Donor Lymphocyte Infusion Is an Effective Management of Increasing Mixed Chimerism, and High Risk Disease with Minimal Side Effects.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3672-3672
Author(s):  
Geothy Kochethu ◽  
Leena Karnik ◽  
Ginny Turner ◽  
Mike Griffiths ◽  
Mark Velangi ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Residual Disease ◽  
Donor Lymphocyte Infusion ◽  
Mixed Chimerism ◽  
Malignant Diseases ◽  
Post Transplant ◽  
Cell Dose ◽  
The Impact ◽  
Cmv Reactivation

Abstract The increasing use of donor lymphocyte infusion (DLI) in both non-malignant and malignant diseases has demonstrated its potential use in cases with either increasing mixed chimerism (i-MC) or minimal residual disease (MRD) post transplant. Little data is available on the efficacy of this therapy in children. We performed a retrospective analysis of 31 consecutive patients who received DLI at Birmingham Children’s Hospital from 1998–2006. 18 patients (58%) had malignant illnesses (5 ALL, 6 AML, 1CML, 4JMML, 1 Hodgkin’s disease, 1 MDS). 13 patients (42%) had non-malignant conditions (3 aplastic anaemia, 1 glycogen storage disorder, 2 FHLH, 2 osteopetrosis, 5 thalassemia major). There were 19 haploidentical (61%) (6 fully matched), 8 unrelated (26%) and 4 sibling (13%) transplants. 15 (48%) were female and 16 (52%) were male. Mean age was 5 years (range 2 months to 16 years). Radiotherapy and non-radiotherapy based myeloablative conditioning regimes were used. 27/31 (87%) grafts were T cell depleted by CD34 selection and were given a T-cell dose between 1×104–105/kg CD3 cells. The mean CD34 cell dose for the haploidentical transplants was 14× 106/kg (range3.63–36.6× 106/kg) and for the allografts was 5.75 ×106/kg (range 1–15 ×106/kg). 19 (61%) patients were at risk of CMV reactivation. The main indications for DLI in the malignant cohort werepost-transplant or extramedullary relapse andidentification of locally-determined pre-transplant high risk features.17/31 (55%) patients satisfied these criteria, of which 11(65%) are alive and 5 (35%) dead. After prompt withdrawal of cyclosporin, upto seven escalating doses of DLI were given to this group till they show signs of GVHD. One to 2 doses of fludarabine 25mg/m2 were given to 7 patients for further immunosuppression, irrespective of their conditioning, prior to their second or subsequent DLI. 14/31 (45%) patients with i-MC, were treated with graded increments of DLI ranging from 5× ×103/kg–1×108/kg, delivered in 1–7 infusions, majority receiving 2 or 3. 10/14 (71%) had complete donor chimerism post DLI. Though 4 (29%) patients failed to show improvement in their chimerism, 2/4 had non malignant diseases and have stable mixed chimerism and 2/4 who had JMML had full autologous reconstitution with normal haemopoiesis. In the whole cohort, 87% had Grade 1–2 skin GVHD or no GVHD. Only 4/31 (13%) patients had severe morbidity due to Grade 3–4 GVHD and all responded to conventional treatment. There were no cases with CMV reactivation. One patient had graft aplasia from which he recovered after temporary cessation of DLI. There were 7 deaths. 6 patients died from relapsed disease. 1 patient given DLI for i-MC, died of streptococcal pneumonia due to non-compliance with penicillin V. Our experience in this age group demonstrates two main pointsDLI can be delivered safely in the setting of high risk malignant disease post transplant but further work is needed to define efficacy.The correction of i-MC with DLI can be achieved with minimal morbidity and mortality. In addition, the use of fludarabine enhances the impact of DLI but carries a theoretical risk of precipitating severe GVHD. No child died as a result of GVHD and to date 24/31 (77%) of the group survive disease free.

