Conditioning Allogeneic Stem Cell Transplantation Research Articles

Impact of Anti-Thymocyte Globulin on Procalcitonin Levels Comparison during Fever in Allogeneic Stem Cell Transplantation Conditioning

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a complex medical procedure that offers hope for patients with various hematological disorders. However, one of the significant challenges associated with allo-HSCT is the risk of infection, which remains a major contributor to non-relapse mortality. Detecting and managing infectious diseases in febrile patients during the pre-transplant conditioning phase is of utmost importance to ensure successful transplantation outcomes. In this context, procalcitonin (PCT) has emerged as a valuable diagnostic tool, serving as an auxiliary marker for severe infections. Additionally, PCT has shown promise as a predictor of infections in patients undergoing allo-HSCT. Its ability to aid in early detection and subsequent intervention has made it an attractive biomarker for clinicians. However, the interpretation of PCT levels in patients receiving anti-thymocyte globulin (ATG) as part of their pre-transplant conditioning has posed specific challenges. ATG, a commonly used immunosuppressive agent in allo-HSCT, plays a vital role in reducing the risk of graft rejection and graft-versus-host disease. However, ATG administration is not without its drawbacks, as it can lead to various side effects such as fever and hypotension. These ATG-induced symptoms must be carefully distinguished from infectious diseases to ensure appropriate treatment decisions. One particular concern in this regard is the potential impact of ATG administration on PCT levels. Unfortunately, there is a paucity of data on PCT levels in febrile patients who have received ATG, making it difficult for clinicians to interpret the results accurately. Furthermore, a comprehensive analysis comparing the increase in PCT levels during the conditioning phase for allo-HSCT and its associated risk factors in ATG and non-ATG regimens is lacking. Understanding how ATG affects PCT levels during febrile episodes and whether PCT can effectively discriminate between infections and ATG-related symptoms is crucial for optimizing patient care. To address these gaps in knowledge, we conducted a retrospective analysis involving 76 patients who developed febrile episodes during the pre-transplant conditioning phase, and their PCT levels were measured and compared in our institution. Our study aimed to elucidate whether ATG administration could lead to increased PCT levels during febrile episodes in the context of pre-transplant conditioning and whether PCT could serve as a reliable marker for distinguishing infections during this critical period. The findings of our analysis shed light on the complex relationship between ATG administration, PCT levels, and infectious diseases. Notably, ATG administration was identified as the sole significant factor contributing to increased PCT positivity during fever (p = 0.01). In contrast, the presence of infectious diseases did not significantly impact PCT positivity in the ATG group (p = 0.24). Intriguingly, bloodstream infection emerged as a significant risk factor for PCT positivity in patients who received non-ATG regimens (p < 0.01). These results underscore the importance of considering ATG administration when interpreting PCT levels in febrile patients undergoing pre-transplant conditioning for allo-HSCT. The administration of ATG can confound the interpretation of PCT levels during febrile episodes, potentially leading to inaccurate diagnoses of infectious diseases. Clinicians must exercise caution and be aware of this confounding factor when incorporating PCT values into the diagnostic workup, particularly in patients receiving ATG regimens. In conclusion, our study highlights the complexity of using PCT as a diagnostic marker in febrile patients undergoing pre-transplant conditioning for allo-HSCT. While PCT shows promise as a valuable tool for predicting and detecting infections, its interpretation must be approached with caution in patients receiving ATG regimens. Future research is warranted to further elucidate the intricacies of PCT dynamics in the context of allo-HSCT, enabling clinicians to optimize its use and improve patient outcomes in this challenging and high-stakes medical procedure.

Clofarabine and High-Dose Melphalan Reduced Intensity Conditioning Regimen with Methotrexate-Based GvHD Prophylaxis

