Post-transplant Cyclophosphamide Research Articles

Post-transplant-cyclophosphamide and short-term Everolimus as graft-versus-host-prophylaxis in patients with relapsed/refractory lymphoma and myeloma-Final results of the phase II OCTET-EVER trial.

Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response. We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years. Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies.

Post-transplant cyclophosphamide, calcineurin inhibitor, and mycophenolate mofetil compared to anti-thymocyte globulin, calcineurin inhibitor, and methotrexate combinations as graft-versus-host disease prophylaxis post allogeneic stem cell transplantation from sibling and unrelated donors in patients with acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Post-transplant cyclophosphamide plus calcineurin inhibitor (CNI)(tacrolimus or cyclosporine A) plus mycophenolate mofetil (PTCy/TAC or CSA/MMF) and anti-thymocyte globulin plus CNI (tacrolimus or cyclosporine A) plus methotrexate (ATG/TAC or CSA/MTX) are common graft-versus-host disease (GVHD) prophylaxis regimens. We compared the two regimens in patients with acute myeloid leukemia (AML) undergoing allogeneic transplantation from matched siblings or unrelated donors. 402 received PTCy/TAC or CSA/MMF and 5648 received ATG/TAC or CSA/MTX. Patients in the PTCy-based group were younger (48.7 vs. 51.5 years, p = 0.024) and there was a higher frequency of patient cytomegalovirus seropositivity and female donor to male patient combination in this group (77.8% vs. 71.8%, p = 0.009 and 18.4% vs. 14.4%, p = 0.029, respectively). More patients in the PTCy-based group received reduced-intensity conditioning (51.5% vs. 41%, p < 0.0001). No differences were observed in the incidence of acute GVHD grade II-IV and III-IV (21.2% vs. 20.4%, p = 0.92 and 8.1% vs. 6%, p = 0.1) or 2-year total and extensive chronic GVHD (33.7% vs. 30%, p = 0.09 and 10.7% vs. 11.2%, p = 0.81) between the groups. In the multivariate analysis, all transplant outcomes did not differ between the groups. PTCy/CNI/MMF and ATG/CNI/MTX are alternative regimens for GVHD prophylaxis in AML patients.

Post-transplant cyclophosphamide at 80 mg/kg with low dose post-engraftment anti-thymocyte globulin in haploidentical transplantation with myeloablative conditioning.

While post-transplant cyclophosphamide (PTCy) is commonly used as graft-versus-host disease (GvHD) prophylaxis in haploidentical stem cell transplantation (haplo-HSCT), its dose remains a matter of debate due to side effect concerns. Standard dose of 100 mg/kg associated with tacrolimus and post-engraftment anti-thymocyte globulin (ATG) was used as the reference GvHD prophylaxis in our center and had demonstrated encouraging results. Though PTCy 80 mg/kg was shown to be feasible in patients in reduced-intensity conditioning, whether it exerts equivalent GvHD prophylactic efficacy in myeloablative conditioning (MAC) setting has not been confirmed. Here, we retrospectively analyzed the efficacy and safety of PTCy 80 mg/kg combined with tacrolimus and post-engraftment ATG as GvHD prophylaxis in patients aged more than 55 years or with cardiac antecedents or HCT-CI score >2 undergoing haplo-HSCT with MAC. The cumulative incidence of grade III-IV aGvHD at day 100 and moderate-to-severe cGvHD at 1 year was 4.8% ± 3.4% and 19.9% ± 7.0%, respectively. When compared with patients receiving the reference regimen, patients from the PTCy 80 mg/kg group had similar incidence of GvHDs and survival as their younger counterparts. Thus, PTCy 80 mg/kg seems to be feasible for patients treated with MAC conditioning regimens in haplo-HSCT, inviting further investigation notably in frail patients.

