Post-infusion Cyclophosphamide Research Articles

Allogeneic Hematopoietic Cell Transplantation (AHCT) in Post Infusion Cyclophosphamide (PIC) Era: The Switch from Anti-Thymocyte Globulin (ATG) to PIC for Graft Versus Host Disease (GVHD) Prophylaxis in AHCT from Alternative Donors

Aim: Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (AHCT). As GVHD prophylaxis regimen, post-transplant cyclophosphamide (Post-Cy) has been associated with less acute and chronic GVHD. Anti-Thymocyte Globulin (ATG), which is another GVHD prophylaxis regimen, could reduce the risk of chronic but not acute GVHD. Anti-thymocyte globulin (ATG) in association with a calcineurin inhibitor (CNI) and methotrexate or mycophenolate mofetil (MMF) is widely used in the setting of unrelated donor transplantation (UDT). Recent studies proned non-inferior results of haplotype matched donor transplantation (HMDT) using Post-Cy in comparison with UDT. However, there is no consensus about the optimal GVHD prophylaxis regimen or choosingwisely. Aim of this study was to compare the outcome of two GVHD prophylaxis regimens; Post-Cy used in HIDT or UDT and ATG used for unrelated donors in a single-cohort of consecutive transplant recipients. Material and Methods: Two hundred adult (17-72 years) patients who underwent HIDT and UDT with a minimum 100 days follow-up at Florence Nightingale Hospital Hematopoietic Stem Cell Transplantation Center between 2011 and 2017 were included in this study. Medical records of patients were reviewed retrospectively. Transplantation was performed in cases with high or very high DRI. HIDT was performed in 73 cases and UDT in 127 cases. One hundred eighty five out of 200 cases with a complete follow-up were included in the statistical analysis. Sixty-seven patients underwent HIDT with Post-Cy (Group 1), 97 patients with UDT receiving ATG (Group 2) and 21 with UDT receiving Post-Cy (Group 3). Patients who completed minimum 100 days post-transplantation follow-up were identified as eligible for survival analysis. Results: Median age of patients was 42.8±14.9 years. Percentage of male patients was 65.6%, 68% and 38% for HIDT with Post-Cy (Group 1), UDT with ATG (Group 2) and UDT with Post-Cy groups (Group 3), respectively, which is significantly different (p=0.03). Bone marrow was used in 58.2% patients as stem cell source in HIDT, contrary to UDT, which is below 1% (p<0.0001). Median follow-up time was 398 days. Patient characteristics (Table 1), were mainly similar, such as donor age, gender, recipient cytomegalovirus (CMV) status, Karnofsky performance status, conditioning regimens, median neutrophil and platelet engraftment time, engraftment failure, acute GVHD incidence and disease status at post-transplant D100. Since the incidence of donor CMV IgG was significantly higher due to regional reasons in HIDT group, CMV activation rate was also significantly higher in this HIDT (p=0.001). No significant difference was found in Kaplan-Meier survival analysis among the HIDT with Post-Cy, UDT with ATG and UDT with Post-Cy groups, even if they were classified according to primary disease, and post transplant 100th day disease status. Transplant related mortality at 30th and 100th days were similar among three groups. Also, donor CMV status (CMV IgG positivity or negativity) and CMV reactivation was not an important factor on survival (for donor CMV status p=0.307; for CMV reactivation p=0.274). Conclusion: We did not find any significant difference among three groups with regards to survival rate and acute GVHD development. Reactivation of CMV does not effect 100th day survival. These findings support our hypothesis that post-Cy infusion regimen is an important factor for higher survival rate rather than the donor type. We believe that post Cy infusion GVHD prophylaxis platform along with MMF and CNI is maturing, proved itself as a standard immune suppressive regimen for alternative donor transplantation. The related donor switch will be expectedly soon, and we have to wait for maturation of data both on related matched and alternative donor AHCT using post Cy infusion. Disclosures No relevant conflicts of interest to declare.

