Incidence, Risk Factors and Clinical Outcome Of Leukemia Relapses Due To Loss Of The Mismatched HLA Haplotype After Partially-Incompatible Hematopoietic Stem Cell Transplantation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 918-918
Author(s):  
Lara Crucitti ◽  
Roberto Crocchiolo ◽  
Cristina Toffalori ◽  
Maria Teresa Lupo Stanghellini ◽  
Andrea Assanelli ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Immune Pressure ◽  
Hla Loss

Abstract Introduction Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) represents the best curative option for many patients with high-risk myeloid malignancies, mainly due to its potent immuno-mediated antileukemic effect. Still, post-transplantation relapse remains an unsolved issue. We and others described genomic loss of the mismatched HLA haplotype as a mechanism by which leukemic cells evade donor T cell-mediated immune pressure and cause clinical relapse after partially HLA-incompatible HSCT (Vago et al, N Engl JMed, 2009), but the actual incidence and risk factors of this phenomenon are to date largely unknown. Methods We analyzed retrospectively 224 consecutive partially HLA-mismatched HSCTs performed in our Institute in the last ten years (Unrelated Donor, UD: 60; Mismatched Related Donor, MMRD: 164) in patients affected by myeloid malignancies (Acute Myeloid Leukemia, AML: 173; Myelodisplastic Syndrome, MDS: 27, Myeloproliferative Neoplasms: 17; others: 7). All patients received myeloablative conditioning and infusion of donor T cells, either as part of the graft or as an add-back. Patients’ follow-up included bone marrow genomic HLA typing to identify HLA loss relapses. In selected cases of HLA loss relapse cryopreserved serial serum samples harvested after HSCT were analyzed for the eventual presence of anti HLA Class I or Class II antibodies. Results We documented 77 cases of relapse: 66 after MMRD and 11 after UD HSCT. Out of 77 relapses 21 (27%) were due to genomic loss of the mismatched HLA in leukemic cells. HLA loss occurred in 19 patients with AML, one with MDS and one with myelofibrosis. All the 21 cases of HLA loss occurred after MMRD HSCT (32%), so the analysis for putative risk factors were limited to this subgroup of transplants (n=164), comparing the frequencies of putative risk factors between patients with HLA loss and “classical” relapses (n=21 and 45, respectively). HLA loss relapses occurred significantly later than their classical counterparts (median time to relapse 307 vs 86 days, p<0.0001) in this very high-risk population, suggesting that outgrowth of the mutant variants require a considerable lapse of time. None of the disease-related factors we addressed (amongst which disease subtype, cytogenetics, molecular profile and disease status at HSCT) correlated significantly with eventual HLA loss. Use of an unmanipulated T cell-repleted graft resulted to be a risk factor for HLA loss relapses (Chi2=6.36; p=0.01). Both acute (HR:4.67, CI 95%: 1.53-14.22; p=0.007) and chronic (HR: 1.71; CI 95%: 0.68-4.28; p=0.01) Graft-versus-Host Disease (GvHD) occurred more frequently in patients with HLA loss relapses. Intriguingly, HLA-C*04 was more frequent in the mismatched haplotype of patients with HLA loss as compared to those with classical relapse (Chi2= 8.07; p=0.04), possibly suggesting an higher immunogenicity of the allele, hinted also by a similarly higher frequency in patients who did not relapse (Chi2=2.77; p=0.096). In our series, predicted NK alloreactivity had no apparent impact on eventual HLA loss. In none of the five patients studied to date we could evidence circulating anti-HLA antibodies, suggesting that humoral immunity does not play a major role in this phenomenon. Since lymphocyte infusions from the original donor are expected to be inefficacious to treat HLA loss relapses, whenever fit these patients were candidate to re-transplantation from alternative donors, HLA-mismatched and putatively alloreactive against the relapsed leukemia. Still, outcome was poor, with 5 of 8 re-transplanted patients dying of transplant-related mortality and only one alive in complete remission at a follow-up of 18 months. Conclusions Genomic loss of the mismatched HLA haplotype is an extremely frequent mechanism of leukemia immune evasion and relapse after MMRD HSCT. It appears to be prompted by selective immune pressure mediated by donor-derived T cells, and accordingly occurs more frequently upon T cell-repleted transplants and in the presence of acute and chronic GvHD, clinical hallmarks of T cell alloreactivity. Conversely the role of NK and B cells in HLA loss needs further investigation, but appears to date less pronounced. Given the poor outcome of re-transplantation, mainly due to toxicity, novel diagnostic and therapeutic approaches are needed to anticipate the detection and improve the treatment of these frequent variants of leukemia relapse. Disclosures: Bordignon: MolMed SpA: Employment. Bonini:MolMed SpA: Consultancy.