Haploidentical transplantation in primary refractory/relapsed secondary versus de novo AML: from the ALWP/EBMT

We compared the outcomes of haploidentical stem cell transplantation (HaploHSCT) with post-transplant cyclophosphamide (PTCy) in 719 patients (pts) with primary refractory (PR) / first relapse (Rel) secondary acute myeloid leukemia (sAML) (n=129) versus those of de novo AML (n=590), transplanted between 2010 and 2022. A higher percentage of pts with sAML versus de novo AML had PR disease (73.6% vs. 58.6%) (p=0.002). In 81.4% of sAML pts, the antecedent hematological disorder was myelodysplastic syndrome. Engraftment was 83.5% vs. 88.4% in sAML and de novo AML, respectively (p=0.13). In multivariate analysis HaploHSCT outcomes did not differ significantly between the groups; non-relapse mortality (NRM) hazard ratio (HR) =1.38 (95% CI 0.96-1.98, p=0.083), relapse incidence (RI) HR= 0.68 (95% CI 0.4.7.-1.00, p=0.051). The HRs for leukemia-free survival (LFS), overall survival (OS), and GVHD-free, relapse-free survival (GRFS) were 0.99 (95% CI 0.76-1.28, p=0.94), 0.99 (95% CI 0.77-1.29, p=0.97) and 0.99 (95% CI 0.77-1.27, p=0.94), respectively. We conclude that outcomes of HaploHSCT with PTCy are not different for PR/Rel sAML in comparison to PR/Rel de novo AML, a finding of major clinical importance.

Younger unrelated donors may be preferable over HLA match in the PTCy era: a study from the ALWP of the EBMT

AbstractThere is a paucity of information on how to select the most appropriate unrelated donor (UD) in hematopoietic stem cell transplantation (HSCT) using posttransplant cyclophosphamide (PTCy). We retrospectively analyzed the characteristics of 10/10 matched UDs (MUDs) and 9/10 mismatched UDs (MMUDs) that may affect transplant outcomes in patients with acute myeloid leukemia (AML) in first or second complete remission (CR1 or CR2). The primary end point was leukemia-free survival (LFS). Overall, 1011 patients were included with a median age of 54 years (range, 18-77). Donors had a median age of 29 years (range, 18-64); 304 (30%) were females, of which 150 (15% of the whole group) were donors to male recipients, and 621 (61%) were MUDs; 522 (52%) had negative cytomegalovirus (CMV-neg) serostatus, of which 189 (19%) were used for CMV-neg recipients. Donor age older than 30 years had a negative impact on relapse (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.06-1.8), LFS (HR, 1.4; 95% CI, 1.12-1.74), overall survival (HR 1.45; 95% CI, 1.14-1.85) and graft-versus-host disease (GVHD) free, relapse-free survival (HR, 1.29; 95% CI, 1.07-1.56). In addition, CMV-neg donors for CMV-neg recipients were associated with improved LFS (HR, 0.74; 95% CI, 0.55-0.99). The use of MMUD and female donors for male recipients did not significantly impact any transplant outcomes. For patients undergoing HSCT from a UD with PTCy for AML, donor age <30 years significantly improves survival. In this context, donor age might be prioritized over HLA match considerations. In addition, CMV-neg donors are preferable for CMV-neg recipients. However, further research is needed to validate and refine these recommendations.

ATG or post-transplant cyclophosphamide to prevent GVHD in matched unrelated stem cell transplantation?