JC Virus and Progressive Multifocal Leukoencephalopathy After Haplo-Identical T-Cell Replete Transplantation with Post-Infusion Cyclophosphamide Recipient

JC Virus and Progressive Multifocal Leukoencephalopathy After Haplo-Identical T-Cell Replete Transplantation with Post-Infusion Cyclophosphamide Recipient

Haploidentical transplantation with post-infusion cyclophosphamide in advanced Hodgkin lymphoma.

We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.

Haploidentical transplantation with post-infusion cyclophosphamide in advanced Hodgkin lymphoma

We investigated the use of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in the treatment of advanced Hodgkin lymphoma (HL). Sixty-two consecutive HL patients underwent haplo-HSCT. Unmanipulated stem cells and post-transplant cyclophosphamide were given to all patients as GVHD prophylaxis. At 100 days, the cumulative incidence of grades 2-3 and grades 3-4 acute GVHD was 23% and 4%, respectively. The chronic GVHD (cGVHD) cumulative incidence was 16%, with one patient experiencing severe cGVHD. The 3-year OS, PFS, relapse rates and 1-year non-relapse mortality (NRM) were 63%, 59%, 21% and 20%, respectively. Uncontrolled disease status and high hematopoietic cell transplantation comorbidity index (HCT-CI) were associated with lower OS, whereas PBSC was an independent protective factor. Uncontrolled disease and HCT-CI >2 was predictive for NRM. Finally, disease status other than CR was predictive of relapse. In conclusion, haplo-HSCT is a valid treatment in advanced HL, offering excellent rates of survival and acceptable toxicities.

Bone marrow donor‐related variables associated with harvest outcome in HLA‐haploidentical transplantation with postinfusion cyclophosphamide

Several transplantation outcomes have been shown to be associated with the infused bone marrow cell dose/kg of the recipient's body weight. The donor bone marrow density is directly related to the infused cell dose. The aim of the present study was to identify donor-related variables that are associated with high donor bone marrow density. We retrospectively analysed the predictive factors of high marrow density in 65 consecutive HLA-haploidentical bone marrow donors harvested at our centre between 2009 and 2013. Body mass index (BMI) and peripheral white blood cell (WBC) count were directly associated with bone marrow density (regression coefficient β = 5·33 and β = 2·93, respectively; P < 0·01). The likelihood of obtaining a collection with a high density was first predicted using BMI (BMI ≥30, mean density = 25·8 TNC/ml × 10(6) ). Second, donors with a BMI <30 were split into two groups according to peripheral WBC count (WBC <8 × 10(3) /mm(3) : mean density = 18·4 TNC/ml × 10(6) ; WBC ≥8 × 10(3) /mm(3) : mean density = 23·1 TNC/ml × 10(6) ). We also observed that the density of the first collected bag directly correlated with the overall density (R(2) = 0·69, P < 0·01). The donor-related features BMI and WBC count affect the cell quantity obtainable with the harvest and should be taken into account when choosing the donor.

Tacrolimus (FK) Compared to Cyclosporine a (CyA) after Haploidentical T Cell Replete Stem Cell Transplantation (Haplo-SCT) with Post-Infusion Cyclophosphamide: A Retrospective Analysis

