Pretransplant Conditioning Regimen Research Articles

Patient-Reported Outcomes in Phase 3 Clinical Trials for Blood Cancers: A Systematic Review

Published research suggests that patient-reported outcomes (PROs) are neither commonly collected nor reported in randomized clinical trials (RCTs) for solid tumors. Little is known about these practices in RCTs for hematological malignant neoplasms. To evaluate the prevalence of PROs as prespecified end points in RCTs of hematological malignant neoplasms, and to assess reporting of PROs in associated trial publications. All issues of 8 journals known for publishing high-impact RCTs (NEJM, Lancet, Lancet Hematology, Lancet Oncology, Journal of Clinical Oncology, Blood, JAMA, and JAMA Oncology) between January 1, 2018, and December 13, 2022, were searched for primary publications of therapeutic phase 3 trials for adults with hematological malignant neoplasms. Studies that evaluated pretransplant conditioning regimens, graft-vs-host disease treatment, or radiotherapy as experimental treatment were excluded. Data regarding trial characteristics and PROs were extracted from manuscripts and trial protocols. Univariable analyses assessed associations between trial characteristics and PRO collection or reporting. Ninety RCTs were eligible for analysis. PROs were an end point in 66 (73%) trials: in 1 trial (1%) as a primary end point, in 50 (56%) as a secondary end point, and in 15 (17%) as an exploratory end point. PRO data were reported in 26 of 66 primary publications (39%): outcomes were unchanged in 18 and improved in 8, with none reporting worse PROs with experimental treatment. Trials sponsored by for-profit entities were more likely to include PROs as an end point (49 of 55 [89%] vs 17 of 35 [49%]; P < .001) but were not significantly more likely to report PRO data (20 of 49 [41%] vs 6 of 17 [35%]; P = .69). Compared with trials involving lymphoma (18 of 29 [62%]) or leukemia or myelodysplastic syndrome (18 of 28 [64%]), those involving plasma cell disorders or multiple myeloma (27 of 30 [90%]) or myeloproliferative neoplasms (3 of 3 [100%]) were more likely to include PROs as an end point (P = .03). Similarly, compared with trials involving lymphoma (3 of 18 [17%]) or leukemia or myelodysplastic syndrome (5 of 18 [28%]), those involving plasma cell disorders or multiple myeloma (16 of 27 [59%]) or myeloproliferative neoplasms (2 of 3 [67%]) were more likely to report PROs in the primary publication (P = .01). In this systematic review, almost 3 of every 4 therapeutic RCTs for blood cancers collected PRO data; however, only 1 RCT included PROs as a primary end point. Moreover, most did not report resulting PRO data in the primary publication and when reported, PROs were either better or unchanged, raising concern for publication bias. This analysis suggests a critical gap in dissemination of data on the lived experiences of patients enrolled in RCTs for hematological malignant neoplasms.

Maintain Efficacy and Spare Toxicity: Traditional and New Radiation-Based Conditioning Regimens in Hematopoietic Stem Cell Transplantation.

Novelty in total body irradiation (TBI) as part of pre-transplant conditioning regimens lacked until recently, despite the developments in the field of allogeneic stem cell transplants. Long-term toxicities have been one of the major concerns associated with TBI in this setting, although the impact of TBI is not so easy to discriminate from that of chemotherapy, especially in the adult population. More recently, lower-intensity TBI and different approaches to irradiation (namely, total marrow irradiation, TMI, and total marrow and lymphoid irradiation, TMLI) were implemented to keep the benefits of irradiation and limit potential harm. TMI/TMLI is an alternative to TBI that delivers more selective irradiation, with healthy tissues being better spared and the control of the radiation dose delivery. In this review, we discussed the potential radiation-associated long-term toxicities and their management, summarized the evidence regarding the current indications of traditional TBI, and focused on the technological advances in radiotherapy that have resulted in the development of TMLI. Finally, considering the most recent published trials, we postulate how the role of radiotherapy in the setting of allografting might change in the future.

Synergistic cytotoxicity of fludarabine, clofarabine, busulfan, vorinostat and olaparib in AML cells

Combinations of nucleoside analog(s) and DNA alkylating agent(s) are used for cancer treatment as components of pre-transplant regimens used in hematopoietic stem cell transplantation. Their efficacies are enhanced by combining drugs with different mechanisms of action, which also allows a reduction in the individual drug dosages and thus potentially in toxicity to the patient. We hypothesized that addition of SAHA and olaparib, an HDAC- and a PARP-inhibitor, respectively, to the established combination of fludarabine, clofarabine and busulfan would enhance AML cell cytotoxicity. Exposure of the AML cell lines KBM3/Bu2506, MV4-11, MOLM14 and OCI-AML3 to the 5-drug combination resulted in synergistic cytotoxicity with combination indexes &amp;lt; 1. Increased protein acetylation and decreased poly(ADP-ribosyl)ation were observed, as expected. Activation of apoptosis was suggested by cleavage of Caspase 3 and PARP1, DNA fragmentation, increased reactive oxygen species, and decreased mitochondrial membrane potential. The reduction in poly(ADP-ribosyl)ation was independent of caspase activation. Several proteins involved in DNA damage response and repair were downregulated, which may be contributing factors for the observed synergism. The increased phosphorylation of DNAPKcs suggests inhibition of its kinase activity and diminution of its role in DNA repair. A similar synergism was observed in patient-derived cell samples. These findings will be important in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.

