specific T-cells were also quantified as controls. The immunophenotype of PBMC was determined by flow cytometry, after dead cell exclusion, with monoclonal antibodies identifying the following surface antigens: CD45, CD3, CD14, CD19 and HLA-DR. The frequencies of spot-forming units (SFU) were reported as per 10 6 CD3+ T-cells. Results: Samples from 46 allografted patients (acute myeloblastic leukemia, N=27, myelodysplastic syndrome, N=19) and 16 healthy controls were available. Characteristics of the population are given in Table 1. All fully vaccinated healthy donors became seropositive and developed a positive T-cell response to spike peptide pools even though variable frequencies were observed. The median response was 195 SFU/10 6 T-cells. By comparison, the frequency of EBV-specific T-cells was 774 SFU/10 6 T-cells (Figure 1). In the group of patients, 78% (n=36/46) had achieved a humoral response after the second dose of vaccine. Among these humoral responders (HR), 89% (n=32/36) also had a positive anti-spike T-cell response with variable frequencies (median =119 SFU/10 6 T-cells. For 8 patients, this T cell response was higher than that of controls (>800 SFU/10 6 T-cells) (Figure 1), which is equivalent to more than 1 specific T-cell per microliter of blood (Figure 2). The humoral responders (HR) who did not develop a T-cell response (11%, n=4/36) had a median time from transplant to vaccination of 523 days compared to 1032 days for cellular responder patients. Among the 10 patients who were non humoral responders (NHR) (22%, n=10/46), 4 (40%) developed a cellular immunity, including one with a very high T cell response (1333 SFU/10 6 T-cells). As expected, the absence of humoral response was observed in patients who were within one year of the transplant. Of note, somehow unexpectedly, patients often presented a high frequency of EBV- and CMV-specific T cells (Figures 1 & 2). As expected, PBMC immunophenotypic analysis revealed that CD3+ frequencies were lower in patients compared to those of controls but were similar between HR and NHR. NHR had very low frequencies of B cells and interestingly, they had an elevated frequency of CD14+ monocytes with low/neg HLA-DR expression potentially corresponding to myeloid-derived suppressor cells (MDSCs) (Figure 3). Conclusion: In this series, 89% of allografted patients who developed an anti-spike humoral response also presented an anti-SARS-Cov-2 cellular immunity. Interestingly, anti-SARS-Cov-2 specific T-cells could be detected in 40% of NHR patients. Although a larger group of patients is required to confirm these results, it remains to be determined whether this T-cell response is protective against SARS-Cov-2 infection as previously demonstrated for CMV (Litjens et al, 2017). Finally, the role of potential immunosuppressive MDSCs must be explored in patients who develop no sign of T-cell response after vaccination. Figure 1 Figure 1. Disclosures Moreau: Oncopeptides: Honoraria; Celgene BMS: Honoraria; Sanofi: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Amgen: Honoraria.

Unrelated Donor (URD) Hematopoietic Stem Cell Transplantation (HCT) for Adults with Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia (ALL) in First Complete Remission (CR1): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3055-3055
Author(s):  
David I. Marks ◽  
Waleska S. Pérez ◽  
Vincent He ◽  
Mei-Jie Zhang ◽  
Armand Keating ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Acute Gvhd ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Term Survival ◽  
Major Barrier ◽  
Hematopoietic Stem ◽  
Risk Of Relapse