scholarly journals Sequential CD19- and CD22-CART Cell Therapies for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2126-2126 ◽  
Author(s):  
Shuangyou Liu ◽  
Biping Deng ◽  
Yuehui Lin ◽  
Zhichao Yin ◽  
Jing Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Car T Cells ◽  
Car T

Abstract With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Chimeric antigen receptor (CAR) T cell therapy targeting at CD19 has demonstrated a significant efficacy on refractory/relapsed (r/r) B-ALL, but single-target CART could not maintain a long-term remission. Recently, CD22-CART has also shown an exciting result in r/r B-ALL. Here we sequentially applied CD19- and CD22-specific CART cells to treat relapsed B-ALL post-HSCT and observed the therapeutic effect. From June 30,2017 through May 31,2018, twenty-four B-ALL patients (pts) relapsing after allo-HSCT with both antigens CD19 and CD22 expression on blasts were enrolled, the median age was 24 (2.3-55) years. Seventeen pts had hematologic relapse, 6 with both bone marrow and extramedullary (EM) involvements and 1 with EM disease (EMD) only. Fourteen pts had failed to previous therapies including chemotherapy, donor lymphocyte infusion, interferon and even murinized CD19-CART in other hospitals. Recipient-derived donor T cells were collected for producing CAR-T cells, which were transfected by a lentiviral vector encoding the CAR composed of CD3ζ and 4-1BB. Eighteen pts were initially infused with murinized CD19-CART, then humanized CD22-CART; while 6 pts (5 failed to prior murinized CD19-CART and 1 had bright CD22-expression) were initially infused with humanized CD22-CART, then humanized CD19-CART. The time interval between two infusions was 1.5-6 months based on patients' clinical conditions. The average dose of infused CAR T cells was 1.4×105/kg (0.4-9.2×105/kg) for CD19 and 1.9×105/kg (0.55-6.6×105/kg) for CD22. All patients received fludarabine with or without cyclophosphamide prior to each infusion, some pts accepted additional chemo drugs to reduce the disease burden. Treatment effects were evaluated on day 30 and then monthly after each CART, minimal residual disease (MRD) was detected by flow cytometry (FCM) and quantitative PCR for fusion genes, EMD was examined by PET-CT, CT or MRI. Sixteen patients finished sequential CD19- and CD22-CART therapies. Three cases could not undergo the second round of CART infusion (1 died, 1 gave up and 1 developed extensive chronic graft-versus-host disease (GVHD)). The rest of 5 pts are waiting for the second CART. After first T-cell infusion, 20/24 (83.3%) pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), MRD-negative was 100% in CR or CRi pts, 3 (12.5%) cases with multiple EMD obtained partial remission (PR), and 1 (4.2%) died of severe cytokine release syndrome (CRS) and severe acute hepatic GVHD. Sixteen patients (15 CR and 1 PR) underwent the second CART therapy. Before second infusion, 3/15 pts in CR became MRD+ and others remained MRD-. On day 30 post-infusion, 1 of 3 MRD+ pts turned to MRD-, 1 maintained MRD+ ( BCR/ABL+) and 1 had no response then hematologic relapse later. The PR patient still had not obtained CR and then disease progressed. As of 31 May 2018, at a median follow-up of 6.5 (4-10) months, among 16 pts who received sequential CD-19 and CD-22 CART therapies, 1 had disease progression, 2 presented with hematological relapse and 2 with BCR/ABL+ only, the overall survival (OS) rate was 100% (16/16), disease-free survival (DFS) was 81.3% (13/16) and MRD-free survival was 68.8% (11/16). CRS occurred in 91.7% (22/24) pts in the first round of T-cell infusion, most of them were mild-moderate (grade I-II), merely 2 pts experienced severe CRS (grade III-IV). The second CART only caused grade I or no CRS since the leukemia burden was very low. GVHD induced by CART therapy was a major adverse event in these post-HSCT patients. After the first CART, 7/24 (29.2%) pts experienced GVHD, of them, 4 presented with mild skin GVHD, 2 with severe hepatic GVHD (1 recovered and 1 died), and 1 developed extensive chronic GVHD. No severe GVHD occurred in the second infusion. Our preliminary clinical study showed that for B-ALL patients who relapsed after allo-HSCT, single CD19- or CD22- CART infusion resulted in a high CR rate of 83.3%, sequentially combined CD19- and CD22-CART therapies significantly improved treatment outcome with the rate of OS, DFS and MRD-free survival being 100%, 81.3% and 68.8%, respectively, at a median follow-up of 6.5 months. The effect of CART on multiple EMD was not good and CART induced GVHD needs to be cautious. Disclosures No relevant conflicts of interest to declare.