Diffuse Alveolar Hemorrhage in Hematopoietic Cell Transplantation.

Diffuse alveolar hemorrhage (DAH) is a morbid syndrome that occurs after autologous and allogeneic hematopoietic cell transplantation in children and adults. DAH manifests most often in the first few weeks following transplantation. It presents with pneumonia-like symptoms and acute respiratory failure, often requiring high levels of oxygen supplementation or mechanical ventilatory support. Hemoptysis is variably present. Chest radiographs typically feature widespread alveolar filling, sometimes with peripheral sparing and pleural effusions. The diagnosis is suspected when serial bronchoalveolar lavages return increasingly bloody fluid. DAH is differentiated from infectious causes of alveolar hemorrhage when extensive microbiological testing reveals no pulmonary pathogens. The cause is poorly understood, though preclinical and clinical studies implicate pretransplant conditioning regimens, particularly those using high doses of total-body-irradiation, acute graft-versus-host disease (GVHD), medications used to prevent GVHD, and other factors. Treatment consists of supportive care, systemic corticosteroids, platelet transfusions, and sometimes includes antifibrinolytic drugs and topical procoagulant factors. Therapeutic blockade of tumor necrosis factor-α showed promise in observational studies, but its benefit for DAH remains uncertain after small clinical trials. Even with these treatments, mortality from progression and relapse is high. Future investigational therapies could target the vascular endothelial cell biology theorized to contribute to alveolar bleeding and pathways that contribute to susceptibility, inflammation, cellular resilience, and tissue repair. This review will help clinicians navigate through the limited evidence to diagnose and treat DAH, counsel patients and families, and plan for future research.

Addition of doxycycline to fluoroquinolones for bacterial prophylaxis in autologous stem cell transplantation for multiple myeloma.

e18732 Background: Autologous stem cell transplant (ASCT) is standard therapy for patients (pts) with multiple myeloma (MM), yet the risks of such treatment include neutropenic fever (NF) and bacteremia. Fluoroquinolones (FQs) are a mainstay of bacterial prophylaxis (ppx) of NF in ASCT at many transplant centers and reduce the incidence of bacteremia. Nevertheless, ppx regimens for ASCT are not standardized and variability exists even within single institutions. While antibacterial ppx decreases infections, antibiotic use can also cause toxicity, resistance, and microbiome disturbance. The addition of doxycycline (doxy) to FQs was previously linked to reduced NF and bacteremia when utilized for ppx in MM pts at our institution, leading some providers to incorporate doxy into their ppx regimens. However, our prior study introduced multiple confounders, including differing pre-transplant conditioning regimens between ppx groups. We sought to further compare the incidence of NF and bacteremia in MM pts receiving ppx with FQ alone and FQ-doxy during a time when ppx strategies varied but transplant conditioning was consistent between groups. Methods: This is a single institution retrospective review. We analyzed all medical charts in the ASCT database of MM pts treated at our institution between Jan 2016 and Dec 2021. The primary objective was to determine the effect of bacterial ppx on the rate of NF and bacteremia within 30 days of ASCT. Data was also collected on several pt characteristics. Results: Out of 341 pts with MM who underwent ASCT following melphalan (mel) conditioning, 121 received FQ (ciprofloxacin or levofloxacin) ppx and 220 received FQ-doxy ppx. Pt characteristics and outcomes of interest are shown in Table 1. NF developed in 71 (58.7%) and 103 (46.8%) pts in the FQ and FQ-doxy groups, respectively (p = 0.042). The odds of NF in FQ-doxy compared to FQ is 0.62 (95% CI 0.4, 0.97). Bacteremia developed in 7 (5.8%) and 6 (2.7%) pts of the FQ and FQ-doxy groups (p = 0.235). The odds of bacteremia in FQ-doxy compared to FQ is 0.46 (95% CI 0.15, 1.39). Documented bacteremia was infrequent, yet resistance profiles demonstrated FQ-resistant E. coli strains in the 7 total Gram-negative bacteremia cases and 5 extended-spectrum beta-lactamases. Conclusions: Overall, there were fewer cases of NF in the FQ-doxy ppx group than FQ, however there was no significant difference in the cases of bacteremia. This finding does not support the addition of doxy to FQ ppx at our institution and a future randomized controlled trial investigating appropriate ppx for ASCT is warranted. [Table: see text]

Evaluation of gastrointestinal complications in Egyptian patients after autologous stem cell transplantation using melphalan-based regimens