Low Pre-DLI Lymphocytes Counts Are Predictive of Good Disease Responses in Patients with Mixed Chimerism Following Campath-Containing Reduced Intensity Transplants.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 261-261
Author(s):  
Bronwen E. Shaw ◽  
Jenny L. Byrne ◽  
Emma Das-Gupta ◽  
Ian Carter ◽  
Nigel H. Russell
Keyword(s):  
Lymphocyte Count ◽  
Residual Disease ◽  
Suppressor Cells ◽  
Mixed Chimerism ◽  
Post Transplant ◽  
Donor Chimerism ◽  
Significant Difference ◽  
Group B ◽  
The Impact ◽  
Reduced Intensity

Abstract Following reduced intensity conditioned (RIC) transplants, donor leukocyte infusions (DLI) are frequently used either to convert mixed chimerism (MC) to full donor chimerism (FDC) or for residual or relapsed disease. Unfortunately, DLI are not universally successful and few factors are known (e. g disease type and level of pre-DLI chimerism) which predict for good responses. We analysed the impact of the chimerism pattern in 125 recipients of (CAMPATH containing) RIC transplants for malignant diseases. Of these, 68 (55%) had FDC (group A), 49 (39%) developed MC and 8 (6%) lost DC and had autologous reconstitution (group D). The patients who developed MC could be further subdivided into those with persisting MC post transplant (27, 55%; group B: non-responders) and MC post transplant with subsequently development of FDC (22, 45%; group C: responders). These two groups were analysed further. The median patient age was 55 (range: 19–71). The donors were siblings (22) or unrelated (27). The diseases were as follows: AML/MDS 14, CML 4, Myeloma, 4, lymphoma/CLL 26, MF 1. Stem cell source was PBSC (38) and bone marrow (11). Conditioning consisted of fludarabine, melphalan and campath (fmc) in 24 patients; fludarabine, busulphan and campath (fbc) in 5; BEAM, campath +/− fludarabine in 18 and FLAG in 2. There were no significant differences in any of these features between groups B and C. 25/49 patients received DLI. This was for disease relapse in10 patients, residual disease in 6 and MC alone in 8 (Unknown in 1). A complete disease response (CDR) was seen in 9/14 (64%) evaluable cases. There was a highly significant difference in CDR between the two groups (group B: 0/4, group C: 9/10, p=0.005). The reason for the difference in response rate was investigated. Median time to DLI was 196 days (range: 57–2123), not significantly different between the groups (p=0.561). The indication for and total number of DLI, the underlying disease and the degree of pre-DLI donor chimerism were not significantly different. In addition there was no significant difference in the incidence of post DLI GvHD (p=0.137), although this was 10/13, 77% in those who responded and 2/5, 40% in those who did not. Conversely, there was a significant difference in the pre-DLI lymphocyte counts (p=0.036). The median count was 2.24 × 109/l. In group B 3/11 (27%) were below this while 10/14 (71%) in group C were below this. The pre-DLI lymphocyte count was not significantly correlated with the time post transplant at which DLI was given, the type of donor, the indication for DLI or the disease, conditioning or post transplant immunosuppression regimen. The predicted overall survival at 2 years was significantly better in group C than in group B (95% versus 57%, p=0.002). This was largely due to the higher relapse risk in group B (77%) compared to group C (32%) (p=0.043). In conclusion, in patients with MC, the development of FDC was significantly associated with a superior OS. In those receiving DLI, the factor most significantly predictive for a ‘responsive’ (C) versus ‘non-responsive’ (B) pattern was the presence of a low pre-DLI lymphocyte count, suggesting that a lack of ‘space’ for expansion or increased suppressor cells in the lymphoid compartment mediate DLI resistance. We postulate that DLI ‘non-responders’ (those with higher lymphocyte counts) may be converted to ‘responders’ by the addition of pre-DLI lymphoreduction, thus reducing relapse and improving outcome.