Abstract Allogeneic HCT has a growing role in the management of adults with ALL in CR1. Recent large prospective donor vs. no donor analyses show HLA-matched sibling allografting to produce superior outcomes to chemotherapy and its use is unquestioned in the highest risk, Ph+ cohort. Investigators have explored the use of allografting with unrelated donors (URD) for patients with Philadelphia negative ALL in CR1 at high risk of relapse. We report outcomes of URD HCT using myeloablative conditioning in 169 patients with ALL in CR1 transplanted between 1995 and 2004, reported to the CIBMTR by 85 centers in 17 different countries. Median (range) age at HCT was 33 (16–59) years and the median white cell count (WCC) at diagnosis was 31 × 109/L. Fifty percent had a WCC >30 × 109/L, 18% had extramedullary disease, 42% achieved CR >8 weeks from diagnosis, 25% had adverse cytogenetics and 19% had T cell disease. Adverse cytogenetics included t(4;11), hypodiploidy or near triploidy or more than 5 abnormalities. Many patients had multiple high risk factors. Twenty-eight of 41 patients with adverse cytogenetics and 28 of 63 patients who took > 8 weeks to achieve CR had a WCC >30 × 109/L. Cyclophosphamide and total body irradiation (TBI) was used as conditioning in 76% of cases; 80% of patients received >13cGy of TBI. 41% were well matched (no known disparity at HLA A,B,C,DR) and 41% partially matched (1 locus known or likely disparity) with their donors; these are analysed together because of similar outcomes. Eighteen percent of patients were more mismatched (≥2 locus disparity). Univariate outcomes, with a median follow-up of 54 (range, 3–133) months were as follows: Outcomes Probability (95%confidence interval) Acute GVHD @ 100 days, grades II-IV 50 (43–58) Acute GVHD @ 100 days, grades III-IV 25 (19–32) Chronic GVHD @ 5 years 43 (35–51) Transplant-related mortality (TRM) @ 5 years 42 (34–50) Relapse @ 5 years 20 (14–26) Leukemia-free survival @ 5 years 38 (31–46) Overall survival @ 5 years 39 (31–47) In adjusted multivariate analyses, the risk of TRM was significantly higher with mismatched donors (RR = 1.83, p = 0.037) and T cell depletion (TCD) (RR = 2.67, p = 0.002). The risk of relapse was higher (RR = 2.22, p = 0.045) if the WCC at diagnosis was >100 × 109/L. Acute and chronic GVHD did not significantly affect the incidence of relapse (RR = 0.73, p = 0.39 and RR = 0.47, p=0.09 respectively). Factors associated with mortality included WCC >100 × 109/L (RR = 1.80, p = 0.014), >8 weeks to CR1 (RR = 1.77, p = 0.006), CMV seropositivity of donor or recipient (RR = 1.61, p = 0.04), ≥2 locus HLA mismatch (RR = 2.09, p = 0.003) and T cell depleted graft (RR = 2.50, p = 0.003). The major causes of death were relapse (25%), infection (23%) and GVHD (14%). In summary, nearly 40% of patients with high risk ALL in CR1 survive 5 years after URD-HCT. The risk of relapse is modest and TRM is the major barrier to survival. These data indicate that selection of only closely matched URD and better prevention and management of GVHD and infection will be needed to enhance long term survival.

Results of an AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Randomized Clinical Trial in Children with Low- and Intermediate-Risk Relapsed Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 65-65
Author(s):  
Franco Locatelli ◽  
Marco Zecca ◽  
Gianni Cazzaniga ◽  
Luciana Vinti ◽  
Andrea Biondi ◽  
...  
Keyword(s):  
T Cell ◽  
Maintenance Therapy ◽  
Induction Therapy ◽  
Lymphoblastic Leukemia ◽  
Continuous Treatment ◽  
Unrelated Donor ◽  
Intermediate Risk ◽  
Hematopoietic Stem ◽  
Line Therapy ◽  
To Receive