Risk Factors of Outcomes after Haploidentical Hematopoietic Stem Cell Transplants for Children with High Risk Acute Leukaemia. A Survey on Behalf of the EBMT.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 440-440
Author(s):  
Jaqueline Cornish ◽  
Thomas Klingebiel ◽  
Myriam Labopin ◽  
Phillip J. Darbyshire ◽  
Rachel Hough ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Hematopoietic Stem Cell ◽  
Acute Leukaemia ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Alternative Option ◽  
Advanced Phase

Abstract In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic stem cell transplantation (HSCT) is an alternative option to treat children with high risk or relapsed acute leukaemia. However very few data is available in a large series of children. With the aim to study risk factors of outcomes we have analyzed 196 children (<16 years old) with ALL (n=131) or AML (n=65) transplanted with a T-cell depleted bone marrow (n=18) or peripheral blood related haploidentical HSCT from 1995 to 2004 in Europe. The median age was 8 years and median follow-up 22 months. In the AML group, 13 (20%) children were transplanted in CR1, 22 (34%) in CR2 and 30 (46%) in advanced phase and in ALL group, 28 (21%) in CR1, 74 (56%) in CR2 and 81 (62%) in more advanced phase. The majority of the patients did not receive drugs for GVHD prophylaxis and all received myeloablative conditioning (61% of TBI). Cumulative incidence with competing risk and KM estimates were used to calculate outcomes probabilities. The median days of neutrophil recovery was 14 days (4–72) and 85% of patients had signs of engraftment. Acute GVHD II–IV was observed in 17% of the patients (8% had grade III–IV). Two-years overall LFS, relapse incidence and TRM were 27±4%, 43±3%, 30±3%, respectively. Patients transplanted with AML or ALL had similar outcomes. LFS was 28±6%for AML and 27±4% for ALL. Among the risk factors analysed only the disease status at transplantation was associated with LFS and relapse incidence. Outcomes are listed below according to disease status at transplant. Outcomes at two years CR1 (n=41) CR2 (n=74) Advanced (n=81) p value Transplant related mortality 32+/−8% 26+/−5% 33+/−5% 0.44 Relapse 32+/−8% 40+/−6% 51+/−6% 0.03 Leukaemia free survival 36+/−8% 34+/−6% 16+/−4% <0.0001 In fact, in a multivariate analysis for LFS and relapse only patients transplanted in remission had better LFS and decreased relapse incidence compared with non remission patients (p<0.001 and p=0.006, respectively). No risk factor was found to be associated with TRM. Most frequently, causes of death were relapse (60%) or infections (22%). In conclusion, haploidentical HSCT is an alternative option to treat children with high risk acute leukaemia in the absence of HLA identical donor.

