Myeloablative haploidentical T‐cell replete hematopoietic cell transplantation with post‐transplant cyclophosphamide in high risk hematological malignancies: bending the learning curve in a middle‐income setting

2020 ◽  
Author(s):  
Sanket P Shah ◽  
Vivek S Radhakrishnan ◽  
Ganesh S Jaishetwar ◽  
Reghu K Sukumaran ◽  
Jeevan Kumar ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Learning Curve ◽  
Cell Transplantation ◽  
Hematological Malignancies ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Middle Income ◽  
Post Transplant

HLA-Haploidentical Familial Donor Hematopoietic Cell Transplantation without Ex Vivo- T Cell Depletion after Reduced-Intensity Conditioning of Busulfan, Fludarabine, and Anti-Thymocyte Globulin: A Preliminary Report.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3077-3077
Author(s):  
Kyoo-Hyung Lee ◽  
Seong-Jun Choi ◽  
Jung-Hee Lee ◽  
Ho-Jin Shin ◽  
Young-Shin Lee ◽  
...  
Keyword(s):  
T Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Cell Depletion ◽  
Reduced Intensity Conditioning ◽  
T Cell Depletion ◽  
Reduced Intensity

Abstract Animal hematopoietic cell transplantation (HCT) models and several small clinical trials showed that successful engraftment can be achieved across HLA-haplotype difference after reduced-intensity conditioning (RIC). Furthermore, decreased graft-versus-host disease (GVHD) and transplantation-related mortality (TRM) after RIC was shown in a swine leukocyte antigen-haploidentical HCT experiment. Therefore, a protocol investigating the role of RIC in HLA-haploidentical familial donor HCT was initiated in April 2004 and 20 patients [13 male and 7 female; median age 26.5 years (16–65)] without HLA-matched donor enrolled until June 2007. The diagnosis were AML (n=9), ALL (n=4), acute biphenotypic leukemia (n=1), MDS (n=4), and SAA (n=2), and all patients had high-risk features, i.e. first complete remission (CR) but with high-risk chromosomal abnormality (n=1), first CR after salvage (n=1), second CR (n=6), recurrent/refractory state (n=7), immunotherapy failure (n=4), and high-risk MDS (RAEB-1, n=1). The RIC included iv busulfan 3.2 mg/kg × 2, fludarabine 30 mg/m2 × 6, plus anti-thymocyte globulin [Thymoglobuline 3 mg/kg (n=17) or Lymphoglobuline 15 mg/kg (n=3)] × 4. After receiving G-CSF, the donors (13 mothers; 5 offsprings; and 2 HLA-haploidentical siblings) underwent 2 or 3 daily leukapheresis, and the collected cells were given to patients without T cell depletion [medians of; 7.9 (3.7–12.1)×108/kg MNC, 6.9 (3.6–73.5)×106/kg CD34+ cells, and 4.6 (1.8–8.5)×108/kg CD3+ cells]. GVHD prophylaxis was cyclosporine 3 mg/kg/day iv from day -1 and a short course of methotrexate. As a part of separate phase 1 study, the two most-recently enrolled patients received additional donor CD34+ cell-derived NK cells 6 weeks after HCT. Except one patients with SAA who died due to K. pneumoniae sepsis on day 18, all 19 evaluable patients engrafted with ANC> 500/μl median 17 days (12–53) and platelet> 20,000/μl median 23 days (12–100) after HCT. Eight patients experienced acute GVHD (grades I, II, III, and IV; 2, 3, 2, and 1, respectively). Cumulative incidences (CI) of overall and grade II-IV acute GVHD were 40 and 30%, respectively. Eight patients experienced chronic GVHD (limited, 4; extensive, 4; CI, 51%). Fourteen showed positive CMV antigenemia, while 2 suffered CMV colitis, which resolved after treatment. As early as 2 weeks after HCT, 15 of 16 evaluable patients, and, by 4 weeks, all of 17 evaluable patients showed donor chimerism ≥95% on STR-PCR, which was maintained until 24 weeks in all 11 patients tested. Thirteen patients are alive after median follow-up of 13.6 months (1.5–37.9; Kaplan-Meier survival, 55.6%). Of 16 patients with acute leukemia and high-risk MDS, 8 remain alive without recurrence (event-free-survival, 40.9%). Two patients died of K. pneumoniae sepsis and grade IV acute GVHD, respectively (CI of TRM, 11%). Immune recovery in 10 patients without relapse for > 6 months showed robust lymphocyte contents and immunoglobulin levels at 6 months (means of; 1,060/ul CD3+, 222/ul CD4+, 767/ul CD8+ cells, and 1,317 mg/dl IgG) and 12 months. After RIC, consistent engraftment and durable complete donor hematopoietic chimerism can be achieved from HLA-haploidentical familial donor. The frequencies of GVHD and TRM were low.