Abstract Leukemia recurrence remains the main cause of treatment failure in children with ALL. The prognosis of children with relapsed ALL is strongly influenced by the site of relapse, time elapsing between diagnosis and recurrence and by blast cell immune-phenotype. Recently, several groups reported probabilities of disease-free survival (DFS) in the order of 60% for children with low/intermediate-risk ALL in 1st relapse using different approaches. Despite this remarkable progress, the best re-induction and consolidation treatment remains to be defined. We, thus, conducted from 10/2003 to 06/2012 a multicenter randomized trial aimed at comparatively evaluating the efficacy of 2 alternative approaches in centers affiliated to the Italian AIEOP network. Included in the study were patients below the age of 18 experiencing late (i.e. more than 6 months from treatment discontinuation) isolated extramedullary (IEM) relapse (S1 patients, #22) or children with B-cell precursor (BCP)-ALL who had early (i.e. between 18 months from diagnosis and 6 months after completion of front-line treatment) or late combined bone marrow (BM) relapse, late isolated BM relapse of BCP–ALL, and very early (i.e. within 18 months from diagnosis) or early IEM of either BCP-ALL or T-cell ALL (S2 patients, # 255). S2 children were randomized to receive induction therapy consisting of either two multiagent chemotherapy courses, F1 and F2 (ARM-A), according to the ALL-REZ BFM P95/96 trial, or a classical 4-drug continuous reinduction therapy (protocol I-A-IDA, ARM-B). After induction, ARM-A patients were given a continuous treatment element including idarubicin (Protocol II-IDA), followed by 5 additional alternating R1/R2 courses and maintenance therapy (24 months). After induction therapy, ARM-B patients received 8 additional alternating R1/R2 courses and maintenance therapy (24 months, see Figure 1). S1 patients received ARM-A treatment with the exception of only 3 alternating R1/R2 consolidation courses and shorter maintenance therapy (12 months). All S2 children with an available HLA-identical sibling were candidate to receive allogeneic hematopoietic stem cell transplantation (allo-HSCT), while those relapsing within 48 months from diagnosis were eligible to receive the allograft also from an unrelated donor (UD) of BM cells or a suitable UD cord blood unit. For S1 patients, both autologous (auto) and allo-HSCT were considered acceptable post-remissional options; auto-HSCT was also employed in a minority of S2 children relapsing more than 48 months from diagnosis. Of the whole cohort of children, 143 were males and 134 were females; median age at diagnosis and at time of relapse was 5 (range 0.2-17) and 9 (range 1.1-17.9) years, respectively. Among the 255 S2 patients, 127 were allocated to ARM-A and 128 to ARM-B. All S1 children obtained a 2nd complete remission (CR), while the probability of reaching 2nd CR of S2 patients was similar in the 2 randomization arms (95% vs 96%). The 6-year DFS for the 22 S1 children was 75% (confidence interval, CI, 55-94); 13 of these children were given either auto-HSCT (#7) or allo-HSCT (#6), while 9 were treated with chemotherapy only. The 6-year DFS for the 255 S2 children was 65% (CI 57-72); the DFS for ARM-A and ARM-B patients was 60% (CI 48-71) and 69% (CI 60-79), respectively (p=ns). Among S2 patients, 179 received allo-HSCT either from an HLA-identical sibling (#51) or a BM/CB UD (#105) or an HLA-partially matched relative (#23) after T-cell depletion of the graft (TCD haplo-HSCT). Of the remaining 76 children, 12 were given auto-HSCT, while 64 received chemotherapy only. The 6-year DFS for S2 children who did or did not receive allo-HSCT was 66% (CI 58-74) and 58% (CI 38-77), respectively (p=ns). Among allo-HSCT recipients, the 6-year DFS was 59% (CI 42-75), 72% (CI 62-82) and 62% (CI 41-83) for children given HLA-identical sibling, UD or TCD haplo-HSCT, respectively (p=ns). Altogether, these results confirm that a high proportion of children with low-/intermediate-risk relapsed ALL can be rescued by second line therapy, including transplantation. A re-induction course similar to that employed in first-line therapy is as effective as that proposed in the ALL-REZ BFM P95/96 trial. UD-HSCT and TCD haplo-HSCT are suitable and effective alternatives for children candidate to an allograft but lacking an HLA-identical sibling. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Targeting Interleukin-2-Inducible T-Cell Kinase (ITK) Differentiates GVL and GVHD in Allo-HSCT

2020 ◽  
Vol 11 ◽  
Author(s):  
Mahinbanu Mammadli ◽  
Weishan Huang ◽  
Rebecca Harris ◽  
Aisha Sultana ◽  
Ying Cheng ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Interleukin 2 ◽  
Treatment Strategies ◽  
Receptor Expression ◽  
Hematopoietic Stem ◽  
Target Organs ◽  
Donor T Cells ◽  
Inducible T Cell Kinase