BackgroundAutologous stem cell transplantation (ASCT) is a curative treatment for patients with hematological malignancies. Melphalan either alone or in combination with other chemotherapeutic agents is a widely used pre-transplant conditioning regimen with known gastrointestinal (GI) complications. We retrospectively evaluate the incidence and severity of GI toxicities, the possible risk factors, and their impact on transplant outcomes in 47 patients who received ASCT using melphalan-based conditioning.ResultsMedian age was 50 years. Among our patients, 48.9% received melphalan at 200 mg/m2. Mucositis was developed in 93.6% of patients, nausea in 87.2% and grade 2 vomiting in 36.2% of patients. Grade 3 diarrhea was detected in 42.6%. Severe GI toxicities were associated with significantly delayed engraftment, longer hospital stay, and increased transfusion requirements but overall survival (OS) and transplant-related mortality (TRM) were not affected by the severity of GI symptoms.ConclusionDespite using prophylactic and supportive care, some patients developed severe GI complications following different doses of melphalan with a negative effect on some transplant outcomes. Melphalan dose or disease type was not identified as a risk factor for severe GI toxicity. Additional larger prospective studies with higher doses, different formulations, and better prophylactic measures are warranted to evaluate potential risk factors and their impact on GI toxicities.

Treosulfan Therapeutic Drug Monitoring: Optimizing Conditioning Therapy in Pediatric Hematopoietic Stem Cell Transplantation

One of the major challenges to improving outcomes in hematopoietic stem cell transplantation is to choose the best conditioning regimen to reduce toxicity and Non Relapse Mortality, while maintaining adequate transplant efficacy. The use of Treosulfan, in combination with other chemotherapeutic agents, as part of the conditioning regimen, has progressively increased during the last decade, given its remarkable myeloablative and immunosoppressive properties and more favorable toxicity profile in comparison with Busulfan and Total Body Irradiation. For a therapy to be considered effective and safe, it is necessary to know its pharmacokinetic and pharmacodynamic properties, so that it reaches and maintains adequate concentrations in blood and tissues. Data on the pharmacokinetics of Treosulfan and the relationship between toxicity and efficacy in the pediatric population are still scarce, with reports of high inter-individual variability of Treosulfan concentrations in blood. The aim of this multicenter, prospective study is to develop a therapeutic drug monitoring system for Treosulfan dosing, in children undergoing hematopoietic stem cell transplantation for both malignant and non-malignant disorders, through the investigation of the pharmacokinetics in a large population of children after the first dose of Treosulfan, during the pre-transplant conditioning regimen (proposed cumulative therapeutic target, 'Area Under the Curve' (AUC) 4800 mg*h/L, range 3840 - 6000 mg*h/L). To achieve this aim, we measure the percentage of patients in therapeutic range, make dose adjustments if required, and define the relationship between Treosulfan exposure, early toxicity and efficacy, measured by time to engrafment and donor chimerism percentage after transplant. Of the 24 patients so far enrolled, the first 14 were analysed (Table I). Seven (54%) required a dose adjustment after the first administration of Treosulfan: reduced in three cases (43%) for a cumulative AUC above 6000 mg*h/L, increased in four (57%) for AUC below the therapeutic target, confirming the wide inter-individual variability. Enrollment continues, and follow-up of patients should allow the definition of the relationship between personalized Treosulfan dosing, toxicity and efficacy. Therefore, the development of a drug monitoring system for Treosulfan may be an important tool to optimize outcomes in the pediatric population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Metabolic Alterations and Elevation of Oxidative Stress during the Early Post-Transplant Period in AML Patients

Introduction Metabolic reprogramming as one of the hallmarks of cancer is necessary to satisfy the increased cell demands for energy and biosynthetic precursors. Our earlier study showed that the concentrations of TCA cycle, glycolysis metabolites, and oxidative stress markers differ significantly among individual stages of AML patient treatment before transplantation, but do not reach the values of healthy metabolism. In this work, we focused on pre-transplant (conditioning regimens) and early post-transplant periods in AML patients, specifically we monitored changes in concentrations of proteinogenic amino acids, metabolites of basic metabolic pathways, and oxidative stress markers. The aim of this study was to characterize concentration profiles of selected metabolites and oxidative stress markers during pre-transplant and early post-transplant periods and to reveal their possible influence on post-transplantation development. Methods Metabolomic profiles were generated using serum samples obtained at pre- and post-transplantation from selected patients treated in the Institute of Hematology and Blood Transfusion, Prague, Czech Republic. Targeted metabolomic profiling of selected metabolites related mainly to TCA cycle, glycolysis, proteinogenic amino acid, and markers of oxidative stress was performed by LC-MS/MS. Results Using non-parametric Wilcoxon test we found a significant decrease in most of the quantified metabolites of the citrate cycle and glycolysis during conditioning regimens. Conversely, in the case of proteinogenic amino acids, we found significant changes in 14 proteinogenic amino acids, specifically in 12 of them there was a significant increase during the conditioning regimens. To assess oxidative stress, we quantified total malondialdehyde as a marker of lipoperoxidation and pyroglutamate as a marker of glutathione depletion. We found that during conditioning regimens, there was a significant increase in malondialdehyde and a simultaneous increase in pyroglutamate. Moreover, we found that oxidative stress presented by malondialdehyde concentration significantly increased 7, 14, and 21 days after transplantation in comparison to the state before conditioning regimens. The lowest decrease in concentrations of TCA cycle and glycolysis metabolites occurred around day 7 post-transplantation. The suppression of monitored metabolic pathways resolved after 21 days post-transplantation. Conclusion The results of our preliminary targeted metabolomic profiling of AML patients contribute to expanding the knowledge of metabolite concentrations and their changes during pre/post-transplantation. Together with the description of the level of oxidative stress, it may reveal a possible influence on development after transplantation and could have a potential impact on supportive treatment regimens even after transplantation. Acknowledgement This work was supported by the European Regional Development Fund and the state budget of the Czech Republic (project AIIHHP: CZ.02.1.01/0.0/0.0/16_025/0007428, OP RDE, Ministry of Education, Youth and Sports) and by the project of the Ministry of Health, Czech Republic (00023736).

