Immune control of cytomegalovirus reactivation in stem cell transplantation

Blood ◽  
2021 ◽  
Author(s):  
Mariapia A Degli-Esposti ◽  
Geoffrey R Hill
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Antiviral Immunity ◽  
Antiviral Drugs ◽  
Viral Reactivation ◽  
High Dose ◽  
Cytomegalovirus Reactivation ◽  
The Impact

The reactivation of viruses from latency after allogeneic stem cell transplantation (SCT) continues to represent a major clinical challenge requiring sophisticated monitoring strategies in the context of prophylactic and/or pre-emptive antiviral drugs that are associated with significant expense, toxicity, and rates of failure. Accumulating evidence has demonstrated the association of polyfunctional virus-specific T-cells with protection from viral reactivation, affirmed by the ability of adoptively transferred virus-specific T-cells to prevent and treat reactivation and disease. The roles of innate cells (NK cells) in early viral surveillance, and dendritic cells in priming of T-cells have also been delineated. Most recently, a role for strain-specific humoral responses in preventing early cytomegalovirus (CMV) reactivation has been demonstrated in preclinical models. Despite these advances, many unknowns remain: what are the critical innate and adaptive responses over time, is the origin (e.g. recipient versus donor) and localization (e.g. in parenchymal tissue versus lymphoid organs) of these responses important, how does GVHD and the prevention/treatment thereof (e.g. high dose steroids) impact the functionality and relevance of a particular immune axis, do the immune parameters that control latency, reactivation and dissemination differ, and what is the impact of new antiviral drugs on the development of enduring antiviral immunity. Thus, whilst antiviral drugs have provided major improvements over the last two decades, understanding the immunological paradigms underpinning protective antiviral immunity after SCT offers the potential to generate non-toxic immune-based therapeutic approaches for lasting protection from viral reactivation.

scholarly journals Altered T-Lymphocyte Biology Following High-Dose Melphalan and Autologous Stem Cell Transplantation With Implications for Adoptive T-Cell Therapy

2020 ◽  
Vol 10 ◽  
Author(s):  
Thomas Mika ◽  
Swetlana Ladigan-Badura ◽  
Abdelouahid Maghnouj ◽  
Bakr Mustafa ◽  
Susanne Klein-Scory ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Cell Phenotype ◽  
High Dose ◽  
Car T ◽  
The Impact

In relapsed and refractory multiple myeloma (MM), adoptive cell therapies (ACT) including CAR-T-cells are under clinical investigation. However, relapse due to T-cell exhaustion or limited persistence is an obstacle. Before ACT are considered in MM, high-dose (HD) melphalan followed by autologous stem-cell transplantation (autoSCT) has been administered in most clinical situations. Yet, the impact of HD chemotherapy on T-cells in MM with respect to ACT is unclear. In this study, T-lymphocytes’ phenotypes, expansion properties, lentiviral transduction efficacy, and gene expression were examined with special respect to patients following HD melphalan. Significant impairment of T-cells’ expansion and transduction rates could be demonstrated. Expansion was diminished due to inherent disadvantages of the predominant T-cell phenotype but restored over time. The quantitative fraction of CD27−/CD28− T-cells before expansion was predictive of T-cell yield. Following autoSCT, the transduction efficacy was reduced by disturbed lentiviral genome integration. Moreover, an unfavorable T-cell phenotype after expansion was demonstrated. In initial analyses of CD107a degranulation impaired T-cell cytotoxicity was detected in one patient following melphalan and autoSCT. The findings of our study have potential implications regarding the time point of leukapheresis for CAR-T-cell manufacturing. Our results point to a preferred interval of more than 3 months until patients should undergo cell separation for CAR-T therapy in the specific situation post-HD melphalan/autoSCT. Monitoring of CD27−/CD28− T-cells, has the potential to influence clinical decision making before apheresis in MM.