scholarly journals Does Early T Cell Chimerism Predict Outcomes after Allogeneic Hematopoietic Cell Transplantation ?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3360-3360
Author(s):  
Tania Jain ◽  
Luke Mountjoy ◽  
Katie L. Kunze ◽  
Pierre Noel ◽  
Nandita Khera ◽  
...  
Keyword(s):  
T Cell ◽  
Clinical Outcomes ◽  
Cell Transplantation ◽  
Hematological Malignancies ◽  
Hematopoietic Cell Transplantation ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
Time Points ◽  
Donor Chimerism ◽  
Time To Relapse

Abstract Introduction: Donor T cell chimerism is tested frequently early after allogeneic hematopoietic cell transplantation (HCT). However, the predictive ability of testing this early after HCT, i.e. at day +30 or day +60, has not been well described, outside of smaller single center studies. Herein, we evaluate the correlation of early donor T cell chimerism with clinical outcomes of overall survival (OS) and relapse in patients undergoing HCT for various hematological malignancies. Methods: We identified patients who received HCT with 8/8 matched unrelated donors at our center between 2007 and 2016 and obtained the clinical data retrospectively. Chimerism studies were included for patients who had testing done at day+30 and/ or day +60. Chimerism is tested using PCR based technique. Due to limited variability in chimerism levels <100% donor chimerism, a cut-off of 100% was used for analysis. Hence, patients were divided into those who achieved full donor chimerism in CD3 fraction (100%) and those in whom CD3 donor chimerism was < 100% at the respective time points. Clinical outcomes evaluate for this abstract were OS and time to relapse. Univariate and multivariate Cox proportional hazard regression models were used using variables of interest, the later adjusted for age at HCT, use of ATG, conditioning regimen and disease risk index (DRI). Results: Baseline patient and HCT data: There were 209 patients who met the selection criteria of which 4 died within 30 days from HCT and hence, were not included in the analysis. Among the 205, 87 (42%) were women and median age at HCT was 55 (range, 18 - 74) years. The hematological malignancy diagnosis was acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS) in 112 (55%), acute lymphoblastic leukemia (ALL) in 35 (17%), chronic leukemias in 13 (6%), lymphomas in 13 (6%) and myeloproliferative neoplasm in 20 (10%); with DRI being very high in 9 (5%), high in 53 (27%), intermediate in 120 (60%) and low in 17 (9%) patients. Myeloablative conditioning was used in 81 (40%) and reduced intensity conditioning in 124 (60%). Graft versus host disease prophylaxis used was calcineurin inhibitor with methotrexate of mycophenolate in all patients while anti-thymocyte globulin was used in 125 (61%) patients. All patients received a peripheral blood graft. Outcomes: Median follow-up for all included patients was 615 (range, 30 - 3147) days. At day +30, 138 patients had achieved 100% donor CD3 chimerism of 189 patients in whom this data was available (73%) while at day +60, 131 (76%) out of 173 had 100% donor CD3 chimerism. In the univariate model, CD3 donor chimerism level at day +30 as well as day +60, was not predictive of OS (HR 1.5, 95% CI 0.82 - 2.9; p = 0.18 for day +30, HR 1.8, 95% CI 0.81 - 4.0, p = 0.15 for day +60). As for time to relapse, CD3 chimerism did not significantly affect the risk of relapse at these time points (HR 0.43, 95% CI 0.17 - 1.1, p = 0.08 for day +30; HR 0.55, 95% CI 0.18 - 1.6, p = 0.28 for day +60). In the multivariate model also, after adjustment as described above, CD3 at day +30 or at day +60 was not significantly associated with the risk of OS or time to relapse (Figure 1). Kaplan Meier curves for OS for CD3 chimerism at day +30 and day +60 are shown in Figure 2. Conclusions: In this study, T cell chimerism as early as day +30 or day +60 does not seem to predict OS or relapse in patients undergoing HCT for various hematological malignancies. Given the limitations of a smaller retrospective design, this must be validated in a larger study, possibly using registry data. If these findings are indeed confirmed, then the practice of testing chimerism early and frequently, that adds additional expense to the overall cost of HCT, must be reconsidered. Disclosures Palmer: Novartis: Research Funding.