Introduction: Reduced-intensity conditioning (RIC) allogeneic stem cell transplant (allo-SCT) remains a curative option for elderly and/or unfit patients with hematologic malignancies. Fludarabine-containing regimens make up the cornerstone of RIC regimens, however, during the nation-wide fludarabine shortage in 2022, many institutions used fludarabine-free RIC regimens out of necessity though data was extremely limited. Clofarabine is a second-generation purine analog with more potent anti-leukemic activity and a different adverse effect profile compared to fludarabine. We report our experience with clofarabine-based RIC conditioning for adult patients with non-Hodgkin's lymphoma (NHL) and myeloid malignancies. Methods: In this retrospective single-center matched cohort study at Stanford Health Care, we compared adult RIC allo-SCT patients receiving clofarabine and melphalan (CloMel) with a matched cohort receiving fludarabine and melphalan (FluMel) from January 1, 2022 to December 31, 2022. CloMel consisted of clofarabine 30 mg/m 2 on days -6 to -2 followed by melphalan 140 mg/m 2 on day -1, while FluMel consisted of fludarabine 30 mg/m 2 on days -5 to -2 followed by melphalan 140 mg/m 2 on day -1. Clofarabine dose adjustments were made in patients with renal dysfunction according to the following institutional guidelines based on creatinine clearance (CrCl): 22.5 mg/m 2 for CrCl 60 to 79 mL/min, 15 mg/m 2 for CrCl 30 to 59, and avoiding clofarabine for CrCl less than 30 mL/min. Dose modifications for fludarabine and melphalan due to renal dysfunction were at the discretion of the care team. Patients received graft versus host disease (GvHD) prophylaxis with tacrolimus and methotrexate. Efficacy and safety outcomes were assessed. Data were analyzed using Mann-Whitney U and chi-square tests. Results: We identified 9 matched pairs for a total of 18 patients. Most patients received an allo-SCT for a myeloid malignancy (8 patients with AML, 8 patients with MDS, and 2 patients with NHL). All patients received a peripheral blood stem cell transplant, with 89% receiving a matched unrelated donor and 11% receiving a matched related donor transplant. Baseline characteristics were balanced between groups. There was no difference in time to neutrophil engraftment (mean 14 vs 14 days; p=0.42), time to platelet engraftment (mean 16 vs 24 days; p=0.33), or 100% donor whole blood chimerism (71% vs 78%; p=0.32) at 6 months in the CloMel and FluMel groups, respectively. No statistically significant difference was observed for the number of patients who experienced acute (2 vs 0; p=0.13) and chronic GvHD (0 vs 4, p=0.09) at 6 months between groups. At 6 months, 2 patients in the CloMel group and no patients in the FluMel group experienced early non-relapse mortality (p=0.13). Both patients who died experienced acute renal failure secondary to conditioning chemotherapy with a median onset of renal dysfunction 6 days after initiation of clofarabine, followed by sepsis and multi-organ failure. Both patients required initiation of external renal replacement therapy and ultimately passed 12 days and 29 days post-transplant, prior to engraftment. Notably, both patients had a history of kidney dysfunction prior to transplant, one patient with chronic kidney disease (CKD) stage 3 and the other patient with lymphomatous involvement of the kidneys, and received appropriate clofarabine renal dose adjustments per institutional standards. Conclusion: CloMel demonstrated similar efficacy outcomes at 6 months and represents a feasible alternative to FluMel as a RIC regimen. However, given the notable occurrence of renal failure and early death in the CloMel arm, careful consideration and particular caution in administering to patients with a prior history of renal disease is recommended.

Reduced-intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for patients with myelofibrosis.

Allogeneic hematopoietic stem cell transplantation (alloSCT) is the sole curative option for myelofibrosis (MF). However, it is unknown as to which of the two, myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), is a better preconditioning regimen. Twenty-five patients with MF were treated with alloSCT, 12 of whom underwent RIC. Baseline characteristics, response to alloSCT, adverse events, including graft-versus-host disease (GVHD), and survival outcomes were reviewed. There was no difference in the neutrophil engraftment rate and time to engraftment between MAC vs. RIC. The time to platelet engraftment was significantly longer in the MAC group (median, 112.8 vs. 28.8 days for MAC vs. RIC, respectively, P=0.049). RIC was more advantageous in terms of achieving complete chimerism (38.5% vs. 83.3%, P=0.041). The incidence of acute GVHD was 84.6% (11 of 13) and 58.3% (7 of 12) in the MAC and RIC groups, respectively. The cumulative incidence of grade III‒IV acute GVHD was significantly higher in the MAC group than in the RIC group (P=0.03). No significant differences were observed in progression-free and overall survival. The 17-month probability of progression-free survival was 38.4% [95% confidence interval (CI), 19.3‒76.5] vs. 47.6% (95% CI, 25.7‒88.2) (P=0.21), and that of overall survival was 53.8% (95% CI, 32.5‒89.1) vs. 48.6% (95% CI, 26.8‒88.3) (P=0.85) for MAC vs. RIC, respectively. RIC offers a significant advantage over MAC, even in younger patients with MF undergoing alloSCT, in terms of cell engraftment, rate of complete chimerism achievement, and incidence of acute GVHD.

The Easix Score Predicts Overall Survival and Late Relapse in Patients Undergoing Reduced Intensity Conditioned Allogeneic Stem Cell Transplantation for Myeloid Disease