There is a high risk of GVHD and non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) from unrelated donors. Prophylaxis with rabbit anti-thymocyte globulin (rATG) is standard in Europe but post-transplantation Cyclophosphamide (PTCy) is an emerging alternative. We analyzed outcomes of rATG (n = 7725) vs. PTCy (n = 1039) prophylaxis in adult patients with hematologic malignancies undergoing peripheral blood alloSCT from 10/10 antigen-matched unrelated donors (MUD) between January 2018 and June 2021 in the EBMT database. The provided P-values and hazard ratios (HR) are derived from multivariate analysis. Two years after alloSCT, NRM in the PTCy group was 12.1% vs. 16.4% in the rATG group; p = 0.016; HR 0.72. Relapse was less frequent after PTCy vs. rATG (22.8% vs. 26.6%; p = 0.046; HR 0.87). Overall survival after PTCy was higher (73.1% vs. 65.9%; p = 0.001, HR 0.82). Progression free survival was better after PTCy vs. rATG (64.9% vs. 57.2%; p < 0.001, HR 0.83). The incidence of chronic GVHD was lower after PTCy (28.4% vs. rATG 31.4%; p = 0.012; HR 0.77), whereas the incidence and severity of acute GVHD were not significantly different. GVHD-free relapse-free survival was significantly higher in the PTCy arm compared to the rATG arm (2 y incidence: 51% vs. 45%; HR: 0.86 [95% CI 0.75-0.99], p = 0.035). In the absence of evidence from randomized controlled trials, our findings support a preference for the use of PTCy in adult recipients of peripheral blood alloSCTs from MUD.

Long-term outcomes after haploidentical stem cell transplantation for hematologic malignancies

AbstractThe introduction of posttransplant cyclophosphamide (PTCy)–based graft-versus-host disease (GVHD) prophylaxis lead to significant improvements in haploidentical stem cell transplantation (haplo-SCT) outcomes over the past decade. We retrospectively assessed long-term outcomes of patients who had their first haplo-SCT between February 2009 and March 2019. Long-term survivors were defined as patients who were alive and disease-free at 2 years after transplant. Three hundred thirty-five patients with a median age of 48 years (range, 18-72) were identified. Of these, 142 patients were disease-free and alive at 2 years after transplant. The 4-year progression-free survival (PFS) and overall survival (OS) for all study patients were 42% and 47%, respectively. With a median follow-up of 52 months for the long-term survivor group, the 4-year PFS and OS were 94% and 96%, respectively. The 4-year cumulative incidence of relapse and non-relapse mortality (NRM) were 2.9% and 3.3%, respectively. Age ≥55 years was the only predictive factor in multivariate analysis for inferior PFS (hazard ratio [HR], 3.41; 95% confidence interval [CI], 1.21-9.60; P = .020) and OS (HR, 3.31; 95% CI, 1.08-10.18; P = .037). Thirteen patients (9%) died in the long-term survivor group, only 2 of whom died of relapsed disease. Secondary primary malignancy was the most frequent cause of NRM (n = 4), followed by infection (n = 2). For haplo-SCT with PTCy–based GVHD prophylaxis, our findings suggest an excellent long-term survival for patients who were disease-free and alive at 2 years after transplant. Late relapses were rare, and age was the only predictive factor for long-term outcomes.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease

AbstractIn the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative–related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier–based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between child and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100.0% and 100.0% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10.0%, and the 2-year moderate–severe chronic GVHD rate was 10.0%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, instead of the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.ClinicalTrials.gov as #NCT01850108.

HLA-haploidentical stem cell transplantation in children with inherited bone marrow failure syndromes: A retrospective analysis on behalf of EBMT severe aplastic Anemia and pediatric diseases working parties.

Haploidentical stem cell transplantation (haplo-SCT) represents the main alternative for children with inherited bone marrow failure syndrome (I-BMF) lacking a matched donor. This retrospective study, conducted on behalf of the EBMT SAAWP and PDWP, aims to report the current outcomes of haplo-SCT in I-BMFs, comparing the different in vivo and ex vivo T-cell depletion approaches. One hundred and sixty-two I-BMF patients who underwent haplo-SCT (median age 7.4 years) have been registered. Fanconi Anemia was the most represented diagnosis (70.1%). Based on different T-cell depletion (TCD) approaches, four categories were identified: (1) TCRαβ+ /CD19+ -depletion (43.8%); (2) T-repleted with post-transplant Cyclophosphamide (PTCy, 34.0%); (3) In-vivo T-depletion with ATG/alemtuzumab (14.8%); (4) CD34+ positive selection (7.4%). The cumulative incidences (CI) of neutrophil and platelet engraftment were 84% and 76% respectively, while that of primary and secondary graft failure was 10% and 8% respectively. The 100-day CI of acute GvHD grade III-IV(95% CI) was 13%, while the 24-month CI of extensive chronic GvHD was 4%. After a median follow-up of 43.4 months, the 2-year overall survival(OS) and GvHD/Rejection-free Survival (GRFS) probabilities are 67% and 53%, respectively. The TCR CD3+ αβ+ /CD19+ depletion group showed a significantly lower incidence of both acute and chronic GvHD and higher OS (79%; p0.013) and GRFS (71%; p < .001), while no significant differences in outcomes have been observed by different diagnosis and conditioning regimens. This large retrospective study supports the safety and feasibility of haplo-SCT in I-BMF patients. TCRαβ+ /CD19+ depletion offers higher chances of patients' survival, with a significantly lower risk of severe a- and c-GvHD in I-BMFs compared to other platforms.