Allogeneic hematopoietic stem cell transplantation is a potentially curative procedure for many malignant diseases. Donor T cells prevent disease recurrence via graft-versus-leukemia (GVL) effect. Donor T cells also contribute to graft-versus-host disease (GVHD), a debilitating and potentially fatal complication. Novel treatment strategies are needed which allow preservation of GVL effects without causing GVHD. Using murine models, we show that targeting IL-2-inducible T cell kinase (ITK) in donor T cells reduces GVHD while preserving GVL effects. Both CD8+ and CD4+ donor T cells from Itk-/- mice produce less inflammatory cytokines and show decrease migration to GVHD target organs such as the liver and small intestine, while maintaining GVL efficacy against primary B-cell acute lymphoblastic leukemia (B-ALL). Itk-/- T cells exhibit reduced expression of IRF4 and decreased JAK/STAT signaling activity but upregulating expression of Eomesodermin (Eomes) and preserve cytotoxicity, necessary for GVL effect. Transcriptome analysis indicates that ITK signaling controls chemokine receptor expression during alloactivation, which in turn affects the ability of donor T cells to migrate to GVHD target organs. Our data suggest that inhibiting ITK could be a therapeutic strategy to reduce GVHD while preserving the beneficial GVL effects following allo-HSCT treatment.

scholarly journals Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Jaime Sanz ◽  
Jacques-Emmanuel Galimard ◽  
Myriam Labopin ◽  
Boris Afanasyev ◽  
Moiseev Ivan Sergeevich ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Cumulative Incidence ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Post Transplant ◽  
Gvhd Prophylaxis ◽  
Donor Type ◽  
Matched Sibling ◽  
The Impact

Abstract Background There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL). Methods We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years. Results Median age of patients was 38 years (range 18–76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II–IV and III–IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS. Conclusions Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.

scholarly journals Increase in polymorphonuclear myeloid-derived suppressor cells and regulatory T-cells in children with B-cell acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asmaa M. Zahran ◽  
Azza Shibl ◽  
Amal Rayan ◽  
Mohamed Alaa Eldeen Hassan Mohamed ◽  
Amira M. M. Osman ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Critical Role ◽  
Suppressor Cells ◽  
Healthy Controls ◽  
Blast Cells ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Impact

AbstractOur study aimed to evaluate the levels of MDSCs and Tregs in pediatric B-cell acute lymphoblastic leukemia (B-ALL), their relation to patients’ clinical and laboratory features, and the impact of these cells on the induction response. This study included 31 pediatric B-ALL patients and 27 healthy controls. All patients were treated according to the protocols of the modified St. Jude Children’s Research Hospital total therapy study XIIIB for ALL. Levels of MDSCs and Tregs were analyzed using flow cytometry. We observed a reduction in the levels of CD4 + T-cells and an increase in both the polymorphonuclear MDSCs (PMN-MDSCs) and Tregs. The frequencies of PMN-MDSCs and Tregs were directly related to the levels of peripheral and bone marrow blast cells and CD34 + cells. Complete postinduction remission was associated with reduced percentages of PMN-MDSCs and Tregs, with the level of PMN-MDCs in this subpopulation approaching that of healthy controls. PMN-MDSCs and Tregs jointly play a critical role in maintaining an immune-suppressive state suitable for B-ALL tumor progression. Thereby, they could be independent predictors of B-ALL progress, and finely targeting both PMN-MDSCs and Tregs may be a promising approach for the treatment of B-ALL.