The Graft-vs-Host Hematopoietic Effect Generated after Nonmyeloablative Allogeneic Stem Cell Transplantation (NST) Cures Patients with Severe PNH.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 811-811
Author(s):  
Yoshiyuki Takahashi ◽  
S. Chakrabarti ◽  
R. Srinivasan ◽  
T. Igarashi ◽  
A. Lundqvist ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Cell Transplantation ◽  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Donor T Cells

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder of hematopoietic stem cells characterized by RBC susceptibility to complement-mediated lysis. Infections related to neutropenia, bleeding associated with thrombocytopenia, and thrombosis all contribute to morbidity and mortality. Although allogeneic hematopoietic cell transplantation (HCT) can be curative, the high-risk of treatment-related mortality with myeloablative HCT precludes this approach for most patients with severe disease. We previously reported in vitro and in vivo data showing PNH cells could be killed by allo-reactive donor T-cells recognizing minor histocompatibility antigens expressed on both normal and GPI negative cells. Here we present updated data on a cohort of 11 patients with severe PNH who received a NST at the NHLBI from 5/99 through 6/2004. Eligibility included a diagnosis of PNH associated with one or more of the following :1) Transfusion dependence (n=9) 2) Prior thrombotic episodes (n=4) 3) Recurrent debilitating hemolytic crisis (n=7). Patients received a T-cell replete G-CSF mobilized blood stem cell transplant from an HLA-matched family donor following nonmyeloablative conditioning with cyclophosphamide (120mg/kg) and fludarabine (125mg/m2). Patients with a significant transfusion history had horse ATG (40mg/kg/day x 4) added to the conditioning regimen (n=9). CSA either alone (n=1) or combined with either MMF (n=4) or mini-dose methotrexate (n=6) was used as GVHD prophylaxis. The median % of GPI anchored protein negative neutrophils pre-transplant was 83% (range 13%–99%). Blood samples obtained post-transplant were analyzed by FACS to determine the percentage of persisting GPI negative neutrophils (CD15+/CD66b−/CD16−). Chimerism was also assessed post-transplant in T-cell and myeloid fractions by PCR assay of polymorphic short tandem repeats (STR). Neutrophil recovery occurred at a median 15 days (range 10–19). STR analysis revealed donor engraftment occurred in both myeloid and T-cell lineages in all patients. Self-limiting febrile hemolytic reactions associated with ATG administration (6/9 patients) and grade II-IV acute GVHD (n=5) were the most common complications associated with transplantation. With a median follow-up of 458 days (range 31–1917), all patients survive either in remission (n=8) or with declining GPI negative populations (n=3); GPI negative neutrophils were detected in all patients at engraftment but gradually declined until no longer detectable (<0.1%) in all 8 patients evaluable more than 100 days after transplantation, while 3 with shorter follow-up (days + 37, +51, +78) have persistent albeit rapidly declining PNH populations. The observation that GPI negative neutrophils populations decrease and ultimately disappear when myeloid chimerism transitions from mixed to full donor chimerism is consistent with PNH cells being eradicated through a graft-vs-host hematopoietic effect. None of the 7 patients with more than 1 year follow-up have had reoccurrence of their PNH clone. Conclusion: Alloreactive donor T-cells mediating graft-vs-host hematopoietic effects can immunologically eradicate PNH following NST. NST should be considered a viable and potentially curative option for patients with severe PNH.

Prolonged Remissions with Autologous and Allogeneic Stem Cell Transplantation for Burkitt’s Lymphoma: Long Term Follow-Up at a Single Institution.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1133-1133
Author(s):  
Purvi Gada ◽  
Todd Defor ◽  
Daniel J. Weisdorf ◽  
Jeffrey S. Miller ◽  
Paul J. Orchard ◽  
...  
Keyword(s):  
Risk Factors ◽  
Stem Cell ◽  
High Risk ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Advanced Stage ◽  
Hematopoietic Stem ◽  
High Risk Factors