PTCy versus ATG as graft-versus-host disease prophylaxis in mismatched unrelated stem cell transplantation

There is an increased risk of GVHD and of non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. In Europe, it is standard practice to use rabbit anti-thymocyte globulin (rATG) to reduce the high NRM and GVHD risks after MMUD alloSCT. As an alternative to rATG, post-transplantation Cyclophosphamide (PTCy) is in increasing clinical use. It is currently impossible to give general recommendations regarding preference for one method over another since comparative evidence from larger data sets is lacking. To improve the evidence base, we analyzed the outcome of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing first peripheral blood alloSCT from MMUD (9/10 antigen match) between Jan 2018 and June 2021 in the database of the European Society for Blood and Marrow Transplantation (EBMT). We performed multivariate analyses using the Cox proportional-hazards regression model. We included 2123 patients in the final analyses (PTCy, n = 583; rATG, n = 1540). p values and hazard ratios (HR) presented here are multivariate outcomes. Two years after alloSCT we found a lower NRM in the PTCy group of 18% vs. 24.9% in the rATG group; p = 0.028, HR 0.74. Overall survival in the PTCy cohort was higher with 65.7% vs. 55.7% in the rATG cohort; p < 0.001, HR 0.77. Progression-free survival was also better in the PTCy patients with 59.1% vs. 48.8% when using rATG; p = 0.001, 0.78. The incidences of chronic GVHD and acute GVHD were not significantly different between the groups. We found significantly lower NRM as well as higher survival in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The results of the current analysis suggest an added value of PTCy as GVHD prophylaxis in MMUD alloSCT.

Durable engraftment after pharmacological pre-transplant immune suppression followed by reduced-toxicity myeloablative haploidentical stem cell transplantation in highly HLA-immunized adults with sickle cell disease.

Allogeneic stem cell transplantation (Allo-SCT) is the only rapidly available curative treatment modality in patients with severe sickle cell disease (SCD). The development of reduced-toxicity myeloablative conditioning (RT-MAC) regimen and the use of partially matched family donors with post-transplantation cyclophosphamide (PT-Cy) have widened the access to Allo-SCT. Antibodies against donor-specific HLA (DSA) increase the risk of engraftment failure in HLA mismatched Allo-SCT. We report the results of five patients with SCD, whereas three with DSA, who underwent an unmanipulated haploidentical stem cell transplantation (Haplo-SCT) after a busulfan-based RT-MAC regimen with PT-Cy. To reduce the risk of engraftment failure, a sequential two courses pharmacological pre-transplant immune suppression (PTIS) phase was added prior to the conditioning regimen. All patients engrafted successfully. The procedure was well tolerated. None of the patients developed acute GVHD, whereas one developed moderate chronic GVHD. After a median follow-up of 5 years (range, 2.2-9), all patients are free of pain with excellent quality of life. Our report shows that Haplo-SCT after a RT-MAC regimen is feasible and safe with stable long-term engraftment and excellent disease control. The risk of graft failure can be abrogated by adding a PTIS phase prior to initiating the conditioning regimen.

