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IMA101 is an actively personalized, multi-targeted adoptive cell therapy (ACT), whereby autologous T cells are directed against multiple novel defined peptide-HLA (pHLA) cancer targets. HLA-A*02:01-positive patients with relapsed/refractory solid tumors expressing ≥1 of 8 pre-defined targets underwent leukapheresis. Endogenous T cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine, cyclophosphamide), followed by T-cell infusion and low-dose interleukin-2 (Cohort 1). Patients in Cohort 2 received atezolizumab for up to 1 year (NCT02876510). Overall, 214 patients were screened, 15 received lymphodepletion (13 women, 2 men; median age, 44 years), and 14 were treated with T-cell products. IMA101 treatment was feasible and well tolerated. The most common adverse events were cytokine release syndrome (Grade 1, n=6; Grade 2, n=4) and expected cytopenias. No patient died during the first 100 days after T-cell therapy. No neurotoxicity was observed. No objective responses were noted. Prolonged disease stabilization was noted in three patients lasting for 13.7, 12.9, and 7.3 months. High frequencies of target-specific T cells (up to 78.7% of CD8+ cells) were detected in the blood of treated patients, persisted for >1 year, and were detectable in post-treatment tumor tissue. Individual TCRs contained in T-cell products exhibited broad variation in TCR avidity, with the majority being of low-avidity. High-avidity TCRs were identified in some patients’ products. This study demonstrates the feasibility and tolerability of an actively personalized ACT directed to multiple defined pHLA cancer targets. Results warrant further evaluation of multi-target ACT approaches using potent high-avidity TCRs.

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pre transplant immune suppression phase (PTIS) and two courses of dexamethasone (DXM) and fludarabine (FLU) followed by pre transplant conditioning with intravenous FLU busulfan (BU) and post transplant graft

Patients with high-risk hematologic diseases require intensive modalities, including high-dose chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Haploidentical T-cell-replete transplantation is a logical choice because of the limited availability of matched sibling donors and the prolonged time needed to identify matched unrelated donors in Thailand.The clinical outcomes data of 43 patients undergoing allo-HSCT were reviewed. All patients had high-risk hematologic malignancies, were younger than 20 years, and were in complete cytological remission at the time of allo-HSCT. We used two different conditioning regimens: total body irradiation (TBI) combined with cyclophosphamide, fludarabine, and melphalan (n = 23) and thiotepa combined with fludarabine and busulfan (n = 20). All patients received a graft-versus-host disease prophylaxis regimen consisting of cyclophosphamide, mycophenolate mofetil, and a calcineurin inhibitor or sirolimus.There was no difference in engraftment between patients receiving either of the regimens. After a median follow-up of 35.8 (range, 0.6-106.2) months, the overall survival (OS) and event-free survival (EFS) rates were 62.4% and 54.7%, respectively. OS and EFS were comparable between the respective regimens.We conclude that thiotepa-based conditioning has similar efficacy and tolerability as TBI-based conditioning for haploidentical HSCT with post-transplant cyclophosphamide.

The therapeutic efficacy of histone deacetylase inhibitors (HDACi) for hematologic malignancies and solid tumors is attributed to their ability to remodel chromatin, normalize dysregulated gene expression, and inhibit repair of damaged DNA. Studies on the interactions of HDACi with PARP inhibitors in hematologic cancers are limited, especially when combined with chemotherapeutic agents. Exposure of hematologic cancer cell lines and patient-derived cell samples to various HDACi resulted in a significant caspase-independent inhibition of protein PARylation, mainly catalyzed by PARP1. HDACi affected the expression of PARP1 at the transcription and/or post-translation levels in a cell line-dependent manner. HDACi-mediated inhibition of PARylation correlated with decreased levels and phosphorylation of major proteins involved in DNA repair. Combination of HDAC and PARP1 inhibitors provided synergistic cytotoxicity, which was further enhanced when combined with a chemotherapeutic regimen containing gemcitabine, busulfan and melphalan as observed in lymphoma cell lines. Our results indicate that the anti-tumor efficacy of HDACi is partly due to down-regulation of PARylation, which negatively affects the status of DNA repair proteins. This repair inhibition, combined with the high levels of oxidative and DNA replication stress characteristic of cancer cells, could have conferred these hematologic cancer cells not only with a high sensitivity to HDACi but also with a heightened dependence on PARP and therefore with extreme sensitivity to combined HDACi/PARPi treatment and, by extension, to their combination with conventional DNA-damaging chemotherapeutic agents. The observed synergism of these drugs could have a major significance in improving treatment of these cancers.