P1377: THE IMPACT OF THE TRAVELED DISTANCE TO THE TRANSPLANT CENTER ON THE CLINICAL OUTCOME OF ALLOGENIC BONE MARROW TRANSPLANT PATIENTS

Background: Several factors affect the outcome of allogeneic stem cell transplantation (Allo-SCT) in hematologic malignancy patients. The disease type, treatment modality and patients’ clinical profile largely determine the outcomes of Allo-SCT; however, the latter may vary among patients with similar aforementioned variables. Proximity to the transplant center could be an independent factor that affects the clinical outcome of Allo-SCT in patients. This is a retrospective study conducted at American University of Beirut Medical Center (AUBMC). Aims: The aim of this study is to determine the differences in the clinical outcome between Allo-SCT patients residing at different distances from the transplant center. Methods: We identified a total of 275 adult patients receiving Allo-SCT between January 2007 and June 2021. The patients were divided into three groups: patients residing within 20 km from AUBMC N=120 (44%) labeled as Urban, patients residing beyond 20 km from AUBMC N=111 (40%) labeled as Rural and patients who arrived from countries abroad N=44 (16%) labeled as Abroad. All patients received Allo-SCT along with the required follow up medical care at AUBMC. Using univariate and multivariate analysis, we examined the impact of distance from the transplant center along with other independent variables on the outcomes of Allo-SCT. Kaplan-Meier curves were also exploited to identify overall survival (OS), progression free survival (PFS) and transplant-related-mortality (TRM). Results: Male predominance is seen in all three groups. The distribution of disease types was similar in all three groups, where acute leukemia was the dominant hematological disease. However, a significant difference in age at transplant was noted, with the Urban group being the eldest (median age=43) and the Abroad group being the youngest (median age=35) (P=0.011). Also, the three groups differed in their median follow up whereby the Abroad group had the shortest (30 months) while the Urban group had the longest (55 months) (P<0.001). Concerning the pre-transplant conditioning regimen, there is no difference in the intensity in all three groups (P=0.052). 89% of patients of the Abroad group, 61% of the Urban and 65% of the Rural received their stem cells from a matched related donor (P=0.047). However, both Urban and Rural groups (35% and 34%) respectively received stem cells from a haplo-identical donor unlike the Abroad group only 9% (P=0.047). On multivariate analysis (Table 2) there was no statistically significant difference at 3 years in terms of OS, TRM and acute GVHD (aGVHD) between the three groups. However, the 3 years PFS was higher among patients from the Abroad group (26.8 months) compared to the Urban group (19.2 months) (P=0.035). Moreover, chronic GVHD (cGVHD) was higher the closer the patient was to the transplant center with a hazard’s ratio (HR) = 2.183 (P=0.044). Image:Summary/Conclusion: Distance didn’t show any significant difference in OS, TRM and aGVHD. On the other hand, the closer patients from the transplant center had higher risk for cGVHD and lower 3 years PFS most probably because they have more frequent and stricter follow up compared to others. More studies should be done on the current matter with adjustments for confounding variables.

ABT199/venetoclax potentiates the cytotoxicity of alkylating agents and fludarabine in acute myeloid leukemia cells.

The antineoplastic activity of pre-transplant regimens in hematopoietic stem cell transplantation (HSCT) is a critical factor for acute myeloid leukemia (AML) patients. There is an urgent need to identify novel approaches without jeopardizing patient safety. We hypothesized that combination of drugs with different mechanisms of action would provide better cytotoxicity. We, therefore, determined the synergistic cytotoxicity of various combinations of the alkylating agents busulfan (Bu) and 4-hydroperoxycyclophosphamide (4HC), the nucleoside analog fludarabine (Flu) and the BCL2 inhibitor ABT199/venetoclax in AML cells. [Bu+4HC] and [Bu+Flu] inhibited cell proliferation and activated apoptosis; addition of ABT199 to either combinations significantly increased these effects with combination indexes < 1. Apoptosis is suggested by cleavages of PARP1 and CASPASE 3, DNA fragmentation, increased reactive oxygen species, decreased mitochondrial membrane potential, and increased pro-apoptotic proteins in the cytoplasm. A similar enhancement of apoptosis was observed in patient-derived cell samples. ABT199/venetocalx upregulated anti-apoptotic MCL1 as a compensatory mechanism but addition of [Bu+4HC] or [Bu+Flu] negated this effect by CASPASE 3-mediated cleavage of MEK1/2 and its substrate MCL1. CASPASE 3 caused cleavage of pro-survival β-CATENIN, which likely contributed to the activation of stress signaling pathways involving SAPK/JNK and AMPK. The observed synergistic cytotoxicity was associated with an inhibition of pro-survival pathways involving STAT1, STAT5 and PI3K. These findings will be useful in designing clinical trials using these drug combinations as pre-transplant conditioning regimens for AML patients.