Fatal ongoing human cytomegalovirus reactivation during high-dose melphalan and autologous stem cell transplantation

2009 ◽  
Vol 81 (5) ◽  
pp. 857-860 ◽  
Author(s):  
Daniele Focosi ◽  
Elisabetta Sordi ◽  
Federico Papineschi ◽  
Edoardo Benedetti ◽  
Sara Galimberti ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Human Cytomegalovirus ◽  
High Dose ◽  
Cytomegalovirus Reactivation ◽  
High Dose Melphalan

Impact of Early Blast Clearance Following Induction Chemotherapy On the Outcome of Patients with Acute Myelod Leukemia Undergoing Allogeneic Stem Cell Transplantation in First Complete Remission

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1998-1998
Author(s):  
Philipp G. Hemmati ◽  
Theis H. Terwey ◽  
Philipp le Coutre ◽  
Gero Massenkeil ◽  
Bernd Dörken ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Induction Chemotherapy ◽  
Allogeneic Stem Cell Transplantation ◽  
High Dose ◽  
Significant Difference ◽  
The Impact ◽  
First Complete Remission

Abstract Abstract 1998 Purpose: In patients with newly diagnosed acute myeloid leukemia (AML) rapid achievement of remission by induction chemotherapy is an important predictor for long-term disease control. In turn, patients who fail to attain early blast clearance after the first chemotherapy course have an inferior outcome. Here, we investigated the impact of early blast clearance on the overall outcome of patients with AML undergoing allogeneic stem cell transplantation (alloSCT) in first complete remission (CR1) as consolidation therapy. Patients and Methods: 169 (90 female, 79 male) patients with AML who underwent alloSCT in CR1 at our center between 1994 and 2011 were included. Data were prospectively recorded in our transplant data base and retrospectively analyzed as of December 31st, 2011. In detail, 107 patients (64%) had de novo AML, 31 patients (18%) had AML evolving from myelodysplastic syndrome (MDS), and 31 patients (18%) had therapy-related AML. According to the criteria of the SWOG/ECOG, cytogenetic risk was either favorable (6 patients, 4%), intermediate (104 patients, 62%), or poor (47 patients, 27%). Prior to alloSCT all patients were treated in a German multicenter AML trial and received at least two courses of induction chemotherapy, i.e. either standard “7+3” (daunorubicin 60 mg/m2, day 3–5 and Ara-C 100 mg/m2, day 1–7) or a “high-dose Ara-C” containing regimen (Ara-C 1–3 g/m2). In 98 patients (58%) induction chemotherapy resulted in blast clearance after the first course, whereas 71 patients (42%) failed to achieve early remission, but entered remission after 1 or 2 subsequent courses. Median age at transplantation was 47 years (range: 17–69 years). In 146 patients (86%) alloSCT was performed using peripheral blood stem cells (PBSCs), whereas 23 patients (14%) received a bone marrow (BM) graft. Conditioning consisted of standard myeloablative conditioning (MAC: 6 × 2 Gy TBI and 2 × 60 mg/m2 cyclophosphamide) in 81 patients (48%), whereas 86 patients (52%) received reduced intensity conditioning (RIC: busulfan 2 × 4 mg/kg, fludarabine 6 × 30 mg/m2 and ATG 4 × 10 mg/kg). A matched related donor was available in 82 patients (49%), whereas 68 patients (40%) or 19 patients (11%) were transplanted from a matched-unrelated or mismatched unrelated donor. Results: After a median follow-up of 45 months (range: 3–196 months) for the surviving patients, 91 patients (54%) are alive and in continuous remission. Causes of death were relapse in 38 patients (22%) or NRM in 33 patients (19%). At 1, 3 or 5 years projected overall survival (OS) was 72±6%, 58±6%, or 54±8% for all patients. Probability of relapse or non-relapse mortality (NRM) at 1, 3, and 5 years was 20±10% (20±11%), 31±12% (20±11%), and 34±12% (20±11%). Although there was no statistically significant difference in OS at 3 and 5 years between patients who achieved early blast clearance as compared to patients who failed to do so (p=0.09), disease-free survival (DFS) and probability of relapse differed significantly between the two groups at 3 years (77±8% vs 55±14%) or 5 years (75%±9% vs 52%±14%) following alloSCT (p=0.02). There was no significant difference in NRM between the two subgroups. Likewise, there was no statistically significant difference between patients conditioned with either MAC or RIC. In multivariate analysis cytogenetic risk group and remission status were identified as independent prognostic factors for DFS and probability of relapse. Conclusions: These results suggest that in patients with AML undergoing alloSCT in CR1 early blast clearance, i.e. following the first course of induction chemotherapy, predicts a very favorable outcome. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Stem Cell Transplantation in Multiple Myeloma