scholarly journals Lower Use of DLI Post Relapse of Malignancy May Result in Shorter Post-Relapse Survival (PRS) in Patients Undergoing T Cell Replete Haploidentical Donor Transplantation (HIDT) Versus Matched Related (MRD) or Matched Unrelated Donor (MUD) Hematopoietic Cell Transplantation (HCT)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1967-1967
Author(s):  
Melhem Solh ◽  
Xu Zhang ◽  
Stacey Brown ◽  
Lawrence E. Morris ◽  
H. Kent Holland ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Transplantation ◽  
Median Time ◽  
Hematopoietic Cell Transplantation ◽  
Risk Index ◽  
Hematopoietic Cell ◽  
Unrelated Donor ◽  
Post Transplant ◽  
Comorbidity Index ◽  
Time To Relapse

Abstract Relapse of hematologic malignancies remains a major cause of treatment failure and mortality among patients receiving allogeneic hematopoietic cell transplantation (HCT). Patients relapsing after a matched related or unrelated donor transplantation may benefit from donor lymphocyte infusion (DLI) as part of their post relapse therapy. DLI post-relapse has less frequently been utilized among recipients of HIDT presumably due to the potential for severe GVHD if high T-cell doss are administered without immunosuppression. However, reluctance to administer DLI may limit the possibility of remission following disease relapse in HIDT. We compared the frequency of use of DLI and survival outcomes for patients relapsing after HIDT using post-transplant cyclophosphamide to those relapsing after MRD or MUD HCT at our institution. 195 consecutive HCT recipients with relapse of hematologic malignancy occurring after HIDT (N=35), MUD (N=74) and MRD (N=81) between 1998 and 2014 were included in this analysis. The median age was 50 years (19-77 years) and median time to relapse was 159 days (25-2465 days) post HCT. Patients receiving HIDT had similar median time to relapse (5.1 vs 5.2 vs 5.2 months, p=0.638), Dana-Farber/CIBMTR disease risk index (DRI), comorbidity index (CMI) scores, longer times to neutrophil engraftment (17 vs 14 vs 14 days, p<0.001), and platelet engraftment (28 vs 19 vs 18 days, p<0.001) when compared to MUD and MRD recipients respectively. Post-relapse survival at 1 year was worse among HIDT recipients when compared to MRD (9% versus 41%, p=0.008) and MUD (9% vs 35%, p=0.025). DLI was used in 3 (8%) relapsed HIDT patients, 48 MRD patients (59%) and 28 (38%) MUD recipients. Among patients relapsing post MRD and MUD HCT, use of DLI was associated with a better post relapse survival (p=0.04). In a multivariate analysis, donor type (HIDT), time to relapse (<3 months versus > 3months post-transplant) and comorbidity index (CMI score >= 3) were all predictive of worse post relapse survival. This analysis shows that relapse post HIDT carries a worse prognosis than relapse post MRD and MUD. Efforts such as post-transplant maintenance and haploidentical DLI infusions should be investigated further in the HIDT setting. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.

Blinatumomab Maintenance After Allogeneic Hematopoietic Cell Transplantation for B-lineage Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Author(s):  
Mahmoud R. Gaballa ◽  
Pinaki Prosad Banerjee ◽  
Denái R. Milton ◽  
Xianli Jiang ◽  
Christina Ganesh ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
High Risk ◽  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cell ◽  
Allogeneic Hematopoietic Cell Transplantation ◽  
T Cell Subsets ◽  
B Lineage

Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after allogeneic hematopoietic cell transplantation (HCT). We conducted a single center phase II study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients. Twenty-one of 23 enrolled patients received at least one cycle of blinatumomab and were included in the analysis. The median time from HCT to the first cycle of blinatumomab was 78 days (range, 44-105). Twelve patients (57%) completed all 4 treatment cycles. Neutropenia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neurotoxicity (5% G2) were minimal. The cumulative incidence of acute GVHD grades 2-4 and 3-4 were 33% and 5%, respectively; two cases of mild (10%) and one case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3 months, the 1-year overall survival, progression-free survival, and non-relapse mortality rates were 85%, 71%, and 0%, respectively. In a matched-analysis with a contemporary cohort of 57 patients, we found no significant difference between groups regarding blinatumomab's efficacy. Correlative studies of baseline and post-treatment samples identified patients with specific T-cell profiles as "responders" or "non-responders" to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Non-responders were T-cell deficient and expressed more inhibitory checkpoint molecules, including TIM3. We found that blinatumomab post-allogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time of treatment.

Sign in / Sign up

Export Citation Format

Share Document