scholarly journals Improved Relapse Rate, T Cell Recovery and Engraftment in High Risk Hematological Malignancies with Enhanced Lympho-Depletion Prior to T-Cell Replete Peripheral Blood Haploidentical (HID) Hematopoietic Stem Cell Transplantation (HCT)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2117-2117
Author(s):  
Yasser Khaled ◽  
Joshua Boss ◽  
Joel Gradowski ◽  
Robert Bradley ◽  
Jason C. Chandler
Keyword(s):  
T Cell ◽  
High Risk ◽  
Relapse Rate ◽  
Peripheral Blood ◽  
First Year ◽  
Early Recovery ◽  
Activated T Cells ◽  
Post Transplant ◽  
Relapsed Disease ◽  
The Impact

Abstract Multiple studies have examined the impact of the intensity of conditioning regimens on myeloablation and the risk of relapse after HCT. In contrast to adoptive cell transfer and Chimeric-Antigen Receptor (CAR) T-Cell therapy, there is limited, if any knowledge that has addressed the impact of intensity of lymphodepletion on relapse after HID HCT. We hypothesize that enhanced lympho-depletion would create an enhanced host immunogenic microenvironment that would foster potent donor T cell expansion and alloreactivity after T-cell replete peripheral blood HID HCT.1,2 We utilized an intensified lympho-depleting conditioning regimen with Fludarabine (Flu) 150 mg/m2, Melphalan (Mel) 140 mg/m2 and Cyclophosphamide (CY) 29 mg/m2 prior to T-cell replete peripheral blood HID HCT to treat 15 consecutive patients with high risk hematological malignancies between July 2015 and June 2017. The intensity of lymphodepletion was confirmed in 12 evaluable patients at day (0) by complete absence of lymphocytes in peripheral smear. In contrast, myeloid elements were detected in 7/12 patients suggesting more intense lympho-depletion than myeloablation. All Patients received graft versus host disease prophylaxis with Tacrolimus/Mycophenolate starting at day +5 and Cyclophosphamide 50 mg/Kg on day +3 & +4. Mycophenolate continued for 30 days and Tacrolimus stopped at Day 180 without taper. Patient characteristics are shown in Table 1. More than half the patients (n=8 Pts) had relapsed/refractory or progressive disease at time of transplant. The median duration of follow up for survivors is 29 months (range 13-37). Chimerism studies were performed at day +30 and +100 post-transplant by variable number tandem repeat PCR analysis of peripheral blood (PB) and bone marrow (BM). All patients engrafted and achieved 100% Chimerism in BM and PB ( CD3, CD33 & CD56) by day 100 except for 1 patient who died at day +25 prior to engraftment. Median time to neutrophil engraftment was 21 days (range 12-57). All patients with refractory/relapsed disease achieved complete remission post-transplant except for 1 patient who died from transplant complications prior to engraftment. The day 100, 1 year & 2 year overall survival was 93%, 73% & 66% respectively. We observed very low cumulative incidence of relapse of 7% at day 100, 1 and 2 years post-HCT (only 1/15 patients). Treatment related mortality (TRM) was 6%, 20% and 27% at day 100, 1 and 2 years respectively (4/15 patients). Severe Cytokine Release Syndrome (CRS), grade 4 by Lee Criteria occurred in 4 patients, all of them have died at day 25, 258, 288 and 540 post HCT. Three of the four patients with severe CRS had refractory relapsed disease at time of HCT. Grade II-IV acute GVHD developed in 4/15 patients (27%), 2 of whom had grade III-IV by day +180. Chronic extensive GVHD developed in 7 patients (46%), which required definitive therapy (Prednisone/Rituximab/Extracorporeal Photopheresis). At 2 years post HCT, only 1/7 patients remain with extensive chronic GVHD requiring active treatment, 3 patients have quiescent disease and 3 patients have died. Post -transplant immune reconstitution panels were obtained at day 60, 120, 180 and 1 year in 14, 13, 13 and 10 evaluable patients respectively as shown in Fig 1. We observed early recovery in all T-cell subsets at day 60 with activated T cells (CD3+, HLA-Dr+) being most pronounced. While the early proliferation in activated T cells declined through the first-year post transplant, NK cells and CD4 maintained their early recovery through the first year. There was initial decline in the number of B cells at day 120 which gradually recovered by 1 year. Conclusion: Enhanced lymphodepletion prior to peripheral blood HID HCT may enhance early T cell proliferation alloreactivity and immune reconstitution. There was low relapse rate at the expense of high TRM in patients who developed grade IV CRS. Future strategies directed at decreasing disease burden prior to lympho-depletion and improved management of severe CRS in high risk patients are needed to harness the benefits of the observed low relapse rate. 1. Beavis et al, Reprogramming the tumor microenvironment to enhance adoptive cellular therapy. Semin Immunol. 2016 Feb;28(1):64-72. 2. Lu X, Ding ZC, Cao Y, Liu C, Habtetsion T, Yu M, Lemos H, Mellor AL, et al. Alkylating agent melphalan augments the efficacy of adoptive immunotherapy using tumor-specific CD4+ T cells.J Immunol. 2015 Feb 15;194(4):2011-21. Disclosures No relevant conflicts of interest to declare.