Abstract Burkitts Lymphoma (BL) is a highly aggressive form of non-Hodgkins lymphoma (NHL) that accounts for 50% of childhood cases of NHL, yet is rare in adults. B symptoms, advanced stage and extranodal disease are risk factors previously associated with poor survival. Hematopoietic stem cell transplantation (HCT) is often used because of either incomplete or short duration of remission with standard therapy yet little published data for HCT and BL exists. We evaluated the comparative safety and efficacy of a cyclophosphamide/total body irradiation-containing myeloablative conditioning regimen followed by either an autologous HCT (autoHCT) or allogeneic related donor HCT (alloHCT) in 38 patients who received transplants between October 1975 and June 2004. Twenty-five patients (median age 16 years [range, 4–65]) underwent an autoHCT; 13 patients (median age 13 [range, 4–62]) received an alloHCT. The median number of conventional chemotherapy regimens prior to transplant was 2 (range 1–4); the median duration of first complete remission (CR) was 0.4 years (range, 0–8.8). The majority of patients were in a complete remission (CR) at transplant (auto HCT - 16 [64%] [40% CR1]), alloHCT - 9 [69%] [23% CR1]). Patient demographics, disease characteristics at diagnosis, at relapse and at transplant were comparable between the two groups except for a greater incidence of high risk factors, including B symptoms, advanced stage at diagnosis, and extranodal (bone marrow and central nervous system) disease in the alloHCT group. The median follow up is 7 years (range 1–12) and 24 years (range 2–27) for the autoHCT and alloHCT groups, respectively. Post-transplant, 71% of auto-HCT and 75% of the alloHCT recipients obtained a CR. The 1-year treatment related mortality (TRM) was comparable in the two groups: 8% and 15% for the autoHCT and alloHCT groups, respectively (p=NS). Ten-year progression free survival (PFS) was 21% (95% CI, 4–38%) and overall survival (OS) 23% (95% CI, 5–41%) after autoHCT compared to 31% (95% CI, 6–66%) and 31% (95% CI, 6–66%) for alloHCT (p=NS). Six patients in autoHCT group and 3 in alloHCT survive disease free between 1 and 27 years; 5 survive beyond 10 years and 3 beyond 15 years from HCT. Donor choice did not significantly alter PFS. Two factors were predictive of superior PFS: fewer chemotherapy regimens prior to transplantation (1 vs ≥ 2) and CR (vs relapsed/persistent disease) at time of transplant. Patients with high risk factors more commonly underwent alloHCT, yet outcomes were comparable to autoHCT, suggesting that a powerful and durable graft versus lymphoma effect exists. These results demonstrate that prolonged remissions can be obtained with either auto or alloHCT, especially for high risk patients in CR. New approaches for patients in relapse are needed to improve these outcomes.

Phase I Clinical Trial of Haplotype Mismatched Myeloablative Stem Cell Transplantation: Higher Doses of Donor Lymphocyte Infusions Depleted of Alloreactive Cells Using ATIR May Improve Outcome without Causing GVHD.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2976-2976
Author(s):  
Denis-Claude Roy ◽  
Sandra Cohen ◽  
Lambert Busque ◽  
Douglas Fish ◽  
Thomas Kiss ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
High Risk ◽  
Stem Cell Transplantation ◽  
Phase I ◽  
Cell Transplantation ◽  
Acute Gvhd