High-dose chemotherapy and autologous stem-cell transplant (HDC/ASCT) is standard treatment for chemosensitive relapsed classical Hodgkin lymphoma, although outcomes of high-risk relapse (HRR) patients remain suboptimal. We retrospectively analyzed all HRR classical Hodgkin lymphoma patients treated with HDC/ASCT at our institution between 01/01/2005 and 12/31/2019. HRR criteria included primary refractory disease/relapse within 1 year, extranodal extension, B symptoms, requiring more than one salvage line, or positron emission tomography (PET)-positive disease at ASCT. All patients met the same ASCT eligibility criteria. We treated 501 patients with BEAM (n=146), busulphan/melphalan (BuMel) (n=38), gemcitabine( Gem)/BuMel (n=189) and vorinostat/Gem/BuMel (n=128). The Gem/BuMel and vorinostat/Gem/BuMel cohorts had more HRR criteria and more patients with PET-positive disease at ASCT. Treatment with brentuximab vedotin (BV) or anti-PD1 prior to ASCT, PET-negative disease at ASCT, and maintenance BV increased over time. BEAM and BuMel predominated in earlier years (2005-2007), GemBuMel and BEAM in middle years (2008-2015), and vorinostat/GemBuMel and BEAM in later years (2016-2019). The median follow-up is 50 months (range, 6-186). Outcomes improved over time, with 2-year progressionfree survival (PFS)/overall survival (OS) rates of 58%/82% (2005-2007), 59%/83% (2008-2011), 71%/94% (2012-2015) and 86%/99% (2016- 2019) (P

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3–6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.

Background A myeloablative conditioning regimen can be safely given to older patients and those with comorbidities without increasing nonrelapse mortality (NRM) by fractionating the dose of intravenous busulfan. How this approach compares in efficacy with traditional, nonfractionated, lower dose regimens is unknown. Methods Outcomes were compared in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome who received either myeloablative, fractionated busulfan (f-Bu) dosed to achieve an area under the curve of 20,000 μmol per minute (f-Bu20K) over 2 weeks (n = 84) or a standard, nonfractionated, lower busulfan dose regimen of 16,000 μmol per minute (Bu16K) over 4 days (n = 78). Both groups also received fludarabine 40 mg/m2 intravenously for 4 days. Graft-versus-host disease prophylaxis was tacrolimus and methotrexate. Patients in the Bu16K group who had unrelated donors also received antithymocyte globulin. The primary endpoint was progression-free survival. Results Roughly one-half of the patients were aged >65 years, approximately 40% had poor-risk cytogenetics, approximately 40% of those with AML were not in complete remission, and approximately 40% had a comorbidity index >3. At 2 years, progression-free survival was significantly improved in the f-Bu20K group compared with the Bu16K group (45% vs 24%, respectively; hazard ratio [HR], 0.6; 95% CI, 0.4-0.8; P = .004). This was because of a significant reduction in progression (34% vs 59%, respectively; HR, 0.5; 95% CI, 0.3-0.8; P = .003) without any increase in NRM (21% vs 15%, respectively; HR, 1.4; 95% CI, 0.7-3; P = .3), which resulted in improved overall survival (51% vs 31%, respectively; HR, 0.6; 95% CI, 0.3-0.9; P = .01). Conclusions A myeloablative, fractionated busulfan regimen reduces relapse and improves survival without increasing NRM in older patients with AML and myelodysplastic syndrome.

Pretransplant conditioning with Fludarabine (Flu)-Busulfan (Bu) is safe, but clofarabine (Clo) has improved antileukemic activity. Hypothesis: Flu+Clo-Bu (FCB) yields superior progression-free survival (PFS) after allogeneic transplantation. We randomized 250 AML/MDS patients aged 3–70, Karnofsky Score ≥80, with matched donors, to FCB (n = 120) or Flu-Bu (n = 130), stratifying complete remission (CR) vs. No CR, (NCR). HCT-CI scores varied, from 0 to 10. All evaluable patients engrafted. Median follow-up was 66 months (interquartile range: 58–80). Three-year relapse incidence (RI), 25% with FCB, vs. 39% with Flu-Bu (p = 0.018), offset by higher non-relapse mortality, 22.6% (95%CI: 16–30.2%) vs. 12.3% (95%CI: 6.5–19%). Three-year PFS was 52% (95%CI: 44–62%) (FCB), vs. 48% (95%CI: 41–58%) (Flu-Bu). FCB benefited CR patients less, NCR patients age ≤ 60 had 3-year 34% RI (95%CI: 19–49%) (FCB) vs. 56% (95%CI: 38–70%) after Flu-Bu (p = 0.037). NCR patients >60 years had 3-year RI 10.0% (FCB), vs. 56.0%, after Flu-Bu (p = 0.003). Bayesian regression analysis including treatment-covariate interactions showed FCB superiority in NCR patients with low HCT-CI (0–2). Serious adverse event profiles were similar for the regimens. Conditioning with FCB did not improve PFS overall, but improved disease control in NCR patients, mandating confirmatory trials. Remission status and HCT-CI should be considered when using FCB.