Venous Thromboembolism in Children with Acute Lymphoblastic Leukemia in Northern Europe

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3652-3652
Author(s):  
Nadine Gretenkort Andersson ◽  
Susanna Ranta ◽  
Tony Frisk ◽  
Maria Winther Gunnes ◽  
Jon Helgestad ◽  
...  
Keyword(s):  
Risk Factors ◽  
Venous Thromboembolism ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Risk Treatment ◽  
The Impact ◽  
All Treatment

Abstract Introduction Children with acute lymphoblastic leukemia (ALL) are at high risk for VTE due to several thrombotic risk factors such as the disease itself, central venous line (CVL), immobilization, infections and treatment with asparaginase and steroids, leading to increased morbidity and mortality. Identifying the clinical risk factors and high risk treatment phases for VTE is important and can lead to a better outcome and quality of life for these children. We conducted this prospective study on symptomatic VTE in children with ALL to characterize the prevalence, the clinical characteristics, and potential clinical predictive factors for symptomatic VTE and the impact of thrombosis on treatment delays. Methods All patients (n=1083), age 1-18 years, diagnosed with B-cell precursor or T-cell ALL between June 2008 and July 2013 and enrolled in the NOPHO ALL 2008 treatment protocol in the Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), Estonia or Lithuania were included in the study. Thrombotic events (TE) were prospectively recorded until the end of December 2013. TE was defined as objectively confirmed symptomatic TE. Main questions were: time of VTE occurrence, impact on treatment delay, type of CVL, dysfunction of the CVL, blood samples including D-dimers and thrombophilia screening, family history of TE, type and duration of antithrombotic therapy, and major bleeding during anticoagulation. Results The cumulative risk of symptomatic VTE was 6.0% (CI 95% 4.7-7.7) for children treated with the NOPHO- ALL 2008 protocol. No arterial TE was found. VTE occurred in median 80 (IQR 43-118) days in the SR and 104 (IQR 39-127) days in the IR protocol and were in majority of cases associated with asparaginase treatment (84.5%, 49/58). See figure 1 for the localization of the VTE. VTE had a high impact on the treatment in the patients. Treatment with asparaginase was shortened in half of patients with VTE and chemotherapy treatment delayed in 25%. Age ≥ 15 years and residual disease ≥ 5% after induction therapy was significantly associated with VTE in the multivariate analysis (Table 1). Conclusions Our findings indicate that Venous Thromboembolism (VTE): - is a major complication of ALL treatment - may lead to reduced intensity of the ALL treatment and subsequently possible long term impact on the EFS - risk is dependent on the patients age and residual disease after leukemia induction The possibility of identifying patients with elevated risk of VTE needs to be studied further and thromboprophylaxis for such patients during high-risk treatment phases can be considered in future ALL protocols. Table 1. Multivariate Cox regression analysis of the risk for VTE Factor HR (95% CI) P value Age category, years 1-7 8-14 15-17 Ref1.9 (1.0-3.7)6.2 (3.4-11.3) <0.000 0.044 0.000 Gender Male 1.6 (0.9-2.8) 0.074 ALL phenotype B-precursor T-cell Bilineage Ref2.3 (1.2-4.2)4.2 (1.0-17.4) 0.019 0.010 0.047 Residual disease ≥ 5% day 29 4.1 (1.9-9.0) 0.001 Figure 1. Localization of VTE Figure 1. Localization of VTE Disclosures No relevant conflicts of interest to declare.