Abstract Infection and disease relapse are the two major complications occurring after haplo-mismatched stem cell transplantation (SCT). Accelerating immune reconstitution would imply broader applicability of SCT by providing a transplant opportunity to the large number of patients who cannot find an HLA-matched related or unrelated donor. We have previously reported that photodynamic therapy (PDT) using TH9402 could selectively deplete donor alloreactive cell populations while preserving lymphocytes for immune responses. We present results of an ongoing Phase I clinical trial of haplo-mismatched allogeneic stem cell transplant (SCT) supplemented with DLIs PDT depleted of host-reactive T cells. Thirteen patients with high-risk hematologic malignancies (7 AML relapsed or refractory, 1 AML in CR3, 1 refractory ALL, 2 MDS, 1 NHL relapsing after autologous SCT, 1 refractory CLL) entered the trial. Eleven pts are evaluable for acute GVHD and reconstitution. Patients (7 M, 4 F) underwent transplantation with donor cells mismatched at 3 HLA Ags: 5 patients; 2Ags: 5 pts, and DR only: 1 pt). Donor mononuclear cells (MNCs) were incubated with recipient MNCs for 4 days, exposed to ATIR™ treatment (TH9402 PDT), stored frozen, and administered on day 33±6 after transplant at 5 graded DLI dose levels: 1×104 to 8×105 CD3+ cells/kg. Anti-host cytotoxic T lymphocyte precursors (CTLp) were depleted from DLIs by approximately 1.5 logs, and flow cytometry showed greater than 90% elimination of activated T cells (CD4+CD25+ and CD8+CD25+) by ATIR. All stem cell grafts underwent in vitro immunomagnetic T cell depletion using CD34+ positive cell selection. Median age at SCT was 56 years (range: 21–60). Eight patients were in partial remission or had progressive disease, and 3 patients were in complete remission at the time of SCT. Conditioning regimen consisted of TBI (1200 cGy), thiotepa (5 mg/kg) and fludarabine (40 mg/m2/day for 5 days) followed by infusion of CD3 depleted HSC grafts. No GVHD prophylaxis was administered. Evaluable patients showed durable hematologic engraftment: median time to >0.5×109 granulocytes/L was 11 days (8–20), and to >20×109 platelets/L without transfusion, 12 days (9–137) and all achieved complete donor chimerism. No patient developed acute GVHD (grade II–IV), while 3 patients developed signs of chronic GVHD. Four of the first 6 pts developed infectious complications in the first 6 months, and all resolved rapidly with appropriate therapy, except for EBV-PTLD in the first patient (1×104 CD3). Five patients died: 1 of relapsed CLL and 4 of infections (all after day+310), and all had received DLI containing 1.3 ×105 CD3+ cells (2 pts) or less. No other patient relapsed. The first 6 pts developed 10 infectious episodes (4 lethal), while none of the 5 pts receiving the highest DLI doses of CD3+ cells/kg developed any infection (median follow-up: 318 days). The overall disease-free-survival and survival are 57% at 1 year (median follow-up: 10.5 mo). Our results indicate that the post-transplant infusion of a ATIR-PDT treated DLI is feasible, does not induce acute GVHD, and suggests a clinical benefit for patients receiving the highest DLI doses to accelerate T cell reconstitution. This PDT strategy represents an appealing alternative for older patients and those at high risk for GVHD.

Metabolic syndrome and risk factors after hematopoietic stem cell transplantation in children and adolescents

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Gizem Guner Ozenen ◽  
Serap Aksoylar ◽  
Damla Goksen ◽  
Salih Gozmen ◽  
Sukran Darcan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Insulin Resistance ◽  
Metabolic Syndrome ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Life Quality ◽  
Control Group ◽  
Hematopoietic Stem

Abstract Objectives The early and late complications after hematopoietic stem cell transplantation (HSCT) determine the patients’ prognosis and life quality. We aim to determine the metabolic syndrome development frequency after HSCT in children to find out the risk factors and compare them with healthy adolescents. Methods Thirty-six children who underwent HSCT at least two years ago were analyzed prospectively and cross-sectionally. Our study included 18 healthy children between the ages of 11 and 17 as a control group. All of the cases were assessed in terms of metabolic syndrome (MS) through the use of Modified WHO Criteria. Results The patients’ median age was 10.6 (5.1–17) years, the median time of follow-up after HCST was 4.1 (2–13.5) years and 70% were male. Two cases were diagnosed with MS (5.6%). When considered in terms of the sub-components of MS, 2 cases (5.6%) were found to have obesity, 17 cases (47%) abnormal glucose tolerance, 11 cases (30.7%) dyslipidemia, and 3 cases (8.6%) hypertension. The MS rate was not different when compared with the 11–17 year-old healthy control group (0 vs. 11%, p=0.48). Myeloablative conditioning regimen (65 vs. 20%) and the increased age at which HSCT was performed were considered to be risk factors in terms of insulin resistance (p=0.025 and 0.002). Conclusions Age and conditioning regimens were found to be the risk factors for insulin resistance development. The long-term follow-up of the cases who had undergone HSCT in childhood in terms of MS and its sub-components is important in order to increase life quality.