Busulfan is given in the conditioning regimens preceding hematopoietic stem cell transplantation (HSCT), and plasma levels can be monitored. A targeted, individualized systemic exposure (SE) dose can be achieved by calculating the area under the plasma concentration versus time curve (AUC). The objective of this study was to determine a cutoff value for safety for the AUC for busulfan plasma levels in patients undergoing HSCT. A total of 149 consecutive HSCT patients were studied. After an oral test dose of busulfan, we set target doses of 4000, 5000, or 6000 µMol⸱min/day, and analyzed the AUC of oral or intravenous Bu. These patients were compared with 53 historical control subjects who had received myeloablative conditioning regimen without busulfan pharmacokinetic monitoring. Using a test dose and the administration route had no impact on the sinusoidal obstructive syndrome (SOS) incidence, transplant-related mortality or 1-year overall survival. However, patients receiving busulfan at doses set up at AUC > 5000 had an increased risk to develop SOS after HSCT (hazard ratio 3.39, p = 0.034, 95% CI 1.09-10.52). Adjusting the busulfan dose according to SE levels target dose during conditioning is associated with lower rates of oral severe mucositis and SOS. A cutoff of 5000 µMol⸱min is safe and does not impair survival.

Aims The purpose of this study was to design and manufacture CD19 chimeric antigen receptor (CAR)-modified T cells for clinical use in Thailand, as a model for how this technology can be directly applied at individual institutions treating high-risk leukemia patients. Methods We constructed second-generation CAR T cells expressing CD19 scFV-CD28-CD3ζ with different lengths of the spacer region: full, intermediate, and short length, by using a lentiviral vector. We wanted to determine whether the difference in length of the spacer would affect the cytotoxic potential of the CD19 CAR T cells against the leukemic cells. Results We found that all constructs of CD19 CAR T cells exhibited a similar level of cytotoxicity against several human lymphoma and leukemia cell lines. For the clinical application, we chose the intermediate length spacer construct CD19 CAR T cells, hypothesizing that the highest transduction efficiency coupled with a slower initial proliferation in vitro might lead to effective leukemic cell kill, yet a lower probability for serious clinical side effects. We then tested the clinical efficacy of our CD19 CAR T cells in one patient with refractory/relapsed acute B-cell lymphoblastic leukemia. This patient indeed had minimal clinical side effects after the CAR T-cell infusion, and he remains in an unmaintained, ongoing complete remission 10+ months after his T-cell treatment. Conclusion Our CD19 CAR T cells demonstrated efficacies in acute lymphoblastic B-cell leukemia, and will be used to establish an immunotherapeutic program for high-risk B-cell acute lymphoblastic leukemia in Thailand. We propose that this approach can be used as a model for how this new exciting technology can be applied directly at individual institutions that treat (a large number of) patients with high-risk leukemia.

Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.

Background Immune reconstitution of T cells has been proven to be a protective factor against cytomegalovirus (CMV) reactivation in patients post-hematopoietic stem cell transplant. Recently, more evidence has suggested that natural killer (NK) cells also play role in the protection against CMV reactivation in these patients. Methods CMV-specific T cells and CMV-reactive NK cells from pediatric patients undergoing hematopoietic stem cell transplant were examined by flow cytometry. These cells were defined as cells producing interferon gamma (IFNγ) upon stimulation with CMV antigens. Results This study demonstrated that NK cells reactive to CMV do exist in pediatric patients after stem cell transplant. These cells vigorously responded to stimulation with CMV peptides (pp65 and IE1) and to a lesser extent to CMV whole lysate by secretion of IFNγ. Patients with CMV reactivation tended to have less CMV-reactive NK cells than those without. Conclusion Reconstitution of CMV-reactive NK cells, together with CMV-specific T cells, may play a role in the control of CMV infections in patients after stem cell transplant.