Infusions of HSV-TK Engineered Donor Lymphocytes Effectively Protect Patients Undergoing Haploidentical Stem Cells Trasplantation (HSCT) from Infectious Mortality.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1056-1056 ◽  
Author(s):  
M.T. Lupo Stanghellini ◽  
C. Bonini ◽  
E. Provasi ◽  
M. Bernardi ◽  
J. Peccatori ◽  
...  
Keyword(s):  
Stem Cells ◽  
Immune System ◽  
T Cell ◽  
High Risk ◽  
Immune Reconstitution ◽  
Opportunistic Infections ◽  
T Cell Response ◽  
Post Transplant ◽  
Cmv Reactivation ◽  
Donor Lymphocytes

Abstract T-cell depletion (TCD) of allogeneic stem cells transplantation (HSCT) is the most powerful approach to overcome HLA barriers in patients with high risk malignancies, lacking a conventional donor. However, the prolonged immune deficiency resulting from TCD significantly impairs the outcome of HSCT from a haploidentical family donor (haplo-HSCT). In a phase I-II clinical trial (protocol MMTK007), we showed that the add-back of suicide-gene transduced donor lymphocytes (TK+ cells) provides early immune-reconstitution (IR), crucial to avoid opportunistic infections and disease relapse. While the achievement of an early and sustained IR significantly reduced the incidence of infectious complications and mortality, the kinetic of abatement of viral reactivations differed in different patients, suggesting variability in the repertoire, function and persistence of viral-specific T cells. To gain insights on the activity of the post-transplant immune system, we focused on immune responses to cytomegalovirus (CMV) and Ebstein Barr virus (EBV) as clinical paradigm of an effective immune system. In our trial 29 patients (median age 52y) were transplanted for high-risk leukemia. Seventeen pts received TK-DLI starting at day +42, 14 pts obtained prompt immune reconstitution with CD3+ >100/mcl at day +86 (median) from SCT and day +21 from TK-DLI. Twelve/14 experienced CMV reactivation, 3 reactivation/patient (median), each reactivation required 14 days (median) of pre-emptive treatment with foscarnet to achieve a complete clearance; in 2/38 events, a CMV antigenemia persistent during foscarnet treatment was cleared by ganciclovir administration. In this series, the last CMV reactivation requiring pre-emptive treatment happened at day +84 from SCT and day +19 from TK-DLI. Nine/14 experienced EBV reactivation, 1 reactivation/patient (median), 6 patients required treatment with rituximab (375 mg/mq weekly) for 3 cycles (median). In 3 cases we documented EBV lymphoproliferative disease, that were completely controlled with the treatment. The proportion of lymphocytes committed to produce IFN-γ upon CMV or EBV stimulation normalized within the first 3 months post transplant. The analysis of CMV and EBV T-cell response showed a prevalent host-restriction pattern, suggesting active modulation of the T-cell repertoire by the host environment. The TCR-Vβ repertoire progressively changed from oligoclonal into polyclonal and normalized by 1 year after transplant. The progressive acquirement of a protective, host-restricted, anti-viral response, highly correlated with a decline in the occurrence of any infectious event, that were nearly abrogated by 6th month post transplant. The overall cumulative infectious mortality beyond day +100 post transplant was 12,5% in TK treated patients demonstrating the efficacy of this strategy in building a protective immune system.