P1825ANALYSIS OF LATE RENAL COMPLICATIONS AND RISK FACTORS IN CHILDREN WITH HEMATOPOIETIC STEM CELL TRANSPLANTATION

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Anar Gurbanov ◽  
Bora Gülhan ◽  
Barış Kuşkonmaz ◽  
Fatma Visal Okur ◽  
Duygu Uçkan Çetinkaya ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Renal Complications

Abstract Background and Aims The aim of the study is to investigate the incidence and risk factors of hypertension (HT) and chronic kidney disease (CKD) in patients who had hematopoietic stem cell transplantation (HSCT) during their childhood. Method Patients who had HSCT between January 2010-2019 with a minimum follow-up period of 6 months were included in the study. Data regarding renal complications were collected from the medical records of the patients. Guidelines of European Society of Hypertension (ESH) and American Academy of Pediatrics (APA) were used for the evaluation of hypertension. 24-hr ambulatory blood pressure monitoring (ABPM) was performed in children older than 5 years of age (68 patients). Ambulatory hypertension is diagnosed when systolic and/or diastolic blood pressure (BP) load is higher than 25%. Ambulatory prehypertension is diagnosed when mean systolic and/or diastolic BP is less than 95th percentile with systolic and/or diastolic BP load higher than 25%. Results A total of 72 patients (41 males and 31 females) were included in the study. The mean age of the patients at last visit was 10.8±4 years. ABPM revealed ambulatory HT in 6 patients (8.8%) and ambulatory prehypertension in 12 patients (17.6%). Office BP revealed HT in 3 patients (4.2%) and increased BP in four patients (5.6%) according to APA guideline (2017). In cohort, 12 patients with normal office BP (according to APA guideline) had ambulatory prehypertension or hypertension with ABPM. Office BP revealed HT in 1 patient (1.4%) and high-normal BP in 3 patients (4.2%) according to ESH guideline. In cohort, 15 patients with normal office BP (according to ESH guideline) had ambulatory prehypertension or hypertension with ABPM (Table 1). After a mean follow-up period of 4.4±2.5 years, CKD developed in 8 patients (11.1%). Patients with chronic graft-versus-host disease, with HLA-mismatched HSCT and/or transplantation of peripheric or cord blood hematopoietic stem cells had increased risk of CKD (p=0.041, p=0.033 and p=0.002, respectively). Conclusion Patients with HSCT should be regularly followed for the development of HT and ABPM should be used on regular basis. Patients with risk factors should be closely monitored for the development of CKD.