Haploidentical stem cell donor choice for patients with acute myeloid leukemia: a study from the ALWP of the EBMT

AbstractThere is a paucity of information to guide the selection of the most suitable donor in haploidentical (Haplo) hematopoietic stem cell transplantation (HSCT). For this reason, from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation, we conducted a retrospective analysis to evaluate the impact of Haplo donor characteristics on outcomes in patients with acute myeloid leukemia (AML) who received graft-versus-host disease prophylaxis with posttransplant cyclophosphamide (PTCy). The primary end point was graft-versus-host disease (GVHD)-free and relapse-free survival (GRFS). Overall, 2200 patients were included. The median age of donors was 37 years (range, 8-71); 820 (37%) were females, including 458 (21%) who were used for male recipients. In addition, 1631 donors (74%) donated peripheral blood (PB). Multivariable analysis identified certain donor-related risk factors with a detrimental impact on transplant outcomes. The use of PB, older donors’ ages (>37 years), and female donors to male recipients negatively affected GRFS. Donor’s age and female donor-to-male recipient combination also affected nonrelapse mortality, leukemia-free survival, and overall survival. In conclusion, donor-related variables significantly influence outcomes in patients with AML after Haplo-HSCT with PTCy. When possible, younger donors and male donors for male recipients should be prioritized. The use of bone marrow can additionally prevent GVHD.

Long-Term Follow-Up of Abatacept, Post-Transplantation Cyclophosphamide, and Sirolimus-Based Haploidentical Transplantation in Younger Patients with Nonmalignant Diseases

BackgroundHaploidentical (Haplo) HCT for nonmalignant diseases (NMD) faces inherent challenges of both alloreactivity and graft failure. Building upon promising results from pilot studies, where abatacept was combined with post-transplantation cyclophosphamide (PTCy) and sirolimus (AbaCyS) in younger NMD patients undergoing haplo-HCT, we present the long-term outcomes of this protocol. Study DesignOn the back of uniform disease-specific conditioning regimens containing ATG (4.5 mg/kg) from day-9 to -7, GVHD prophylaxis (AbaCyS) consisted of abatacept administered on days 0, +5, +20, +35, and monthly until 180 days with PTCy and sirolimus. The patients were followed up with longitudinal assessment of immune reconstitution, growth and reproductive development and quality of life (QoL) analysis. ResultsAmongst 40 patients (aplastic anemia-24, hemoglobinopathies-14, and primary immunodeficiencies-2) with a median age of 10 years (range, 2-25), 95% achieved sustained engraftment. Post-transplant Hemophagocytic Syndrome was detected in 3 patients, leading to graft failure in 2 cases. The incidence of aGVHD was 2.6%, while that of cGVHD was 14.3%. CMV, adenovirus and EBV infections were observed in 45%, 5% and 0% respectively. Non-relapse mortality, overall survival, EFS and GEFS rates were 5%, 95% 90% and 82%, respectively at a median follow-up of 4.6 years. Absence of cGVHD correlated with younger patient age and early sustained recovery of Tregs and mature NK cells, which in turn was associated with improved QoL and lack of late infections. ConclusionsAbaCyS protocol is associated with excellent long-term survival with attenuation of both early and late alloreactivity in over 80% of younger patients undergoing Haplo-HCT for NMD. The study sheds light on predispositions to cGVHD and its impact on QoL, warranting further optimization of this approach.

Graft Failure Incidence, Risk Factors, and Outcomes in Patients Undergoing Non-Myeloablative Allogeneic Hematopoietic Cell Transplantation Using Post-Transplant Cyclophosphamide