Background Allogeneic hematopoietic stem cell transplantation (alloSCT) is an effective treatment for myeloid malignancies, however outcomes post-transplant are variable and predictive scores limited. The Endothelial Activation and Stress Index (EASIX) measured at key timepoints pre- and post-transplant has been shown to predict outcomes in alloSCT, including overall survival, non-relapse mortality and incidence of sinusoidal obstructive syndrome (SOS). It can be readily calculated using standard biomarkers (LDH (U/L) x creatinine (mg/dL)/platelets (x109/L). We sought to examine its predictive role in a homogenous population of patients. Methods We conducted a retrospective national review of 117 patients undergoing reduced-intensity alloSCT for myeloid disease including AML (n=56), MDS (n=35) and MPN (n=26). All included received fludarabine, busulfan and rabbit anti-thymocyte globulin (Flu/Bu/ATG) conditioning from 2015-2020. We calculated the EASIX score on the day prior to conditioning, on day 0, at onset of acute graft versus host disease and 1 year post transplant. Univariate analysis was conducted in the STATA statistical package. Results At the pre-conditioning time-point the mean EASIX was 3.11 (0.3-17.54). Increased scores correlated with and were reliably predictive of reduced overall survival (p=0.034) (fig. 1). Higher scores at this time-point did not predict chronic GVHD or relapse, however an increased rate of acute GVHD was seen in those with lower EASIX (p=0.012). At day 0 the mean EASIX was 15.38 (1.07-179.02), however we could not demonstrate a predictive effect on SOS as no events occurred in this cohort. Nor did we identify a predictive value at this point for GVHD risk or relapse. At onset of acute GVHD (n=67, mean 3.52, 0.44-51.43), the EASIX score was predictive of overall survival (p=0.027) but did not predict risk of chronic GVHD or relapse. At 1 year post-transplant (n=88, mean 2.09, 0.48-13.59) a higher score showed a trend towards decreased overall survival (p=0.1) but was associated with an increased risk of subsequent relapse (p=0.01)(fig. 2). Conclusions The EASIX score is an easily applicable clinical tool using real world biomarkers readily available at serial time-points in transplant recipients. When applied to our homogenously treated cohort it retains its value in predicting overall mortality at the key time points of pre-conditioning and at onset of GVHD. Adoption of this simple score may be of benefit in risk stratifying the transplant process for reduced intensity conditioned allograft recipients, particularly when combined with established prediction tools for non-relapse mortality such as the HCT-CI. In addition to this, we have shown that the EASIX score may be a useful predictive tool for late relapse in those patients who are alive at 1 year post transplant. We suspect that this effect is primarily reflective of those patients with persistent thrombocytopenia and raised LDH, both markers of potential disease activity. Importantly, the use of this score in the reduced intensity population may be particularly relevant due to the increasing age of transplant eligibility and its use as a surrogate of endothelial dysregulation and potential for end organ complications through the transplant process. To assess the underlying T cell mediated and cytokine secretome effects on endothelial dysfunction, an observational study is ongoing at our institution, examining the interplay of immunomodulatory therapy, graft T cell content, early T and NK cell recovery and the cytokine secretion patterns at various time points before, during and after transplant in reduced intensity conditioned patients with myeloid disease. We plan to correlate these data with serial EASIX assessments to identify the determinants of the underlying biological process and identify potential time-points and biological targets for future study.

Outcomes After Donor Lymphocyte Infusion in Patients With Hematological Malignancies: Donor Characteristics Matter

In the context of T-cell depletion, failing to achieve full donor chimerism (FDC) entails higher risk of graft loss and disease relapse. Donor lymphocyte infusion (DLI) is an adoptive immunotherapy for mixed chimerism (MC) or relapsed disease after reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (HSCT). Nevertheless, little is known of factors associated with attaining FDC or disease remission. We carried out a retrospective study with 100 adult patients to identify patient and donor factors that can predict achievement of FDC and disease remission and describe complications after DLI. Indications for DLI were T-cell MC in 61 patients and relapsed disease in 39 patients. Forty patients (65.6%) with MC attained T-full donor chimerism (T-FDC), with higher responses seen in patients whose donors were female (81.5% versus 52.9%, P = .004) and cytomegalovirus negative (76.5% versus 52%, P = .004). However, only patients with younger donors (<30 years old) compared to older donors (94.4% versus 53.5%, P = .013) and those attaining unfractionated whole blood (UWB) FDC after DLI (76.6% versus 28.6%, P < .001) had a survival benefit and subsequently a better graft-versus-host disease (GvHD)–free/relapse-free survival. Nineteen of 39 patients (48.7%) with relapsed disease achieved remission after DLI. In this cohort, attaining T-FDC impacted favorably in disease control (76.7% versus 12.5%, P = .012) and improved survival (45.5% versus 12.5%, P = .007). In the whole population, the cumulative incidence of acute GvHD (aGvHD) at day 100 after DLI was 23%, and chronic GvHD (cGvHD) at 1 year after DLI was 22%. In the whole population, donor age was also a determining factor for aGvHD, because patients with younger donors had a lower incidence of aGvHD (8% versus 36%, P = .021). The cGvHD was more likely to occur in patients who converted to T-FDC (34% versus 10.3%, P = .025). Donor characteristics are increasingly considered when deciding approaches for HSCT. Donor age should be considered when planning HSCT, as well as doses and scheduling of DLI. As per our experience, this should be done alongside T/UWB chimerism to achieve the maximal clinical benefit with less associated toxicity. Selection of younger male donors from stem cell registries can minimize the risk of GvHD and improve survival.

Impact of donor types on reduced-intensity conditioning allogeneic stem cell transplant for mature lymphoid malignancies.