scholarly journals B Cell Maturation Antigen-Specific CAR T Cells for Relapsed or Refractory Multiple Myeloma: A Meta-Analysis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3113-3113 ◽  
Author(s):  
Nico Gagelmann ◽  
Francis Ayuketang Ayuk ◽  
Djordje Atanackovic ◽  
Nicolaus Kroeger
Keyword(s):  
T Cells ◽  
T Cell ◽  
High Risk ◽  
Research Funding ◽  
Response Rates ◽  
Overall Response ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Background Cellular immunotherapies represent an enormously promising strategy for relapsed/refractory multiple myeloma (RRMM). Chimeric antigen receptor (CAR) T cells targeting B cell maturation antigen (BCMA) have shown impressive results in early-phase clinical studies. Here, we summarize the current body of evidence on the role of anti-BCMA CAR T cell therapy for RRMM. Methods We performed a systematic literature review to identify all publicly available prospective studies. We searched Medline, Cochrane trials registry, and www.clinicaltrials.gov. To include the most recent evidence, meeting abstracts from international hematology congresses were added. A conventional meta-analysis was conducted using meta and metafor packages in R statistical software. Pooled event rates and 95% confidence intervals (CIs) were calculated using the inverse variance method within a random-effects framework. Main efficacy outcomes were overall response, complete response (CR), and minimal residual disease (MRD). Furthermore, relapse rates, progression-free survival, and overall survival were evaluated. In terms of safety, outcomes were cytokine release syndrome (CRS), neurotoxicity, and hematologic toxic effects. Results Fifteen studies comprising a total of 285 patients with heavily pretreated RRMM were included in quantitative analyses. Patients received a median of seven prior treatment lines (such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, stem cell transplantation) which included autologous stem cell transplantation in 90% of patients. The median age of patients was 59 years and median follow-up duration ranged from 1.1 to 11.3 months. Most studies used 4-1BB (or CD137), a member of the TNF receptor superfamily, as an activation-induced T-cell costimulatory molecule. Most studies used fludarabine and cyclophosphamide for lymphodepletion while one study used busulfan and cyclophosphamide and one study used cyclophosphamide only. Most studies used the former Lee criteria for CRS grading. Anti-BCMA CAR T cells resulted in a pooled overall response of 82% (95% CI, 74-88%). The pooled proportion of CR in all evaluable patients was 36% (95% CI, 24-50%). Within responders, the pooled proportion of MRD negativity was 77% (95% CI, 67-85%). Higher dose levels of infused CAR+ cells were associated with higher overall response rates resulting in a pooled proportion of 88% (95% CI, 78-94%). In addition, peak CAR T cell expansion appeared to be associated with responses.The presence of high-risk cytogenetics appeared to be associated with lower overall response rates resulting in a pooled proportion of 68% (95% CI, 47-83%). The presence of extramedullary disease at time of infusion did not influence outcome and was associated with similar response rates compared with RRMM patients who did not have extramedullary disease, resulting in a pooled proportion of 78% (95% CI, 47-93%). The pooled relapse rate of all responders was 45% (95% CI, 27-64%) and the median progression-free survival was 10 months. In terms of overall survival, pooled survival rates were 84% (95% CI, 60-95%) at last follow-up (median, 11 months). In terms of safety, the pooled proportion of CRS of any grade was 69% (95% CI, 51-83%). Notably, the pooled proportions of CRS grades 3-4 and neurotoxicity were 15% (95% CI, 10-23%) and 18% (95% CI, 10-31%). Peak CAR T cell expansion appeared to be more likely in the setting of more severe CRS in three studies. Most hematologic toxic effects of grade 3 or higher were neutropenia (85%), thrombocytopenia (70%), and leukopenia (60%). Conclusion Anti-BCMA CAR T cells showed high response rates, even in high-risk features such as high-risk cytogenetics and extramedullary disease at time of CAR T cell infusion. Toxicity was manageable across all early-phase studies. However, almost half of the patients who achieved a response eventually relapsed. Larger studies with longer follow-up evaluating the association of response and survival are needed. Disclosures Ayuk: Novartis: Honoraria, Other: Advisory Board, Research Funding. Kroeger:Medac: Honoraria; Sanofi-Aventis: Honoraria; Neovii: Honoraria, Research Funding; Riemser: Research Funding; JAZZ: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; DKMS: Research Funding.

scholarly journals CD34+ Hematopoietic Stem Cells Exert Accessory Function in Lipopolysaccharide-induced  T Cell Stimulation and CD80 Expression on Monocytes

1999 ◽  
Vol 189 (4) ◽  
pp. 693-700 ◽  
Author(s):  
Taila Mattern ◽  
Gundolf Girroleit ◽  
Hans-Dieter Flad ◽  
Ernst T. Rietschel ◽  
Artur J. Ulmer
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cells ◽  
Cell Stimulation ◽  
Hematopoietic Stem ◽  
Accessory Function ◽  
T Cell Stimulation ◽  
Blood Stem Cells

CD34+ hematopoietic stem cells, which circulate in peripheral blood with very low frequency, exert essential accessory function during lipopolysaccharide (LPS)-induced human T lymphocyte activation, resulting in interferon γ production and proliferation. In contrast, stimulation of T cells by “conventional” recall antigens is not controlled by blood stem cells. These conclusions are based on the observation that depletion of CD34+ blood stem cells results in a loss of LPS-induced T cell stimulation as well as reduced expression of CD80 antigen on monocytes. The addition of CD34-enriched blood stem cells resulted in a recovery of reactivity of T cells and monocytes to LPS. Blood stem cells could be replaced by the hematopoietic stem cell line KG-1a. These findings may be of relevance for high risk patients treated with stem cells or stem cell recruiting compounds and for patients suffering from endotoxin-mediated diseases.

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