Pre-transplant conditioning regimens in allogeneic transplantation for patients with aplastic anemia

Pre-transplant conditioning regimens in allogeneic transplantation for patients with aplastic anemia

Safety of Autologous Hematopoietic Stem Cell Transplantation in Patients over 75 Years Old. Single Center Experience Serving a Minority Population

Background:Autologous hematopoietic stem cell transplant (auto-HSCT) is a commonly used treatment for multiple myeloma (MM) and for relapsed/refractory non-Hodgkin lymphomas (NHL) for patients who are <65 years old. However, the majority of new diagnoses of MM and NHL are in patients >65 years old, and nearly half of those are in patients >75 years old. While some studies have evaluated the use of auto-HSCT in older patients 65-75 years of age, there are few studies evaluating the relative safety of this treatment in patients above the age of 75 years. Such patients and their providers require outcome data of auto-HSCT in the elderly in order to help guide informed decision-making.Methods:We conducted a retrospective cohort study comparing short-term outcomes for auto-HSCT in patients >75 years old and 55-65 years old for the diagnosis of MM or NHL, who were conditioned with either melphalan or BEAM (carmustine, etoposide, cytarabine, melphalan) respectively.To identify patients, we used an internal database of auto-HSCT performed between 2005 - 2021. The study group included patients >75 years old. The control group included patients 55-65 years old that were matched to the study group patients by sex and time of transplant. Medical records were reviewed to gather data on demographics, pre-transplant functional status, transplant indication and conditioning regimen, length of stay, admission mortality, 30-day rehospitalization rate, ICU admission, neutropenic fever and infectious workup results, and time to WBC and platelet engraftment.The primary outcomes of the study were admission mortality, length of stay, time to WBC and platelet engraftment incidence, incidence of neutropenic fever, positive blood culture, ICU admission, and 30-day rehospitalization rate.Averages were calculated using medians and IQR. Admission mortality was evaluated using log rank test. P values were calculated using Fisher's test for categorical data and Wilcoxon rank sum test for continuous data. Significance was denoted by α =0.05.Results:We identified 43 patients aged >75 years old who underwent autologous stem cell transplant for multiple myeloma or lymphoma with melphalan or BEAM conditioning at Montefiore Medical Center between 2005-2021.Patient characteristics (Table 1) The earliest transplant in out cohort was in 12/2005 and the latest was in 3/2021. The median time between transplants of patients in the study and cohort groups was 14 [7.5, 24] days. 24 (55.8%) patients were female. The median age in the study group was 77.1 [76.2, 77.9] years old and 61.9 [57.4, 63.0] years old in the control group. Both groups predominantly included patients from minority populations: 55.8 and 46.5% were Spanish/Hispanic/Latino and 25.6% and 14.0% were African American, in study and control groups respectively. Multiple myeloma was the most common indication for auto-HSCT.Primary outcomes (Table 2) Admission mortality did not differ significantly between the groups, with only one death in the control group (p = 0.083). The length of stay was comparable at 18 [17, 22] days and 19 [16, 20] days (p = 0.2) for study and control groups, respectively.Time to WBC engraftment in the study group was 12 [11, 12] days and 11 [11, 12] days in the control group (p = 0.032). Time to platelet engraftment in the study group was 14 [12, 15] days and 12 [11, 14] days in the control group (p = 0.014). Although both time to WBC and platelet engraftment was significantly longer in the study group, the clinical significance of this finding is questionable, especially as it did not seem to prolong length of stay.There was no significant difference between incidence of neutropenic fever, or between incidence of positive blood cultures in patients with neutropenic fever. There was a non-statistically significant increase in the rate of ICU admissions in the study group vs control group 4/43 and 0/43 respectively (p=0.12). 30-day rehospitalization rate was comparable between the two groups.Conclusion:We did not find a statistically significant increase in morbidity or mortality for patients 75-80 years of age undergoing auto-HSCT compared with patients 55-65 years old. To our knowledge this is the largest cohort to date demonstrating the safety of auto-HSCT in this elderly population. [Display omitted] DisclosuresGritsman: iOnctura: Research Funding. Shastri: Onclive: Honoraria; GLC: Consultancy; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy. Verma: Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding.

Tre-P-20 - Evaluation of haematopoietic stem cell transplantation in patients diagnosed with cutaneous T cell lymphoma at a tertiary care centre

Tre-P-20 - Evaluation of haematopoietic stem cell transplantation in patients diagnosed with cutaneous T cell lymphoma at a tertiary care centre

Treosulphan versus busulphan: pros and cons.

Treosulphan versus busulphan: pros and cons.