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 311-316 ◽  
Author(s):  
Michel Attal ◽  
Philippe Moreau ◽  
Herve Avet-Loiseau ◽  
Jean-Luc Harousseau
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Dose Intensity ◽  
Hematologic Malignancies ◽  
Common Disease ◽  
High Dose ◽  
The Impact ◽  
Proof Of Efficacy

AbstractMultiple myeloma (MM) is one of the key hematologic malignancies in which the impact of dose intensity has been demonstrated. Consequently, in 2005, MM was the most common disease for which autologous stem cell transplantation (ASCT) was indicated both in Europe and in the U.S. However, ASCT is not curative, and most patients relapse within a median of 3 years. Novel agents such as thalidomide (Thalidomid), bortezomib (Velcade), or lenalidomide (Revlimid) have been introduced to improve high-dose therapy, and promising results have been reported. Conversely, results from myeloablative allogeneic stem cell transplantation remain disappointing due to high transplantation-related mortality, justifying the exploration of strategies such as reduced-intensity conditioning, which have been shown to be feasible but for which proof of efficacy requires continued study.

scholarly journals Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma

JCI Insight ◽  
2019 ◽  
Vol 4 (4) ◽  
Author(s):  
Alfred L. Garfall ◽  
Edward A. Stadtmauer ◽  
Wei-Ting Hwang ◽  
Simon F. Lacey ◽  
Jan Joseph Melenhorst ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
High Dose ◽  
Car T Cells ◽  
Car T ◽  
High Dose Melphalan

Positron emission tomography using 18-fluorodeoxyglucose in pre- and post-transplantation in lymphoma patients treated with autologous stem cell transplantation: Impact

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8060-8060
Author(s):  
X. Cuenca ◽  
N. Mounier ◽  
G. L. Deville ◽  
P. Brice ◽  
J. Larghero ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Emission Tomography ◽  
Clinical Staging ◽  
High Dose ◽  
Positron Emission ◽  
The Impact

8060 Background: The pre-transplant evaluation of lymphoma with Positron Emission Tomography (PET) scanning using 18- FluoroDeoxyGlucose may ease a decision making. The impact on patient outcome of post-transplant assessment is unknown. Methods: Between July 04 and December 05, patients (pts) who achieved tumor response and received high-dose chemotherapy plus autologous stem cell transplantation (ASCT) were explored with PET, prior and 100 days after ASCT, without knowledge of conventional imaging nor clinical history. PET results (negative or positive) were related to event-free survival (EFS) and overall survival (OS). Results: 60 pts were included. 50 had Non-Hodgkin Lymphoma (26 aggressive) and 10 Hodgkins Lymphoma. Median age was 52 [19-68]. 22 pts received front-line ASCT mainly after ACVBP (n=14) or CHOP. Platinum-based salvage chemotherapy was the most used (n=38), and most of the pts received rituximab (n=40). Prior ASCT,by clinical staging, there were 31 complete remission (CR), 23 uncertain CR and 6 partial remission. Conditioning regimen was BEAM in 39 pts; Zevalin BEAM in 11, Total Body Irradiation in 10. 75% were pre-ASCT-PET negative and 80% post-ASCT-PET negative. 6 pts (10%) converted from pre-ASCT-PET positive to post-ASCT-PET negative and 2 pts from negative to post-ASCT-PET positive. Median follow-up was 1.25 years [0.5–2]. 12 pts died (OS 80%) and 19 relapsed (EFS 68%). OS and EFS was better in pre-ASCT-PET-negative pts than in PET-positive (92% vs 53% (p=0.0009), 77% vs 35%, (p=0.0002) respectively). OS was estimated to 90% in post-ASCT-PET-negative pts vs 50% in PET-positive (p<0.0001), EFS was 79% vs 25%, respectively (p<0.0001). In multivariate analysis,including analysis by histology subtypes, the only adverse prognostic factor was PET positive either pre-ASCT (Relative Risk(RR)=4) or post-ASCT (RR=12). Conclusions: A positive PET after induction chemotherapy indicates a high risk of ASCT failure which is increased by a positive PET after ASCT. In pre-ASCT-PET-positive pts, more experimental approaches are required. In pre-ASCT-PET-negative patients, post-ASCT-PET assessment may be omitted. No significant financial relationships to disclose.