▪Introduction. Investigators from Johns Hopkins University pioneered the use of post-transplantation cyclophosphamide (PT-Cy) after T cell-replete haploidentical bone marrow (BM) infusion. A significant component of this scheme is tacrolimus (FK), associated to mycophenolate mofetil (MMF), to prevent immunological complications. FK is a calcineurin inhibitor, almost 100-fold more potent than cyclosporine A (CyA) in its inhibitory activity.In this retrospective study, we analyzed 100 patients grafted with Haplo-SCT with PT-Cy, and receiving FK or CyA.Patients and Methods. From April 2009 until April 2013, we analyzed 100 consecutive patients at two institutions (Institut Paoli Calmettes Marseille, France and Humanitas Cancer Center, Rozzano, Italy). Conditioning regimen was identical consisting of Fludarabine, Cyclophosphamide, and low dose TBI. GVHD prophylaxis consisted of Cy 50 mg/kg on days +3 and +4, FK or CyA and MMF. FK (at a total dose of 1 mg) was administered as a continuous infusion and then converted to oral formulation. CyA was dosed at 3 mg/kg as a continuous infusion and was then converted to oral formulation. MMF was administered at 45 mg/kg/day until day +35. FK, CyA and MMF were started on day +5. FK and CyA were tapered by day +100-180. Stem cell source was BM or peripheral blood stem cells (PBSC).Results. Patient and transplant characteristics are shown in Table 1. The cumulative incidence of engraftment was similar between FK and CyA groups: 30-days absolute neutrophil count > 500 was 79% vs 91% (p 0.3), and unsupported platelet count more than 20 000 at 60 days was 77% vs 84% (p 0.7), respectively.The incidence of grade 2-4 acute GVHD was 26% vs 30% (p 0.5) and the incidence of chronic GVHD was 13% vs 8% (p 0.9), respectively. The 2-year progression free survival (PFS) and overall survival (OS) were 53% vs 64% (p 0.2) and 65% vs 65%, respectively (p 0.7). The 2-year relapse incidence (RI) was 28% vs 12% (p 0.08) and the 2-year non relapse mortality was 16% vs 14% (p 0.7), respectively. In univariate analysis, only disease status (CR vs not CR) impacted the PFS, OS, and RI.Patients were regrouped in 3 cohorts (1 patient excluded because received FK + PBSC): FK + BM (n 42), CyA + BM (n 14), and CyA + PBSC (n 43). 1-year NRM was not different (17% vs 14% vs 15%, p 0.8). Compared to FK +BM and CyA + PBSC, a trend in favor of CyA + BM was observed in terms of aGVHD (7% vs 24% vs 38%, p 0.05) and cGVHD (0 vs 13% vs 10%, p 0.9).Conclusions. Although this is a retrospective study with potential selection bias, using CyA instead of standard FK did not seem to affect any major clinical outcome, with special interest for aGVHD and cGVHD. The NRM is acceptable in line with that published. GVHD incidence was lower in the group CyA + BM compared to other 2 groups. Disease status before haplo SCT was the only prognostic factor for survival and relapse.Table 1Patient and transplant characteristics.All ptsFKCSApN%N%1004357Male Female58/4222/2151/4936/2163/370.229Age (mean)4644480.135Disease status at haplo0.466CR5623533358PR2914331526SD61259PD951247Armand Risk0.646Low937611Int7233773968High/Very high197161221Previous transplant<0.001Relapse after ALLO800814Relapse after HDC4021491933Sex D/R0.533F/F16921712F/M218191323M/M3814332442M/F2512281323CMV D/R0.009POS/POS7035813561NEG/NEG18251628POS/NEG1161459Donor0.578children2612281425Mother15716814Father1161459Sibling4717403053Cousin1Stem cell source<0.001BM5642981425PBSC44124375HCT-CI0.007031184213231-22313301018>34612283460CD34 (mean)4,43,55,2<0.001 DisclosuresNo relevant conflicts of interest to declare.

Haploidentical stem cell transplantation (Haplo-HSCT) with nonmyeloablative conditioning regimen (NMAC) and postinfusion cyclophosphamide in advanced non-Hodgkin lymphoma (NHL) patients.

7039 Background: In patients lacking HLA identical (HLA-id) donors, haploidentical (Haplo) donors is increasingly considered as a valid alternative stem cell source.The introduction of post-infusion Cyclophosphamide (Cy) as prophylaxis for immunological complications using T-cell replete graft is one of the most usual strategy. However, efficacy is still a matter of debate. Here we reviewed the outcome of 28 consecutives Haplo-HSCT patients with advanced NHL that we compared to an historical control cohort of patients transplanted from HLA-id donors. Methods: 28 Haplo-HSCT were performed between 04/06/2010 and 27/09/2013. Diagnoses were aggressive NHL in 22 patients and low-grade NHL in 6. Median age was 48 years (19-67). At transplant, 64% were in complete remission, 29% in partial remission and 7% in stable disease. These 28 patients were fully matched to 61 HLA-id patients. Conditioning regimen varied according to donor source. Haplo-HSCT patients received a NMAC associating of Fludarabine (150mg/m² to...