We retrospectively compared the outcomes of reduced-intensity conditioning (RIC) transplantation from matched related donors (MRD; n = 266), matched unrelated donors (MUD; n = 277), and umbilical cord blood (UCB; n = 513) for mature lymphoid malignancies. The 3-year overall survival rates for the MRD, MUD, and UCB groups were 54%, 59%, and 40%, respectively (P < 0.001). Multivariate analysis showed no differences in survival between the MRD group and the MUD or UCB group. However, survival was significantly affected by the conditioning regimen and graft-versus-host disease (GVHD) prophylaxis in the UCB group, but not in the MRD and MUD groups. Notably, multivariate analysis showed that the risk of overall mortality in the UCB recipients who received the optimal conditioning regimen and GVHD prophylaxis (n = 116) was lower than that in the MRD group (relative risk [RR], 0.69; P = 0.03) and tended to be lower than that in the MUD group (RR, 0.75; P = 0.09). Our results suggest that UCB transplantation performed with the optimal conditioning regimen and GVHD prophylaxis is highly effective. Moreover, UCB is readily available. Thus, UCB transplantation with the optimal conditioning regimen and GVHD prophylaxis is preferable to MUD transplantation when MRD are not available in the setting of RIC transplantation for mature lymphoid malignancies.

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Final Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO - SFGM-TC French intergroup)

RIC Allogeneic Stem Cell Transplantation for High Risk CLL Followed By Preemptive MRD-Based Immunointervention - Final Results from the Phase II ICLL03 Ricac-Pmm Trial (FILO - SFGM-TC French intergroup)

Trudności w leczeniu chorego na ostrą białaczkę szpikową z mutacją FLT3-ITD i wysokim stosunkiem allelicznym — oporność na standardową chemioterapię indukującą w połączeniu z midostauryną

The development of targeted therapies in AML patients enabling treatment individualization, such as new FLT3 tyrosine kinase inhibitors, is a promising option for improving treatment outcomes and prolonging patient survival. However, the treatment of patients with a high FLT3-ITD allelic ratio (FLT3-ITD high ) associated with an extremely unfavourable prognosis remains a major clinical problem. The study presents a case of a 20-year-old patient with FLT3-ITD high extramedullary AML at diagnosis. Individualized chemotherapy according to the DA ‘3 + 7’ regimen combined with midostaurin was administered. After the induction treatment, complete remission (CR) was not achieved. After second induction chemotherapy, CR1 was achieved with the presence of residua disease. One cycle of consolidation chemotherapy was then administered, and after myeloablative conditioning allogeneic hematopoietic stem cell transplantation from an unrelated donor was performed. The patient has remained in CR with no residual disease for 18 months.

BEAM-Campath Allogeneic Stem Cell Transplant for Patients with Relapsed/Refractory Lymphoma: High Incidence of Long-Term Mixed Donor-Recipient Chimerism and the Response to Donor Lymphocyte Infusions

BiCNU (carmustine), etoposide, Ara-C, melphalan (BEAM) and Campath conditioning was developed to reduce the high transplant-related mortality in patients with lymphoma while delivering intensive antilymphoma immunotherapy, as well as to some extent a platform for allogeneic stem cell engraftment. Significant numbers of patients appeared to have persistent recipient-derived hematopoiesis, and therefore we retrospectively analyzed patients with lymphoma undergoing BEAM-Campath conditioned allogeneic stem cell transplantation at our center (2003 to 2017) to characterize the patterns of chimerism and patient outcomes. Chimerism was analyzed with short tandem repeat PCR. Mixed donor-recipient chimerism (MDRC) was defined as 5% to 94.9% donor. Fifty-two patients (n=30 male), with a median age of 45 years, were identified with histologic diagnoses of Hodgkin lymphoma (n=13), diffuse large B cell lymphoma (n=7), low-grade non-Hodgkin lymphoma (n=16), mantle cell lymphoma (n=10), and T cell lymphoma (n=6). Pretransplant, 93% achieved complete response (52%) or partial response (41%) with a median of 3 prior therapies (n=3 prior autologous stem cell transplantation). Donors were Matched sibling donors (MSD) (n=21), matched unrelated donors (MUD) (n=24), miss-matched unrelated donors (MMUD) (n=6), and syngeneic (n=1). Acute graft-versus host disease (GVHD) developed in 52% (81% grade I to II) and chronic GVHD (83% extensive) in 12%. MDRC of T cells (MDRCt) developed in 62% (n=32), and 29% (n=15) developed MDRC of myeloid cells (MDRCm) at a median onset of 100 days. Donor lymphocyte infusion (DLI) was given to 17 patients, with a median starting dose of 1×106/kg. The first DLI was given at a median of 225 days post-transplant (range, 99 days to 5.3 years). Of these, 9 developed acute post-DLI GVHD and 2 limited chronic GVHD. Conversion to full donor occurred in 47% MDRCt and 50% MDRCm. Multivariate analysis identified sibling donor type as associated with increased MDRCt (P=.035; hazard ratio [HR], 0.17) and reduced total nucleated cell dose with increased MDRCm (P=.021; HR, 0.76). The median follow-up was 6 years, and 2-year NRM cumulative incidence was 16% (95% confidence interval [CI], 7% to 27%). Ten-year progression and extensive GVHD-free survival was 45% (95% CI, 28% to 61%), and overall survival was 66% (95% CI, 50% to 78%). One-year landmark analysis identified no increased GVHD or relapse risk with MDRCt or MDRCm but reduced nonrelapse mortality (NRM) risk with MDRCt (P=.001). BEAM-Campath allografts for high-risk lymphoma achieve long-term disease-free survival with low rates of GVHD and transplant-related mortality. The frequent development of myeloid MDRC demonstrates that BEAM-Campath is a nonmyeloablative conditioning regimen in almost a third of patients. MDRCt is associated with reduced NRM, but neither MDRCt or MDRCm is associated with increased GVHD or relapse.