Bisantrene (Bis), a topoisomerase-II inhibitor, is less cardiotoxic than the current anthracyclines. Its synergistic cytotoxicity with newly developed antineoplastic drugs has not been reported. We demonstrated the synergism of [Bis + ABT199/venetoclax] in combination with panobinostat (Pano), decitabine (DAC), or olaparib (Ola), known inhibitors of BCL2, histone deacetylase, DNA methyltransferase, and poly(ADP-ribose) polymerase, respectively, in AML cells. [Bis + ABT199] with Pano, DAC, or Ola synergistically inhibited cell proliferation with combination indices of 0.25-0.6, 0.2-0.35, and 0.2-0.4 (at 50% inhibition of proliferation), respectively. Increased γ-H2AX suggests enhanced DNA damage; cleavages of Caspase 3 and PARP1, DNA fragmentation, increased ROS, and decreased MMP indicate potent apoptosis activation. Similar results were observed using mononuclear cells from leukemia patients but not from healthy donors. The SAPK/JNK signaling pathway was strongly activated by the combination treatments, whereas the PI3K/mTOR and Wnt/β-catenin pro-survival pathways were inhibited. These drug combinations may be used in cytoreductive clinical trials for AML patients.

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 indexes1. 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.

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four-day regimen (Popat et al Lancet Haematology 2018). This longer duration of conditioning regimen allows addition of targeted agents like Venetoclax, which may be synergistic with conditioning chemotherapy and may further improve disease control with this regimen. We therefore added Venetoclax to our ongoing prospective clinical trial with f-Bu-Flu-Cladribine conditioning (NCT02250937). After enrolling 83 patients, the study was amended and venetoclax was added for the next 33 patients. Here we report the safety and preliminary efficacy of venetoclax and fractionated busulfan regimen. Methods: Between 2/2019 and 3/2021, 33 patients with AML (n=21) or MDS (n=10) up to 70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor were enrolled on a prospective trial. The conditioning regimen was f-Bu to target an area under the concentration vs time curve (AUC) of 20,000 ± 12% μmol.min given over a period of 2-3 weeks. The first two doses of busulfan (80 mg/m2 IV each) were administered either consecutively (days -13 and -12) or with further fractionation, one week apart (days -20 and -13) on outpatient basis. Then, inpatient fludarabine 10 mg/m 2, and cladribine 10 mg/m 2 were given followed by Bu on days -6 to -3. Venetoclax 400mg daily was given from day -22 to -3. Azoles were avoided during this period. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and tacrolimus from day 5. Results: The median age was 59 years (range, 23-69); High or very high disease risk index was present in 21%; Comorbidity index score of >3 was present in 45%; Donor was a sibling in 39%; and peripheral blood stem cells was the graft source in 100%. The median follow up was 8 months. At 1-year, overall survival was 84% (95% confidence interval, 71-100), progression-free survival 77% (64-94), relapse 13% (1-25), and non-relapse mortality 10% (0-20) [Table 1, Figure 1]. Incidence of acute GVHD grade 2-4 was 28% (12-43) and grade 3-4 acute GVHD was 3% (0-9) at day 100. All patients engrafted. The median time to neutrophil engraftment was 15 days (13 -19) and median time to platelet engraftment was 23 days (11-85). Full donor chimerism at day 30 was noted in 76%. Common grade 3 or 4 toxicity were neutropenic fever (58%), mucositis (18%) and pulmonary toxicity in 21%. Conclusion: Venetoclax can be safely added to the fractionated busulfan regimen. Early data on efficacy appear promising. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Syndax: Research Funding; Incyte: Research Funding; Kadmon: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Gulbis: EUSA Pharma: Other: Advisory board participation. Rezvani: AvengeBio: Other: Scientific Advisory Board ; Pharmacyclics: Other: Educational grant, Research Funding; GemoAb: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board ; Caribou: Other: Scientific Advisory Board; Takeda: Other: License agreement and research agreement, Patents & Royalties; Virogin: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Bristol-Myers Squibb: Other: Advisory Board; Oncopeptides: Other: Advisory Board; Amgen: Research Funding; Angiocrine: Research Funding; NexImmune: Research Funding; Biolline: Research Funding; Janssen: Research Funding. Kadia: Cure: Speakers Bureau; Novartis: Consultancy; Dalichi Sankyo: Consultancy; Cellonkos: Other; Ascentage: Other; Genfleet: Other; Sanofi-Aventis: Consultancy; Genentech: Consultancy, Other: Grant/research support; Astellas: Other; Liberum: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; Pfizer: Consultancy, Other; AstraZeneca: Other; AbbVie: Consultancy, Other: Grant/research support; Pulmotech: Other; Jazz: Consultancy. Konopleva: Calithera: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Ascentage: Other: grant support, Research Funding; Cellectis: Other: grant support; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AstraZeneca: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; Forty Seven: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; KisoJi: Research Funding. Shpall: Axio: Consultancy; Magenta: Consultancy; Novartis: Consultancy; Bayer HealthCare Pharmaceuticals: Honoraria; Adaptimmune: Consultancy; Navan: Consultancy; Takeda: Patents & Royalties; Novartis: Honoraria; Affimed: Patents & Royalties; Magenta: Honoraria.