Outcomes in the Recent Seattle Cord Blood Experience: Low TRM and Relapse; High Mild Acute GVHD and CMV Reactivation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2019-2019
Author(s):  
Jonathan A. Gutman ◽  
Ann E. Woolfrey ◽  
Frederick R. Appelbaum ◽  
Brenda M. Sandmaier ◽  
Jean E. Sanders ◽  
...  
Keyword(s):  
High Risk ◽  
Cord Blood ◽  
Single Unit ◽  
Residual Disease ◽  
Cord Blood Transplantation ◽  
Chronic Gvhd ◽  
High Risk Population ◽  
Close Monitoring ◽  
Cell Dose ◽  
Cmv Reactivation

Abstract Studies of simultaneous transplantation of two cord blood units have suggested that as compared to single unit cord blood transplantation (CBT), increased cell dose may overcome graft rejection and improve survival, particularly in mismatched CBT, as well as enhance the graft-versus-malignancy effect. Successful double CBT has been reported following both myeloablative and reduced intensity (RIT) conditioning. However, several concerns remain, including the possibility of increased incidence of GVHD compared to single unit CBT, as well as persistent delays in hematopoietic recovery and immune reconstitution despite the increase in cell dose achieved by double CBT. We have used an algorithm to guide selection of units in our most recent cohort of CBT patients (pts), such that single unit CBT is allowed only for units matched for 5/6 HLA with total nucleated cell (TNC) dose of at least 4.0 ×107/kg or matched for 6/6 HLA with TNC at least 3.0 ×107/kg. Between February 2006 and June 2007, 22 pts underwent CBT for high risk hematologic malignancies (21 in complete morphologic remission, 8 with minimal residual disease, 1 with active mycosis fungoides). Fourteen pts median age 20.5 years (range 0.6–42) underwent myeloablative transplantation following conditioning with fludarabine (FLU) 75mg/m2, cyclophosphamide (CY) 120mg/kg, and total body irradiation (TBI) 13.2 GY. Eight pts median age 52.5 years (range 24–68) underwent RIT following FLU 200mg/m2, CY 50mg/kg, and TBI 2 GY with the addition of ATG 90mg/kg if there was no exposure to chemotherapy in the three months preceding transplant. GVHD prophylaxis was cyclosporine and MMF. Donor-recipient matching based on intermediate resolution for HLA-A and B and high resolution for HLA-DRB1 was as follows: single 5/6 unit for three pts (14%), two units 4/6 for 12 pts (55%), two units 5/6 for three pts (14%), one 4/6 and one 5/6 unit for three pts (14%), and two units 6/6 for one patient (5%). All double CBT units were at least 4/6 matched to each other. At a median follow-up of 243 days among surviving pts (range 71–451), overall survival (OS) is 77% (17/22). OS is 93% (13/14) among pts treated with myeloablative conditioning and 50% (4/8) among RIT pts. 14% (3/22) of pts have relapsed. Day 100 transplant related mortality (TRM) is 5% (1/22). Incidence of grade II–IV and III–IV aGVHD in 19 of 22 pts who had sustained engraftment and survived past day 30 are 89% (17/19) and 26% (5/19) respectively. Three pts are non-evaluable due to septic death prior to engraftment, early relapse, and graft failure. 100% (11/11) of pts seropositive for CMV prior to transplant developed CMV reactivation measured by PCR at a median of 22 days (range 3–39). No (0/11) seronegative pts developed CMV. There was one case of non-fatal CMV pneumonitis. Using this strategy, we have observed limited early TRM and a lower than expected incidence of relapse in a high-risk population. We have seen a higher incidence of a GVHD than reported at other centers, and long term monitoring for chronic GVHD will be important. Though we have observed few significant infectious complications, all seropositive patients reactivated CMV early post-transplant, emphasizing the need for close monitoring of CMV reactivation and improved treatment strategies. Ongoing experience will confirm the efficacy of our algorithm for the use of two CB units for all 4/6 HLA matched units and low dose 5/6 and 6/6 units.

scholarly journals Cisplatin +/− rucaparib after preoperative chemotherapy in patients with triple-negative or BRCA mutated breast cancer

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Maitri Kalra ◽  
Yan Tong ◽  
David R. Jones ◽  
Tom Walsh ◽  
Michael A. Danso ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Neoadjuvant Therapy ◽  
Triple Negative ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Parp Inhibition ◽  
High Risk Population ◽  
Risk Population ◽  
The Impact