Graft failure (GF) is a major complication of allogeneic hematopoietic cell transplantation (alloHCT) that results in significant morbidity and mortality. Post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has emerged as an effective regimen across the spectrum of donor-match settings, but few studies have investigated the characteristics of GF in the setting of PTCy-based GVHD prophylaxis. The objective was to detail the incidence, clinical features, risk factors, and outcomes for patients with primary graft failure (PGF) and secondary graft failure (SGF). In this retrospective study at a single institution, 958 consecutive patients undergoing first nonmyeloablative (NMA) alloHCT with PTCy-based GVHD prophylaxis were analyzed. PGF was defined as a failure to achieve an ANC ≥ 500 cells/m3 by day 30 of transplant in the absence of residual disease. SGF was defined as complete loss of donor chimerism after initial engraftment. The incidences of PGF and SGF were 3.8% (n = 37) and 1.8% (n = 17), respectively. Neither PGF nor SGF were associated with HLA disparity. In a multivariate analysis, risk factors for PGF in this cohort included age ≥ 65 (OR 2.4, 95% CI 1.2 to 4.8, P = .0120), an underlying diagnosis of MDS, MPN, or MDS/MPN overlap (OR 2.8, 95% CI 1.4 to 5.7, P = .0050), post-transplant viremia with HHV-6 (OR 2.9, 95% CI 1.5 to 5.7, P = .0030), and low CD34+ dose (OR 0.7, 95% CI 0.5 to 0.9, P = .0080). Patients with PGF had poor overall survival, driven primarily by a high rate of nonrelapse mortality (59% at 36 months). SGF was associated with use of a bone marrow graft source and a diagnosis of Hodgkin lymphoma. Patients with SGF had excellent clinical outcomes with only one of seventeen patients experiencing relapse and relapse-related mortality. The incidence of PGF and SGF in patients receiving NMA conditioning and PTCy is low and is not impacted by HLA disparities between donors and recipients. PGF is more common in recipients with age ≥ 65, a diagnosis of MDS, MPN, or MDS/MPN-overlap, post-transplant HHV-6 viremia, and low CD34+ cell dose. Low total nucleated cell dose is also a risk factor for PGF in patients receiving a bone marrow graft source. Patients who experience PGF have poor outcomes due to high rates of nonrelapse mortality, whereas patients who experience SGF have excellent long-term outcomes.

Immunosuppression-Free Status at 1 Year after Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide

Chronic GVHD among transplant patients who are one-year survivors after matched related or unrelated transplantation was shown to be associated with higher NRM and worse OS. The impact of chronic graft-versus-host disease (GVHD) requiring immunosuppression (IS) on haploidentical (HIDT) recipients with post-transplant cyclophosphamide (PTCY) who have survived one-year post-transplant has not been studied and was investigated for this analysis. A total of 322 adult patients who received HIDT at our center were included in this study. The effect of IS-free status on post-transplant outcomes was assessed. Median follow up for survivors was 63.9 months (18.3-165). A total of 163 patients (65%) were IS free at one-year post HIDT. Baseline characteristics were like those still requiring IS, except for higher female-male donor (28% vs 15 %, P=0.03) and female donors (48% vs 30%, p=0.008). Logistic regression to identify patients more likely to be on IS at 1-year post HIDT showed that female donor sex to be a significant risk (OR 2.11, p=0.009). In a Cox analysis patients requiring IS 1-yr post-transplant had higher NRM (HR 4.18, CI 1.80-6.72, p<0.001) and a trend towards worse DFS (HR 1.59, CI .95-2.66, p=0.08), without impact on OS (HR 1.44, CI 0.90-2.31, p=0.13) or relapse (HR 0.77, CI 0.37-1.61, p=0.49). These results indicate that female donors are significant risk factor for requiring IS at one-year post HIDT. Additionally, chronic GVHD requiring IS at one-year post haplo has no significant effect on relapse but is associated with higher NRM and a trend towards worse DFS.