Donor CD3 Chimerism After Allogeneic Transplantation Predicts Probability Of Relapse For Patients Treated For Acute Myelogenous Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), and Non-Hodkgin's Lymphoma (NHL)

Introduction The ability to predict relapse in patients after HSCT is crucial for tailoring therapy including pre transplant conditioning regimens and post transplant interventions. Donor bone marrow CD34+ cell chimerism analyses has previously been reported to be predictive for post transplant relapse for acute leukemia. Rapid immune reconstitution after HSCT may be important in the development of a robust graft versus leukemia response. Methods We performed for a sequential series of patients a retrospective analysis of donor cell chimerism (DCC) of peripheral blood CD3+ cells at 4 week intervals starting at day 28 after transplantation. Donor bone marrow CD34+ chimerism was evaluated at day 84 after transplantation. Percent chimerism was measured by PCR based amplification of short tandem repeats (STR). From 2009-2012, percent DCC data were collected for patients with ALL (n=39), NHL (n=26), and AML (n=68). Median age at diagnosis was 45 (range 25-69), 51 (range 23-66), and 57 (range 38-75), respectively. Patients received either PBSC or bone marrow cells from related (n=81) or unrelated donors (n=52). At transplantation, patients with ALL were in CR1 (n=27), CR2 (n=4), CR3 (n=1), PIF (n=3), relapse (n=2), PR (n=5); patients with NHL were in PR (n=9), CRU1 (n=4), CRU2 (n=3), Cr1 (n=4), CR2 (n=3), CR3 (n=4); patients with AML were in CR1 (n=38), CR2 (n=6), relapse (n=8), PIF (n=13). Conditioning regimens for patients with ALL were cyclophosphamide (cy) and fractionated total body irradiation (TBI) (n=27) or fludarabine (flu) and melphalan (mel) (n=11). Patients with NHL were conditioned with flu/cy and rituximab (n=15), or flu/mel (n=8). Patients with AML were conditioned with either a myeloablative regimen of flu/busulfan+TBI (n=51), or a reduced intensity regimens of flu/mel or flu/cy/TBI (n=16). Those who had NHL or AML and received unrelated donor cells were given rituximab. Post transplant immunosuppression was tacrolimus and methotrexate for most patients. Patients were censored for relapse or death. For analysis of DCC, patients who relapsed or did not relapse were divided into quartiles by diagnosis. The probability of relapse was tested for quartile groups using chi square analysis. Adjustments were not made for competing risks. Results ALL patients in the upper three quartiles of CD3+ DCCs (1 of 34 patients, median=100%, range=84-100%, [Table 1][1]) compared to patients in the bottom quartile were less likely to relapse (3 of 7 patients, median=94%, range=82-95%, p<0.002). Similarly, the upper 2 quartiles of NHL patients who had at least 95% day 28 CD3+ DCC were less likely to relapse (2 of 16 patients, median 95%, range 63-100%, p<0.007, [Table 1][1]). 7 of 48 patients with AML in the upper 3 quartiles who had day 28 CD3+ DCC of at least 90% (median=100%, range 60-100%) relapsed, trending lower compared to those in the lower quartile (p<0.06). CD3+ DCCs for day 56 and day 84 were not statistically significant for predicting future relapse. View this table: Table 1 CD3+ DCC at 28 days Day 84 CD34+ DCCs were also analyzed as described. The upper quartile of patients with ALL who did not relapse achieved a 100% DCC (1 of 23 patients relapsed, median 100%, range 82-100%, [Table 2][2]). Those that did not achieve 100% DCC for CD34+ cells by day 84 more likely to relapse (p<0.009). For patients with NHL, the upper 3 quartiles of those who did achieve 83% CD34+ DCC (1 of 7, median=90%, range 83-100%, p<0.008) by day 84 were less likely to relapse. The same method was used for patients with AML and those that did achieve 90% CD34+ DCC for cells by day 84 were not likely to relapse (5 of 35, median=96%, range=63-100%, p<0.09). View this table: Table 2 CD34+ DCC at 84 days Conclusions These findings suggest that failure to achieve early donor cell engraftment predicts for relapse. Relapse remains a major cause for treatment failure. Improvements in transplant conditioning may improve early lymphoid (CD3+) and myeloid (CD34+) engraftment and decrease the risk of disease relapse. Early monitoring of CD3+ DCC may identify patients who would benefit from post transplant intervention. Disclosures: No relevant conflicts of interest to declare. [1]: #T1 [2]: #T2

SY12-3 Hematopoietic transplantation for AML

Hematopoeitic stem cell transplantation (HSCT) has been an important modality for the treatment and cure of patients with high risk acute myeloid leukemia (AML). Improved stratification of AML patients with genetic markers (e.g. FLT3, CEBPA, NPM1 and others) has allowed better selection of patients for HSCT. Outstanding results from cord blood and haploidentical transplants have also increased the availability of donors for transplantation. Novel drugs like hypomethylating agents, BCL-2 inhibitors and various FLT 3 inhibitors have also improved the remission status of patients before transplant while also facilitating post-transplant consolidation and maintenance to improve disease control. Transplantation of older patients has also been made possible by the reduction of transplant-related mortality and morbidity through improved pre-transplant conditioning regimens and better management of post-transplant complications. Cellular engineering has also made possible the expansion of hematopoietic stem and progenitor cells to improve the results of HSCT while genetic engineering and expansion of cellular subsets has facilitated targeted therapy against viruses and leukemia. The outcomes of HSCT for the treatment of AML has improved significantly due to the above measures and HSCT remains a mainstay in the treatment of this disease.