AbstractPatients with triple-negative breast cancer (TNBC) who have residual disease after neoadjuvant therapy have a high risk of recurrence. We tested the impact of DNA-damaging chemotherapy alone or with PARP inhibition in this high-risk population. Patients with TNBC or deleterious BRCA mutation (TNBC/BRCAmut) who had >2 cm of invasive disease in the breast or persistent lymph node (LN) involvement after neoadjuvant therapy were assigned 1:1 to cisplatin alone or with rucaparib. Germline mutations were identified with BROCA analysis. The primary endpoint was 2-year disease-free survival (DFS) with 80% power to detect an HR 0.5. From Feb 2010 to May 2013, 128 patients were enrolled. Median tumor size at surgery was 1.9 cm (0–11.5 cm) with 1 (0–38) involved LN; median Residual Cancer Burden (RCB) score was 2.6. Six patients had known deleterious BRCA1 or BRCA2 mutations at study entry, but BROCA identified deleterious mutations in 22% of patients with available samples. Toxicity was similar in both arms. Despite frequent dose reductions (21% of patients) and delays (43.8% of patients), 73% of patients completed planned cisplatin. Rucaparib exposure was limited with median concentration 275 (82–4694) ng/mL post-infusion on day 3. The addition of rucaparib to cisplatin did not increase 2-year DFS (54.2% cisplatin vs. 64.1% cisplatin + rucaparib; P = 0.29). In the high-risk post preoperative TNBC/BRCAmut setting, the addition of low-dose rucaparib did not improve 2-year DFS or increase the toxicity of cisplatin. Genetic testing was underutilized in this high-risk population.

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&lt;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&lt;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&lt;.001; ATG/pTCD: 127±38, p&lt;.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 Clinical Significance of the Interaction between Human Papillomavirus (HPV) Type 16 and Other High-Risk Human Papillomaviruses in Women with Cervical Intraepithelial Neoplasia (CIN) and Invasive Cervical Cancer

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Arsenio A. Spinillo ◽  
Mattia M. Dominoni ◽  
Anna A. C. Boschi ◽  
Cecilia C. Sosso ◽  
Giacomo G. Fiandrino ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
High Risk ◽  
Residual Disease ◽  
Invasive Cervical Cancer ◽  
Intraepithelial Neoplasia ◽  
Human Papillomaviruses ◽  
Multiple Infections ◽  
Cervical Lesions ◽  
Hpv 16 ◽  
The Impact

The aim is to evaluate the clinical consequences of coinfection between HPV 16 and other high-risk HPVs among women with a histological diagnosis of CIN or invasive cervical cancer. A total of 2985 women, with a diagnosis of either CIN or cancer (<IB) on cervical or cone biopsy, were included. HPV genotypes were identified using the INNO-LiPA HPV genotyping assay, version EXTRA, on cervical scraping, before the colposcopic evaluation and the colposcopic biopsies or conization. In the overall population, HPV16 interacted positively with HPV18 (RR = 2, 95% CI 1.5–2.6) and negatively with HPV33, 51, 52, and 66, in log-linear analysis. There was an excess of CIN3 diagnoses among subjects coinfected with HPV16 and HPV18 or HPV52, although the absolute number of cases was relatively small. In a logistic model, the odds ratio of CIN3+ associated with coinfection of HPV16 and HPV18 (OR = 3.8, 95% CI 2.5–5.7, p = 0.004 compared to single HPV16) or HPV52 (OR = 3.6, 95% CI 2.6–5.1, p = 0.009 compared to single HPV) was higher than that associated with single HPV 16 infections. Finally, multiple infections had no effect on residual disease and did not influence the recurrence of high-grade CIN during a median follow-up of 25 months (IR 17–41). HPV16 interacted positively with HPV18 and negatively with HPV33, 51, 52, and 66 supporting the notion that HPV16 interacts mostly negatively with other HR-HPVs in CIN lesions. Among specimens coinfected with HPV16 and 18 or 52, there was an excess of CIN3+ although the impact on the prevalence of severe cervical lesions was limited.