Mismatches In Killer Immunoglobulin Receptor (KIR) Ligands and Inhibitory KIR Receptors Between Donor and Recipients Improve Survival After Non T Cell Depleted Haploidentical Transplantation

IntroductionAlloreactivity triggered by interaction of Killer immunoglobulin-like receptors (KIRs) on donor Natural killer (NK) cells and their ligands on recipients plays a role in the graft-versus-tumour effect. Different predictive models have been postulated for measuring alloreactivity: ligand incompatibility model, receptor-ligand model, missing ligand model and KIR gene-gene model. Our aim in this study is to evaluate the importance of differences in KIR and HLA genotype between donor and recipient (missing ligand model and KIR gene-gene model) in the setting of non T cell depleted haploidentical haematopoietic stem cell transplantation (HSCT) with high-dose, post-infusion cyclophosphamide (Cy) Patients and Methods33 consecutive patients with haematological malignancies who received haploidentical HSCT with high-dose Cy post-transplantation between 2007 and 2013, and their donors were included for analysis (Table 1). HLA typing was used to identify KIR ligands HLA-B and HLA-C. KIR genotype was analyzed by PCR (KIR Typing, Miltenyi Biotec) on genomic DNA (Maxwell 16 Blood DNA Kit, Promega) from peripheral blood samples, and revealed with ethidium bromide after agarose gel electrophoresis. ResultsDemographic data and KIR genotype characteristics of donors and recipients are listed in Table 1. We found that KIR ligands mismatch between donor and recipient is related with improve of OS (52% vs. 82%; p=0,041) and DFS (63% vs. 22%; p=0,037) a year after transplant (Figure 1). Mismatch of inhibitors KIR receptors (iKIR) gene content between donors and recipients is also related with an improvement of OS (94% vs. 75%; p=0,049) and DFS (13% vs. 61%; p= 0,028) compared with no mismatch pairs. In the multivariable analysis, both KIR ligands mismatches (HR=4,38 CI:0.9-21; p=0,061) as well as iKIR mismatches (HR=4,15 CI:1-16; p=0,047), show a tendency to be independent variables for the reduction of disease relapse rate. Cumulative incidence of relapse for both variables studied is shown in Figure 2. Conspicuously, a sub-analysis in Hodgkin Lymphoma patients group shows and improve in DFS a year after transplant in patients with KIR ligands mismatches ( 100% vs. 48% p: 0,006) and iKIR mismatches (100% vs. % 33% p: 0,049), despite the small number of patients. Contrary to data published by other groups, patients receiving donor's progenitors with Bx haplotype with centromeric genes (Cen-BB) did not show a benefit in survival (SG 85% vs. 90%, p= 0,05 and DFS 66% vs. 10%, p=0,047) a year after transplant [Display omitted] [Display omitted] ConclusionOur data suggest that in the setting of non T cell depleted haploidentical HSCT with high dose Cy post-infusion, KIR ligands and iKIR mismatch are related with an improve in survival, specially in the sub-group of patients with Hodgkin disease Disclosures:No relevant conflicts of interest to declare.

Low-Dose Total Marrow/Total Lymphoid Irradiation (TMI/TLI) Instead of TBI Induce Full Donor Chimerism Before T-Replete Haploidentical Transplantation

Nonmyeloablative (NMA) T replete haploidentical transplantation (TR-H) has been increasingly applied in high-risk hematologic patients when a HLA-matched donor was absent. Some data suggested that the outcome was similar to those obtained with matched related bone marrow transplantation, mainly in lymphoproliferative diseases. Recently, the Baltimora group reported a low dose TBI-based NMA regimen followed by T cell replete bone marrow, with post-infusion cyclophosphamide (Cy) to control GVHD and graft rejection.