Recombinant Human Thrombopoietin Promotes Platelet Engraftment in Severe Aplastic Anemia Patients Following Treatment With Haploid Hematopoietic Stem Cell Transplantation using Modified Post-Transplantation Cyclophosphamide

BackgroundRecombinant human TPO (rhTPO) promotes platelet engraftment in patients after allogeneic HSCT (allo-HSCT). However, the effects of rhTPO on platelet recovery after Haplo-HSCT in patients with severe aplastic anemia (SAA) have not been intensively studied. ObjectiveWe aimed to evaluate the efficacy of rhTPO on platelet engraftment in patients with SAA who were treated with Haplo-HSCT using post-transplantation cyclophosphamide (PTCy). Study DesignSAA patients who received Haplo-HSCT plus PTCy regimen were divided into the rhTPO group (with subcutaneous injection of rhTPO, n = 28) and Control group (no rhTPO administration, n = 27). The engraftment of platelet/neutrophil, platelet infusion amount, and transplant-related complications between the 2 groups were compared. ResultsAll 55 patients showed successful hematopoietic reconstitution. The median time of platelet engraftment was 11 (9 to 29) days in the rhTPO group and 14 (9 to 28) days in the Control group (P = .003). The rhTPO group had a significantly reduced amount of infused platelets compared to the Control group (2 (1 to 11.5) versus 3 (1 to 14) therapeutic doses; P = .004). There was no significant difference between the 2 groups regarding median time of neutrophil engraftment, incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD), incidence of cytomegalovirus or Epstein–Barr virus reactivation, 3-yr overall survival rate, and failure-free-survival rate. No obvious adverse reactions were observed in the rhTPO group. ConclusionrhTPO promoted platelet engraftment, reduced the amount of transfused platelets, and demonstrated good safety profiles without evidence of adverse reactions in patients with SAA who received Haplo-HSCT using PTCy regimen.

Pretransplant Blinatumomab Improves Outcomes in B Cell Acute Lymphoblastic Leukemia Patients Who Undergo Allogeneic Hematopoietic Cell Transplantation

BackgroundBlinatumomab, a bispecific monoclonal antibody, effectively controls refractory B cell acute lymphoblastic leukemia (ALL) and promotes measurable residual disease (MRD) negativity. This study investigated the impact of pretransplant blinatumomab on allogeneic hematopoietic cell transplantation (HCT) outcomes in B cell ALL patients. MethodsWe analyzed the effect of pretransplant blinatumomab on transplant outcomes of 117 adults undergoing allogeneic HCT for B cell ALL at Princess Margaret Hospital, Toronto, between 2010 and 2021. Outcomes assessed included overall survival (OS), graft-versus-host disease and relapse-free survival (GRFS), cumulative incidences of relapse (CIR), and nonrelapse mortality (NRM). ResultsThe median follow-up was 36 months. Thirty-one participants (26.5%) received blinatumomab. Blinatumomab group had higher proportions of individuals with high disease risk index, primary induction failure and was more likely to receive dual T cell depletion with antithymocyte globulin and post-transplant cyclophosphamide. Two-year OS, GRFS, NRM, and CIR in the blinatumomab and nonblinatumomab groups were, respectively: 65.4% versus 45.6% (P = .05), 42.2% versus 17.3% (P = .01), 3.2% versus 43.0% (P = .007) and 34.4% versus 14.4% (P = .02). Blinatumomab was associated with a lower incidence of day-100 grade 2 to 4 and grade 3 to 4 acute graft-versus-host disease (aGVHD): 27.5% versus 56.7% (P = .009), and 10.9% versus 34.7% (P = .04), respectively. Multivariate analysis confirmed the association between pretransplant blinatumomab and improved OS and NRM. ConclusionsPretransplant blinatumomab is associated with improved OS and lower risk of NRM in B cell ALL patients undergoing allogeneic HCT, likely reflecting lower burden of treatment-related toxicity in this population. Larger prospective trials are warranted to validate our findings.

First complete remission favours haploidentical haematopoietic stem cell transplantation with post-transplant cyclophosphamide over cord blood transplantation in acute lymphoblastic leukaemia.