Non-myeloablative matched sibling stem cell transplantation with the optional reinforced stem cell infusion for patients with hemoglobinopathies.

The NIH protocol for non-myeloablative (NMA) conditioning allogeneic stem cell transplantation (alloSCT) with alemtuzumab and low-dose total body irradiation corrected the abnormal sickle cell disease (SCD) phenotype without the risk of graft-versus-host disease. However, alloSCT using NMA conditioning had been rarely applied to β-thalassemia major (β-TM) patients. To avoid prolonged immunosuppression, we developed a two-stage strategy. Mixed donor chimerism was initially achieved using the protocol developed by the NIH protocol. Thereafter, we facilitated donor chimerism using the optional reinforced stem cell (SC) infusion in cases requiring protracted immunosuppression or experiencing impending graft failure. In this study, β-TM (n=9) and SCD (n=4) patients were equally effectively treated with eradicating the abnormal hemoglobin phenotype. Five patients, including four β-TM, achieved stable mixed chimerism without receiving optional reinforced SC infusion. All patients that received optional reinforced infusion achieved complete (n=4) or mixed chimerism (n=1). The overall survival rate and event-free survival at 4years were 91.7% (95% CI; 53.9-98.8) in both groups, with a thalassemia-free survival rate in β-TM patients of 87.5% (95% CI; 38.7-98.1). This study is the first to report successful NMA conditioning alloSCT to achieve stable mixed chimerism correcting the abnormal hemoglobin phenotype in adult β-TM patients.

A gut microbiota score predicting acute graft-versus-host disease following myeloablative allogeneic hematopoietic stem cell transplantation.

Although studies have reported that intestinal microbiota are associated with acute graft‐versus‐host disease (aGVHD), they lacked a satisfactory method for predicting aGVHD. We collected stool and blood samples at day 15 posttransplant from 150 patients from two centers who underwent myeloablative conditioning allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Stool microbiota were detected by 16S ribosomal RNA gene sequencing; inflammatory factors and T lymphocytes were detected by multiplex immunoassays and flow cytometry, respectively. A gut microbiota score (GMS) from a LASSO (least absolute shrinkage and selection operator) model was developed and validated to predict aGVHD. In the discovery cohort, the GMS could predict II‐IV aGVHD (area under the receiver operating characteristic [ROC] curve [AUC] = 0.904, P < .0001). Furthermore, the validation model was consistent with the discovery set (AUC = 0.887, P < .0001). Regulatory T/T‐helper 17 (Treg/Th17) cells ratio in the low GMS subgroup was higher compared with the high GMS (P = .012), and the validation set is consistent with the discovery set (P = .003). In addition, high cytokine levels were associated with high GMS. In conclusion, the GMS at neutrophil engraftment could predict aGVHD, and it was a potential and novel method. The GMS was associated with the inflammatory factor and Treg/Th17 balance.

Risk factors associated with the development of moderate to severe chronic graft-versus-host disease after non-myeloablative conditioning allogeneic stem cell transplantation in patients with AML or MDS

Moderate to severe chronic graft-versus-host disease (cGVHD) is associated with high morbidity, hospital dependency and poor quality of life. In this study, we analyzed a well-defined consecutive series of 98 patients with acute myelogenous leukemia/myelodysplastic syndrome (AML/MDS) who received allogeneic stem cell transplantation with non-myeloablative (NMA) conditioning to determine risk factors associated with the severity of cGVHD. cGVHD was defined according to the 2005 National Institute of Health consensus criteria. Transfusions before transplantation, presence of HLA antibodies, composition of the graft (CD3+, CD19+, CD34+ cells), sibling or matched unrelated donor, female donor to male recipient, CMV serology and the development of acute GVHD (aGVHD), were considered potential risk factors. Multivariate Cox regression analysis identified the number of CD19+ 106/kg (HR 2.79; 95% CI 1.35–5.74), CD3+ 106/kg (HR 2.18; 95% CI 1.04–4.59) infused cells and the presence of patient HLA antibodies before transplantation (HR 2.34; CI 1.11–4.95) as significant risk factors for the development of moderate to severe cGVHD. In summary, we identified in a small, but well-defined cohort, 3 risk factors associated with the severity of cGVHD that should be validated in a larger multi-center study.