Pretransplant hemoglobin and serum creatinine levels correlate with progression free survival in myeloma patients undergoing autologous stem cell transplantation.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19532-e19532
Author(s):  
Taner Demirer ◽  
Guldane Cengiz Seval ◽  
Selami Kocak Toprak ◽  
Sinem Civriz Bozdag ◽  
Meltem Kurt Yuksel ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Serum Creatinine ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Progression Free Survival ◽  
High Dose ◽  
Free Survival ◽  
The Impact

e19532 Background: High dose melphalan and autologous stem cell transplantation (ASCT) significantly prolong survival for patients with multiple myeloma (MM). The purpose of this study is to assess the effects of hemoglobin (Hgb) and serum creatinine (Crea) values at the time of transplantation on the overall outcome of patients with multiple myeloma treated at our transplant center. Material & Methods: This analysis included 247 consecutive patients who underwent ASCT for MM between 2010-2016. Hemoglobin was grouped as low or high relative to their sample median. Patients were also stratified according to serum Crea value at the time of transplantation ( < 2 or ³2 mg/dl). Results: The median age was 57 (29-75) years and most patients were male (n = 151, 61.1%), IgG subtype (n = 124, 50.2%), and ISS stage 3 (n = 122, 49.4%). The interval from the time of diagnosis to ASCT was median 7 months and median follow-up from ASCT was 49 months (range, 3-198 months). The most commonly induction regimens included VAD (vincristine, doxorubicin and dexamethasone) and VCD (bortezomib, cyclophosphamide, dexamethasone), respectively. Since maintenance was not an approved treatment in myeloma most patients did not receive any. For the entire cohort, the median Hgb and Crea were 11.5 g/dL and 0.9 mg/dL respectively. No difference in progression free survival (PFS) was observed between a lower and higher Hgb (82 vs. 81 months, p = 0.96). However, the median PFS was significantly longer in patients with a lower Crea compared to those with a higher Crea (83 vs. 48 months, p = 0.01). Patients with both a lower hemoglobin and higher Crea experienced shorter PFS compared to those with a higher hemoglobin and lower Crea (45 vs. 82 months, p < 0.001). We failed to demonstrate the impact of creatinin levels on time to neutrophil and platelet engraftment. There were no differences in OS according to lower vs. higher Hgb (58 vs. 52 months; p = 0.29, respectively) but in higher crea cohort worse OS was observed (41 months vs. 57 months; p = 0.02, respectively). Conclusions: We demonstrate that hemoglobin and creatinine represent important determinants of clinical outcomes after ASCT. A lower hemoglobin and higher creatinine, individually and when combined, were associated with shorter PFS. Therefore, further studies of larger randomized cohorts are required to clarify the impact of pre-transplant Hgb and Crea levels on ASCT outcomes.

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