To assess the benefits of HLA-haploidentical haematopoietic stem cell transplantation using post-transplant cyclophosphamide (PTCy-haplo) relative to those of umbilical cord blood (UCB) transplantation in acute lymphoblastic leukaemia (ALL), we analysed 1999 patients (PTCy-haplo, 330; UCB, 1669), using the nationwide Japanese registry. PTCy-haplo was associated with a significantly higher relapse rate, but lower non-relapse mortality, which results in overall survival and disease-free survival, comparable to those of UCB. Among patients in CR1, PTCy-haplo showed a significantly higher survival than UCB regardless of the CD34+ cell dose. Our findings provide valuable insights into the donor selection algorithm in allogeneic HSCT for adult patients with ALL.

Post-transplant cyclophosphamide versus anti-thymocyte globulin after reduced intensity peripheral blood allogeneic cell transplantation in recipients of matched sibling or 10/10 HLA matched unrelated donors: final analysis of a randomized, open-label, multicenter, phase 2 trial

The use of post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis is not established after reduced intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) from fully matched donors. This was a randomized, open-label, multicenter, phase 2 trial. All patients received a RIC regimen with fludarabine, intravenous busulfan for 2 days (Flu-Bu2), and a peripheral blood stem cell (PBSC) graft from a matched related or 10/10 HLA-matched unrelated donor. Patients were randomly assigned to receive anti-thymocyte globulin (ATG) 5 mg/kg plus standard GVHD prophylaxis or PTCy 50 mg/kg/d at days +3 and +4 plus standard GVHD prophylaxis. The primary endpoint was the composite endpoint of GVHD- and relapse-free survival (GRFS) at 12 months after HSCT. Eighty-nine patients were randomly assigned to receive either PTCy or control prophylaxis with ATG. At 12 months, disease-free survival was 65.9% in the PTCy group and 67.6% in the ATG group (P = 0.99). Cumulative incidence of relapse, non-relapse mortality, and overall survival were also comparable in the two groups. GRFS at 12 months was 54.5% in the PTCy group versus 43.2% in the ATG group (P = 0.27). The median time to neutrophil and platelet count recovery was significantly longer in the PTCy group compared to the ATG group. Except for day +30, where EORTC QLQ-C30 scores were significantly lower in the PTCy compared to the ATG group, the evolution with time was not different between the two groups. Although the primary objective was not met, PTCy is effective for GVHD prophylaxis in patients receiving Flu-Bu2 conditioning with a PBSC graft from a fully matched donor and was well tolerated in term of adverse events and quality of life. This trial was registered at clinicaltrials.gov: NCT02876679.

Peripheral blood stem cell transplantation using HLA-haploidentical donor with post-transplant cyclophosphamide versus HLA-matched sibling donor for lymphoma.

Data comparing HLA-haploidentical donors and HLA-matched sibling donors (MSDs) in peripheral blood stem cell transplantation (PBSCT) for lymphoma are scarce. We retrospectively analyzed 465 patients with lymphoma aged 16 years or older who underwent PBSCT using haploidentical donors with post-transplant cyclophosphamide (PTCy-haplo) (n = 166) or MSDs with calcineurin inhibitor-based graft-versus-host disease (GVHD) prophylaxis (n = 299). Two-year overall survival (OS), progression-free survival (PFS), and GVHD-free, relapse-free survival (GRFS) in the PTCy-haplo and MSD groups were 49.2% versus 51.9% (P = 0.64), 38.0% versus 39.9% (P = 0.97), and 27.7% versus 18.5% (P = 0.006), respectively. In multivariable analyses, PTCy-haplo recipients had slower neutrophil recovery (hazard ratio [HR], 0.62; P < 0.001) and platelet recovery (HR, 0.54; P < 0.001), lower risk of chronic GVHD (HR, 0.64; P = 0.038) and extensive chronic GVHD (HR, 0.45; P = 0.008), and better GRFS (HR, 0.66; P = 0.003) than MSD transplant recipients. OS, PFS, relapse or progression, and non-relapse mortality were similar between the groups. The difference might be mainly due to PTCy use rather than donor type; however, the results suggested that PTCy-haplo could be a possible option as an alternative to conventional MSD transplantation for lymphoma in PBSCT.