Total Skin Electron Beam Therapy in Patients with Advanced Cutaneous T Cell Lymphoma Undergoing Allogeneic Stem Cell Transplantation: A Single Centre Experience

Introduction: Total skin electron beam (TSEB) therapy represents a valid treatment option in the management of patients with cutaneous T-Cell lymphoma (CTCL) with diffuse skin involvement. While the efficacy of TSEB for palliative treatment is well established, its inclusion as a debulking strategy before reduced-intensity conditioning allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been only recently reported. Due to the lack of hematopoietic toxicity, TSEB may also be effectively administered in patients relapsing after allo-HSCT. With this study we aimed to retrospectively investigate the use of TSEB among patients who underwent to allo-HSCT in our Center for advanced CTCL. Patients &amp; Methods: As of July 2019, 45 CTCL patients (26 M and 19 F, median age 54 years, range 19-66) all having stage IIB to IV refractory Mycosis Fungoides (MF, n=33) or Sézary Syndrome (SS, n=12) underwent allo-HSCT from HLA-identical sibling (n=18), unrelated donors (n=23) or haploidentical related donors (n=4). Median time from diagnosis to HSCT was 46 months and median number of previous treatment lines was 6. Source of stem cells was peripheral blood in 40 patients, bone marrow in 4 patients and cord blood in 1 patient. Conditioning regimens included FC/TBI200, pentostatin/TBI200, fludarabine/melphalan and TT/CTX/Fluda/TBI200. Outcomes at 5-years were: OS 51% (33%-66%), DFS 40% (20%-50%), NRM 15% (4%-27%) and relapse incidence 48% (32%-65%). Clinical charts of the whole series of patients were extensively reviewed to collect information on the use of TSEB from diagnosis to the last follow up date. Results: Overall 21 patients of the series received TSEB with dose fractionation of 2 Gy in 2 days administered with the Stanford Technique as part of their treatment strategy. In six cases it was included among the lines of treatment administered over the disease course preceding transplant referral, with a total dose of 36 Gy in all of them. In 13 patients TSEB was part of the debulking strategy for patients with chemorefractory disease just prior to allo-HSCT with a median total dose of 24 Gy (range 10.8- 36). In 4 patients TSEB was administered after transplantation: as a salvage treatment for skin relapse during early post tranplant intense immunosuppression phase in 3 cases (12, 36, 21.6 Gy respectively) and as palliative treatment for disease progression in one case (36 Gy). Among patients who received TSEB as a bridge to transplant strategy, CR was achieved in 5 cases: at the last follow up visit (median time from transplantation 23 months, range 6-80) 4 were alive with persistent CR, whereas 1 patient who experienced graft failure died from disease progression 31 months after transplantation. Partial remission (PR) was documented in 7 (very good in 2): at the last follow up visit (median time from transplantation 14 months, range 6-52) 2 patients were alive in CR and 5 died: 3 from disease progression, 1 from GVHD and 1 from myocardial infarction 42 months after transplantion. In 1 patient, who only showed minimal response to TSEB therapy, death from disease progression occurred 9 months after an autologous-allogeneic tandem transplant strategy. All the 3 patients receiving TSEB after allo-HSCT for early relapse achieved a new and durable CR maintained at the last follow up date (42, 21 and 10 months after transplant respectively), suggesting the occurrence of a durable graft-versus-lymphoma effect following TSEB. As far as safety is concerned, only grade 1 skin toxicity (erythematous reactions) was observed in a minority of patients, while no case of haematological toxicity was documented. Conclusions: Our experience confirmed TSEB as a particularly safe and potentially effective treatment strategy in CTCL patients, both to induce remission prior to allo-HSCT and to rescue early post transplant relapse occurring before immunosuppression withdrawal. Disclosures No relevant conflicts of interest to declare.

Myeloablative and Reduced-Intensity Conditioned Allogeneic Hematopoietic Stem Cell Transplantation in Myelofibrosis: A Retrospective Study by the Chronic Malignancies Working Party of the European Society for Blood and Marrow Transplantation.

This retrospective study by the European Society for Blood and Marrow Transplantation analyzed the outcome of 2224 patients with myelofibrosis (MF) who underwent allogeneic stem cell transplantation (allo-SCT) between 2000 and 2014; 781 (35%) underwent myeloablative conditioning (MAC) and 1443 (65%) reduced-intensity conditioning (RIC). Median patient age was 52.9 years (range, 18 to 74 years) and 57.5 years (range, 21 to 76 years) in the MAC and RIC cohorts, respectively. Donor type was similar: matched sibling donors (MAC, 317 [41%]; RIC, 552 [38%]) and unrelated donors (MAC, 464 [59%]; RIC, 891 [62%]). Median time to both neutrophil and platelet (>20 × 109/L) engraftment did not differ between cohorts. Rates of grade II to IV acute GVHD were 28% (MAC) and 31% (RIC; P = NS). Cumulative chronic GVHD rates (limited/extensive) were 22%/27% (MAC) and 19%/31% (RIC; P = .10). Cumulative incidences of nonrelapse mortality (NRM) at 1, 3, and 5 years were 25.5%, 32.2%, and 34.6% (MAC) and 26.3%, 32.8%, and 34.4% (RIC), respectively. There was a trend toward a higher relapse rate with RIC regimens compared with MAC (P = .08); rates at 1, 3, and 5 years were 10.9%, 17.2%, and 20.1% (MAC) and 14%, 19.7%, and 23.2% (RIC), respectively. No significant difference in 5-year probabilities of overall survival (OS) was noted: MAC (53.0%; 95% confidence interval [CI], 49.1% to 56.9%) and RIC (51.0%; 95% CI, 48.3% to 53.7%); P = .78. Regarding the composite end point of GVHD-free/relapse-free survival (GRFS), the unadjusted Kaplan-Meier estimate of 5-year GRFS was 32.4% (95% CI, 29.0% to 36.1%) in the MAC group and 26.1% (95% CI, 23.9% to 28.2%) in the RIC group (P = .001). In the MAC cohort, multivariable analysis confirmed worse OS and NRM with older age (>50 years), using an unrelated donor and a Karnofsky Performance Status of 80 or less. For the RIC cohort, worse OS and NRM were associated with age 60 to 70 years compared with younger recipients, use of a mismatched donor, and poor performance status. In conclusion, although similar OS rates existed for both cohorts overall, this study suggests that MAC should still be used for younger individuals suitable for such an approach due to a trend toward less relapse and an overall suggested advantage of improved GRFS, albeit this should be examined in a more homogeneous cohort. RIC allo-SCT still offers significant survival advantage in the older, fitter MF allograft patient, and optimization to reduce significant relapse and NRM rates is required.