Use of Pre-Emptive Donor Lymphocyte Infusions To Achieve Durable Remission Following Alemtuzumab Based Reduced Intensity Conditioning (RIC) Transplantation for AML or MDS.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1124-1124
Author(s):  
ZiYi Lim ◽  
Laurence Pearce ◽  
Wendy Ingram ◽  
Rafael Duarte ◽  
Stephen Devereux ◽  
...  
Keyword(s):  
T Cell ◽  
Advanced Disease ◽  
Disease Stage ◽  
Mixed Chimerism ◽  
Donor Chimerism ◽  
Significant Difference ◽  
Cell Source ◽  
Recipient Age ◽  
The Impact

Abstract Use of alemtuzumab in RIC HSCT reduces the incidence of graft rejection and graft vs host disease(GvHD). However, there can be a delay in full T-cell donor engraftment. As a dominant donor T-cell chimerism may be important to achieve a strong graft vs leukaemia effect(GvL), we examined the impact of pre-emptive DLI (pDLI) on patients with falling donor chimerism. 76 patients with AML or MDS were treated with RIC HSCT (fludarabine 150mg/m2, busulphan 8mg/kg, alemtuzumab 100mg). Complete sublineage chimerism data up to day +100 was available on all patients. The underlying diagnoses were AML n=27, MDS n=49. 33 patients had early disease vs 44 advanced disease (advanced disease as defined by AML &gt;CR1, MDS RAEB or AML with multilineage dysplasia). The median recipient age was 51.6 years (range:19–72), with median follow-up of 526 days (range:137–1256). There were 30 sibling and 50 VUD allografts. Stem cell source was 61 PBSC vs 15 BM. 62 patients were fully HLA matched and 14 patients were HLA mismatched. CD15 engraftment occurred rapidly with 95% of patients achieving full donor chimerism(FDC) at day 30 and 96% at day 100. In contrast, CD3 engraftment was significantly delayed, with only 50% of patients FDC at day 30, 47% at day 100. Incremental doses of pDLI were considered for patients with falling donor chimerism (&lt;50% donor) after day 100. Patients had immunosuppresion withdrawn, and had to have no GvHD. 20 patients received a total of 55 doses of pDLI. 10/20 had advanced disease, and 6/20 had unfavourable cytogenetics. Median donor CD3 chimerism at time of pDLI was 31.5%(range:7–59). The median CD3 dose of pDLI was 8.4x106/kg, with the first dose given at a median of day +176 (range:104–494). The median interval between pDLI was 8 weeks(range:4–22). 15 patients had FDC restored at median of 130 days following first doses of pDLI (range:36–523). 8/20 developed acute Gd II-IV GvHD following pDLI, with 2 patients dying of GvHD related complications. 2 patients relapsed with AML following treatment: with 1 death, and 1 patient currently undergoing treatment. 2 patients had not reached FDC at follow-up. A further 9 patients received DLI for cytogenetic or morphological relapse. Time to first dose of DLI was 257 days (range:76–837). The median CD3 dose was 1.67 x 107/kg. 3 patients were FDC and 6 patients MDC at time of relapse. All 3 patients with FDC failed to respond to DLI. Complete remission was seen in 3/6 patients with MDC. 4/9 patients developed acute Gd II-IV GvHD. 5/9 patients have died(all of underlying AML). The outcome of patients receiving pDLI was compared with patients with FDC(n=28), and stable mixed chimerism(defined as donor CD3 chimerism &gt;70%) who did not receive DLI(n=18). There was no significant difference in recipient age, disease, disease stage, HLA type, cell source or cell dose between groups. However, there were more sibling donors in the group receiving pDLI(p=0.02). The 2 year DFS, OS and relapse rate was comparable between patients with FDC, stable chimerism and those receiving pDLI (59% vs 83% vs 67% p=0.22), (62% vs 88% vs 75% p=0.13), (12% vs 17% vs 15% p=0.74) respectively. In summary, pre-emptive DLI is effective in reversing falling donor chimerism, and can induce prolonged remission, even in a sub-group of patients with high risk disease. A dominant donor CD3 chimerism(&gt;70%) may be sufficient to acheive an allo-immune effect in majority of patients.

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