Impact of clostridiodes difficile infection on acute graft-versus-host disease in allogenic transplant patients.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19027-e19027
Author(s):  
Prasanth Lingamaneni ◽  
Vatsala Katiyar ◽  
Rohit Kumar ◽  
Maha A.T. Elsebaie ◽  
Hashim Mann ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Lymphoblastic Leukemia ◽  
Index Admission ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
Hospitalization Costs ◽  
Acute Graft

e19027 Background: Clostridiodes difficile infection (CDI) is reported to occur up to 9-fold higher in allogenic hematopoietic stem cell transplant (HSCT) recipients compared to the general population of hospitalized patients. This is attributed to disruption of gut microbiome by antibiotics, myeloablative regimens, neutropenia, prolonged hospitalization, and immunosuppressive regimens administered to prevent acute graft-versus-host disease (aGVHD). CDI by disruption of the intestinal microbiome may trigger gastrointestinal aGVHD. Previous studies from HSCT centers have reported conflicting data on the relationship between CDI and subsequent development of aGVHD. Methods: The Nationwide Readmissions Database was queried for admissions of adult allogenic HSCT patients between 2016 and 2018. Those with and without CDI during index admission were compared. Multivariable logistic regression was used to evaluate the primary outcome of risk of aGVHD in the index admission or within 100 days post-engraftment. Results: A total of 13518 allogenic HSCT patients were included in the study. Mean age was 52.4 years. 57.2% of patients were female. The most common underlying diagnoses were acute myeloid leukemia (38%), myelodysplastic syndrome (17%) and acute lymphoblastic leukemia (14%). 11.1% of the index admissions were complicated by CDI. Rates of aGVHD during the index admission or 100 days post-engraftment were similar between CDI and non-CDI groups: 13.8% vs. 12.1%, p=0.19 during index admission and 29.2% vs. 26.1%, p=0.09 during 100 days post-engraftment. Nonetheless, patients with CDI had longer length of hospital stay (34.6 vs 29.8 days, p<0.0001), higher hospitalization costs ($608K vs $506K USD) and greater rate of inpatient mortality (7.3% vs 4.6%, p<0.001). In the multivariate regression analysis, CDI during index admission was not associated with risk of development of aGVHD (Adjusted Odds Ratio 1.14, 95% Confidence Interval 0.87-1.48, p=0.34). Age and unrelated donor HSCT were predictive of risk of aGVHD. Conclusions: CDI during index admission was not predictive of aGVHD during the first 100 days post-allogenic HSCT. HSCT patients are frequency colonized with C.difficile. Diarrhea secondary to CDI may resemble gastrointestinal aGVHD. Therefore, overdiagnosis of CDI in this population is a concern. Antimicrobial stewardship and use of clinical decision support tools have been advocated recently to decrease testing of HSCT patients with C.difficile colonization. Multivariable analysis of risk factors of aGVHD.[Table: see text]

scholarly journals V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites⋆

2002 ◽  
Vol 195 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Rodrig Marculescu ◽  
Trang Le ◽  
Paul Simon ◽  
Ulrich Jaeger ◽  
Bertrand Nadel
Keyword(s):  
T Cell ◽  
Genomic Instability ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Lymphoid Malignancies ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Normal Human ◽  
Hodgkin's Lymphomas ◽  
The Impact

Most lymphoid malignancies are initiated by specific chromosomal translocations between immunoglobulin (Ig)/T cell receptor (TCR) gene segments and cellular proto-oncogenes. In many cases, illegitimate V(D)J recombination has been proposed to be involved in the translocation process, but this has never been functionally established. Using extra-chromosomal recombination assays, we determined the ability of several proto-oncogenes to target V(D)J recombination, and assessed the impact of their recombinogenic potential on translocation rates in vivo. Our data support the involvement of 2 distinct mechanisms: translocations involving LMO2, TAL2, and TAL1 in T cell acute lymphoblastic leukemia (T-ALL), are compatible with illegitimate V(D)J recombination between a TCR locus and a proto-oncogene locus bearing a fortuitous but functional recombination site (type 1); in contrast, translocations involving BCL1 and BCL2 in B cell non-Hodgkin’s lymphomas (B-NHL), are compatible with a process in which only the IgH locus breaks are mediated by V(D)J recombination (type 2). Most importantly, we show that the t(11;14)(p13;q32) translocation involving LMO2 is present at strikingly high frequency in normal human thymus, and that the recombinogenic potential conferred by the LMO2 cryptic site is directly predictive of the in vivo level of translocation at that locus. These findings provide new insights into the regulation forces acting upon genomic instability in B and T cell tumorigenesis.

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