Comparison of Two Doses of Antithymocyte Globulin in Reduced-Intensity Conditioning Allogeneic Hematopoietic Stem Cell Transplantation.

The appropriate dose of antithymocyte globulin (ATG) to be used in reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) is yet to be determined. We retrospectively analyzed the outcomes of patients who underwent unrelated or mismatch related RIC allo-HSCT for hematologic malignancies and received r-ATG (4.5 mg/kg, 141 patients) versus R-ATG (6 mg/kg, 216 patients). There was a higher incidence of cytomegalovirus (P < .001) and Epstein-Barr virus viremia (P =.03) in the R-ATG group than in the r-ATG group. The cumulative incidences of acute graft-versus-host disease (aGVHD) grades II to IV at day 180 in the r-ATG and R-ATG groups were 59% and 44% (P = .006) and grades III to IV 20% and 12% (P = .029), respectively. In multivariable models adjusting for disease diagnosis, the risk of aGVHD grades III to IV did not reach statistical significance (P = .087). The respective cumulative incidences of chronic GVHD in the r-ATG and R-ATG groups were 26% and 15% (P = .10), respectively. There were no significant differences in relapse rate (P = .24), nonrelapse mortality (P = .96), progression-free survival (P = .24), overall survival (P = .70), and GVHD-free relapse-free survival (P = .24). In this retrospective analysis, aGVHD incidence was higher in those treated with r-ATG compared with R-ATG, but this did not translate into significant differences of clinical outcome. Given the increasing use of RIC allo-HSCT for treating malignant hematologic conditions, the correct dose and schedule of ATG administration should be defined by prospective randomized controlled trials.

Brentuximab vedotin prior to allogeneic stem cell transplantation increases survival in chemorefractory Hodgkin's lymphoma patients.

This study reports a retrospective multicenter experience by the Rete Ematologica Pugliese (REP) over the past 16years, aiming to compare the patients characteristics and outcomes of 21 brentuximab vedotin (BV)-pre-treated patients to 51 patients who received reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (SCT) without prior BV. In total, 72 patients with classical Hodgkin's lymphomas who received allogeneic SCT were retrospectively studied. Prior use of BV had no effect on either engraftment or the incidence and severity of acute graft versus host disease (GVHD). Indeed, a lower incidence of chronic GVHD was observed in the BV group, with a 43% cumulative incidence at 3years versus 47% in the no BV group, although this was not statistically significant. Despite the low incidence of chronic GVHD, survival was not worse in the BV-treated group: 3-year progression-free survival (PFS) was 53%, 3-year overall survival (OS) was 62%, 3-year non-relapse mortality (NRM) was 24%. In the no BV group, the 3-year PFS was 33%, 3-year OS was 44%, and 3-year NRM was 14%. In chemorefractory patients at the time of transplant, we found a statistically significant difference in PFS between the BV and no BV groups (51% vs. 10%, p = 0.013).

A unique case of durable complete remission after salvage with azacitidine and DLI for high risk flt-3 positive acute myeloid leukemia, following relapse 18 months post allogeneic stem cell transplant.

A unique case of primary refractory FLT3-itd mutated acute myeloid leukemia in an elderly patient, who achieved completed morphological remission, and FLT3-itd negativity, following 9 cycles of azacitadine in combination with escalating doses of donor lymphocyte infusions following relapse 18 months post reduced intensity HLAA mismatch Campath conditioning allogeneic stem cell transplant.