Prospective PhaseⅡ Study of Reduced Toxicity Conditioning Consisted of High Dose-Cytarabine, Fludarabine, Cyclophosphamide +/- Total Body Irradiation Followed By Allogeneic Stem Cell Transplantation

Introduction: Allogeneic hematopoietic stem cell transplantation (allo-SCT) using reduced intensity conditioning (RIC) has been widely applied to elderly or frail patients who are not eligible for conventional conditioning regimen. However, benefit provided by reduced toxicity has been often offset by increased incidence of relapse. So far, the optimal conditioning for those patients has not been established. Here, to investigate whether addition of high dose cytarabine (AraC) to RIC regimen consisting of fludarabine (Flu) and cyclophosphamide (Cy) +/- total body irradiation (TBI) can be available for elderly or frail recipients, phase II study has been designed.Methods: This study was conducted from April 2011 to December 2015. The protocol was approved by each institutional review board (Trial identifier: UMIN000007281). Patients aged from 55 to 70, or patients who have some organ damage or a history of SCT aged from 20 to 54 with hematologic malignancies were enrolled after obtaining written informed consent. Bone marrow (BM), peripheral blood (PB), or cord blood (CB) was used as stem cell sources. Pretransplant conditioning regimen consisted of 30 mg/m2 of Flu for 5 days (total 150 mg/m2), 4 g/m2 of AraC for 2-4 days (divided by 2 daily, total 8-16 g/m2) and 50mg/kg of Cy for a day. Four gray of TBI was used for all CB transplant recipients, whereas 2 gray of TBI was used in other stem cell sources except a matched related donor according to each institutional policy. Calcineurine inhibitors (cyclosporine or tacrolimus) and short term methotrexate were used as GVHD prophylaxis. Donor cell engraftment and 60 day-survival were assessed as a primary end point to evaluate feasibility of this protocol.Results: Thirty nine patients including 7 recipients with a history of SCT were enrolled. Median age was 61 (28-69), 21 were male, and 18 were female. Nineteen were acute myeloid leukemia, 11 myelodysplastic syndrome, 6 malignant lymphoma and 3 acute lymphoblastic leukemia. Donors were 4 matched related PB, 8 matched unrelated BM, 5 1-Ag/allele-mismatched unrelated BM, and 22 ≤2-Ag-mismatched CB. Thirty seven (94.9%) patients have passed 60-day-point post-transplant. In 38 (97.4%) recipients, engraftment was obtained, a patient died before engraftment due to sepsis caused by enterococcus faecium (male CB recipient, 55y, day15). Median neutrophil recovery to over 500/μl was obtained on day 19 (16-38). Fourteen blood stream infections (13 bacteremias and 1 candidemia) judged as grade 3 toxicity and 2 cases (1 sepsis and 1 endotoxemia ) of grade 4 toxicity were observed within 60 days post-transplant. There were 2 deaths of post-engraftment due to cerebral bleeding (1 female CB recipient, 64y, day 46) and GVHD (1 male CB recipient, 60y, day 77) within 100 days. Although no relapse was observed up to day 60, 7 relapses were observed up to 1 year. Overall survival and disease-free survival were estimated to be 82.1% and 73.8 % at 1 year post-transplant, respectively.Conclusions: RIC using Flu/high dose AraC /Cy +/- TBI was well tolerated with acceptable low toxicities and was sufficient to allow donor cell-engraftment post allo-SCT for elderly or frail patients with hematologic malignancies. Longer follow up and another prospective study enrolling more patients are required to evaluate the eventual survival benefit by reducing relapse. DisclosuresNo relevant conflicts of interest to declare.

Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death.

The growth factor Flt3 ligand (Flt3L) is central to dendritic cell (DC) homeostasis and development, controlling survival and expansion by binding to Flt3 receptor tyrosine kinase on the surface of DCs. In the context of hematopoietic cell transplantation, Flt3L has been found to suppress graft-versus-host disease (GvHD), specifically via host DCs. We previously reported that the pre-transplant conditioning regimen consisting of bendamustine (BEN) and total body irradiation (TBI) results in significantly reduced GvHD compared to cyclophosphamide (CY)+TBI. Pre-transplant BEN+TBI conditioning was also associated with greater Flt3 expression among host DCs and an accumulation of pre-cDC1s. Here, we demonstrate that exposure to BEN increases Flt3 expression on both murine bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs). BEN favors development of murine plasmacytoid DCs, pre-cDC1s, and cDC2s. While humans do not have an identifiable equivalent to murine pre-cDC1s, exposure to BEN resulted in decreased plasmacytoid DCs and increased cDC2s. BEN exposure and heightened Flt3 signaling are associated with a distinct regulatory phenotype, with increased PD-L1 expression and decreased ICOS-L expression. BMDCs exposed to BEN exhibit diminished pro-inflammatory cytokine response to LPS and induce robust proliferation of alloreactive T-cells. These proliferative alloreactive T-cells expressed greater levels of PD-1 and underwent increased programmed cell death as the concentration of BEN exposure increased. Alloreactive CD4+ T-cell death may be attributable to pre-cDC1s and provides a potential mechanism by which BEN+TBI conditioning limits GvHD and yields T-cells tolerant to host antigen.