Safety and Efficacy of Myeloablative Conditioning Autologous Stem Cell Transplantation, Targeted Immunotherapy, and Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation in Children, Adolescents, and Young Adults with Relapsed/Refractory Mature B-Cell Non-Hodgkin Lymphoma

Background Despite high cure rates for children, adolescents and young adults (CAYA) with mature B-cell non-Hodgkin lymphoma (B-NHL) (Cairo, JCO, 2012), the results are dismal in those with relapsed/refractory (r/r) disease following reinduction therapy with myeloablative conditioning (MAC) and autologous stem cell transplantation (AutoSCT) (Cairo, BBMT, 2013). Sequential MAC AutoSCT and reduced intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) has achieved 59% 10-year event-free survival (EFS) in CAYA with Hodgkin (Satwani/Cairo, Leukemia, 2015). The addition of Y-ibritumomab tiuxetan to an RIC based regimen prior to AlloSCT in a cohort of adults with high risk B-NHL was proven to be safe and efficacious (Boubdallah, Annals of Oncology, 2015) and may further improve outcomes. Objective To investigate the safety and efficacy in CAYA with poor risk r/r B-NHL of sequential MAC AutoSCT followed by RIC AlloSCT with or without targeted radioimmunotherapy. Design/Methods CAYA patients with poor risk r/r mature B-NHL who underwent MAC AutoSCT followed by RIC AlloSCT ± targeted radioimmunotherapy are included in this study. Twelve of thirteen patients with chemo-sensitive disease underwent sequential MAC AutoSCT followed by RIC AlloSCT (Fig 1). Six patients received radioimmunotherapy with Yttrium-90 ibritumomab tiuxetan prior to MAC. In addition to EFS, patients were assessed for time to hematological recovery, graft failure, whole blood chimerism, aGVHD ≥ Gr 2 and extensive chronic GVHD. Results Thirteen patients with a mean age of 15.3 years and mean follow-up of 48 months were analyzed. Median time to neutrophil and platelet engraftment is 18.8 and 36.4 days, respectively (Fig. 2). Whole blood chimerism at D+100 is 98.4 ± 1.5 %. Eleven patients are in complete remission with an EFS of 91% (Fig. 3). The transplant-related mortality was 0% and no graft failures developed. Conclusions CAYA with r/r B-NHL receiving MAC AutoSCT, targeted radioimmunotherapy, and RIC AlloSCT can achieve long-term EFS. The combination of radioimmunotherapy comprised of Yttrium-90 ibritumomab tiuxetan with MAC AutoSCT was safe and effective in our cohort. A potential graft versus lymphoma effect may explain the favorable outcomes in this cohort of patients with otherwise dismal outcomes.

Effect of Sirolimus Exposure on the Need for Preemptive Antiviral Therapy for Cytomeglovirus Infection after Allogeneic Hematopoietic Stem Cell Transplantation.

The current study evaluates the clinical effect of sirolimus exposure on the occurrence of cytomegalovirus (CMV) DNAemia necessitating preemptive antiviral therapy. A total of 167 consecutive recipients of reduced-intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT) who received sirolimus- and tacrolimus-based graft-versus-host disease (GVHD) prophylaxis and whose CMV serostatus was positive for donors and/or recipients were included in this multicenter retrospective study. A parametric model with consecutive sirolimus blood levels describing the time to CMV DNAemia-RAT was developed using NONMEM version 7.4. Overall, 122 of 167 patients (73%) were allografted from an unrelated donor, and the donor CMV-serostatus was negative in 51 cases (31%). Fifty-six recipients (34%) developed CMV DNAemia necessitating preemptive therapy, with a cumulative incidence of 36% at a median follow-up of 25 months. Time to CMV DNAemia necessitating preemptive therapy was best described using a Gompertz function. CMV DNAemia necessitating preemptive therapy-predicting factors were antithymocyte globulin-based conditioning regimen (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.1 to 4.1; P < .01) and sirolimus concentration (HR, .94; 95% CI, .87 to .99; P < .01). The risk of CMV DNAemia-RAT decreased by 6% for each 1 ng/mL increase in sirolimus trough concentration. In conclusion, we provide evidence on the association between sirolimus blood concentration and incidence of CMV DNAemia necessitating preemptive therapy in allo-HSCT recipients. Moreover, this study presents the first predictive model describing the time to CMV DNAemia necessitating preemptive antiviral therapy as a function of sirolimus drug concentration.

TCRαβ/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy.

T cells engineered to express chimeric antigen receptors (CARs) against B cell antigens are being investigated as cellular immunotherapies. Similar approaches designed to target T cell malignancies have been hampered by the critical issue of T-on-T cytotoxicity, whereby fratricide or self-destruction of healthy T cells prohibits cell product manufacture. To date, there have been no reports of T cells engineered to target the definitive T cell marker, CD3 (3CAR). Recent improvements in gene editing now provide access to efficient disruption of such molecules on T cells, and this has provided a route to generation of 3CAR, CD3-specific CAR T cells. T cells were transduced with a lentiviral vector incorporating an anti-CD3ε CAR derived from OKT3, either before or after TALEN-mediated disruption of the endogenous TCRαβ/CD3 complex. Only transduction after disrupting assembly of TCRαβ/CD3 yielded viable 3CAR T cells, and these cultures were found to undergo self-enrichment for 3CAR+TCR-CD3- T cells without any further processing. Specific cytotoxicity against CD3ε was demonstrated against primary T cells and against childhood T cell acute lymphoblastic leukemia (T-ALL). 3CAR T cells mediated potent antileukemic effects in a human/murine chimeric model, supporting the application of cellular immunotherapy strategies against T cell malignancies. 3CAR provides a bridging strategy to achieve T cell eradication and leukemic remission ahead of conditioned allogeneic stem cell transplantation.