Donor-Host Lineage-Specific Chimerism Monitoring and Analysis in Pediatric Patients Following Allogeneic Stem Cell Transplantation: Influence of Pretransplantation Variables and Correlation with Post-Transplantation Outcomes

The impact of donor-host chimerism in post-hematopoietic stem cell transplantation (HSCT) outcomes is poorly understood. We were interested in studying whether pre-HSCT variables influenced lineage-specific donor-host chimerism and how lineage-specific chimerism impacts post-HSCT outcomes. Our main objective was to study pre-HSCT variables as predictors of lineage-specific donor-host chimerism patterns and to better characterize the relationship between post-HSCT lineage-specific chimerism and adverse outcomes, including graft failure and disease relapse. We conducted a retrospective data analysis of all patients who underwent allogeneic HSCT at the Pediatric Transplantation and Cellular Therapy service at Memorial Sloan Kettering Cancer Center between January 2010 and June 2015 and had at least 2 measurements of split-lineage chimerism. The trend of lineage-specific donor-host chimerism post-HSCT and the impact of age, disease, graft type, and pretransplantation conditioning regimen on chimerism at 3 months and 12 months post-HSCT were studied. The Wilcoxon signed-rank test, Mann-Whitney-Wilcoxon test, and Cox proportional hazard models were used for statistical analyses. A total of 137 patients were included (median age, 11.3 years). Most patients had a hematologic malignancy (n=95), and fewer had a nonmalignant disorder (n=27) or primary immune deficiency (n=15). Myeloablative conditioning regimens (n=126) followed by T cell-depleted (TCD) peripheral blood stem cell or bone marrow grafts (n=101) were most commonly used. Mixed chimerism (MC) of total peripheral blood leukocytes (PBLs) did not predict loss of donor chimerism in all lineages and when stable was not associated with graft failure or rejection in this analyses. Split chimerism with complete donor chimerism (CC) of myeloid, B, and natural killer cells, but not T cells, occurred early post-HSCT, but full donor T cell chimerism was achieved at 12 months post-HSCT by most patients. MC within the T cell lineage was the major contributor to PBL MC, with lower median donor T cell chimerism at 3 months than at 12 months (91%) post-HSCT (51% versus 91%; P < .0001).Predictors of MC at 3 and 12 months were (1) age <3 years (P=.01 for PBLs and P=.003 for myeloidlineage); (2) nonmalignant disorder (P=.007 for PBLs); and (3) the use of reduced-intensity conditioning regimens. TCD grafts produced lower donor T cell chimerism at 3 months post-HSCT compared with unmodified grafts (P < .0001), where T cell lineage CC was achieved early post-HSCT. The donor T cell chimerism was similar at 12 months in the 2 types of grafts. Umbilical cord blood grafts had CC in all lineages at all time points post-HSCT. Loss of donor B cell chimerism was associated with increased risk of relapse in hematologic malignancies (hazard ratio, 1.33; P=.05). Age, underlying disease, conditioning regimen, and graft manipulation can impact post-HSCT donor-host chimerism and be predictors for early MC. MC in total PBLs and T cells was not related to graft failure or disease relapse. Whole-blood PBL chimerism analysis is not sufficient to assess the significance of post-HSCTdonor-host status; rather, lineage-specific chimerism, particularly for myeloid, T, and B cells, should be analyzed to guide interventions and inform outcomes.

Dose intensity for conditioning in allogeneic hematopoietic cell transplantation: can we recommend "when and for whom" in 2021?

Allogeneic hematopoietic stem-cell transplantation is a potentially curative therapy for various hematologic diseases. An essential component of this procedure is the pre-transplant conditioning regimen, which should facilitate engraftment and reduce or eliminate tumor cells. The recognition of the substantial association of a graft-versus- tumor effect and the high toxicity of the commonly used conditioning regimen led to the introduction of more differentiated intensity strategies, with the aim of making hematopoietic stem-cell transplantation less toxic and safer, and thus more applicable to broader populations such as older or unfit patients. In general, prospective and retrospective studies suggest a correlation between increasing intensity and nonrelapse mortality and an inverse correlation with relapse incidence. In this review, we will summarize traditional and updated definitions for conditioning intensity strategies and the landscape of comparative prospective and retrospective studies, which may help to find the balance between the risk of non-relapse mortality and relapse. We will try to underscore the caveats regarding these definitions and analyses, by missing complex differences between intensity and toxicity as well as the broad influences of other factors in the transplantation procedure. We will summarize evidence regarding several confounders which may influence decisions when selecting the intensity of the conditioning regimen for any given patient, according to the individual risk of relapse and non-relapse mortality.