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan (Bu) over a longer period (fractionated (f)-Bu) with fludarabine (Flu) than the standard four-day regimen. (Popat et al Lancet Haematology 2018). We added thiotepa (Thio) to this f-Bu/Flu regimen in patients with haploidentical (haplo) donors to promote engraftment and to reduce relapse. With encouraging results, Thio was then added in matched unrelated (MUD) and sibling (MSD) donor recipients also. However, the optimal doses of Thio and Bu were undefined. To further optimize the regimen, we tested two different f-Bu/Flu/Thio regimens in parallel prospective cohorts: (a) higher dose Bu with lower dose Thio, and (b) lower dose Bu with a higher dose Thio. Patients were enrolled on these cohorts based on age and co-morbidity index (HCT-CI). Herein, we report on the safety and preliminary efficacy of these regimens (NCT02861417). Methods: Patients 60 years with HCT-CI 3, or >60 years with HCT-CI >2, or >70 years irrespective of HCT-CI received f-BU to target AUC of 16,000 with Thio 5mg/kg (Bu16K/Thio5; Cohort 2). In both cohorts, the first two doses of Bu (80 mg/m2 IV each) were given as outpatient on days -20 and -13. The last four Bu doses were given as inpatient following each dose of Flu 40 mg/m2 on days -6 through -3. Thio was given on day -7. GVHD prophylaxis was post-transplant cyclophosphamide (PTCy) 50mg/kg on days 3 and 4, tacrolimus and MMF. Results: 66 patients were enrolled - 25 in cohort 1 and 41 in cohort 2, with a median age 60 years (range, 22-69) vs 62 years (range, 30-74), respectively (P=0.14). Diagnoses were AML/MDS (64% vs 54%), CML/MPD (24% vs 22%), ALL (12% vs 22%) and 1 myeloma; P=0.24. Most had intermediate disease risk index (80% vs 73%, P=0.57); median HCT-CI was 1 (range, 0-6) vs 3 (range, 0-9); P Primary graft failure occurred in 1 patient in cohort 1 and none in cohort 2. The median time to neutrophil engraftment was 17.5 days (range, 14-26) vs 18 days (range, 12-26); P=0.12, respectively; platelet engraftment > 20K was 30 days in both groups; P=0.75. Median donor chimerism at day 30 was 100% in both groups. The incidence of acute GVHD grade III-IV was 4% vs 5%; P=0.88 at day 100; extensive chronic GVHD at 1 year was 13% vs 10%; P=0.83. At 1-year overall survival was 72% vs 78%; P=0.95; relapse was 12% each; non-relapse mortality was 20% vs 17%; P=0.97 [Table 1, Fig 1]. Common grade >3 toxicities were neutropenic fever (64% vs 42%; P=0.13), bacterial infection (44% vs 34%; P=0.45), nausea (12% vs 2%; P=0.15), mucositis (8% vs 5%; P=0.63), pneumonitis (12% vs 7%; P=0.67), hemorrhagic cystitis (8% vs 5%) and sinusoidal obstructive syndrome (8% vs 2.4%). Conclusion: In this population of older patients and/or high co-morbidities, both myeloablative regimens with f-Bu/Flu with thiotepa and PTCy were well tolerated and led to low NRM, low risk of relapse and encouraging survival. Although both regimens led to similar outcomes, the f-Bu/Flu/Thio regimen with Bu16K and thiotepa 5 mg/kg dose may be preferred as this was used in patients who were older and/or had high co-morbidities. Figure 1 Figure 1. Disclosures Popat: Bayer: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding. Mehta: CSLBehring: Research Funding; Kadmon: Research Funding; Syndax: Research Funding; Incyte: Research Funding. Hosing: Nkarta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Rezvani: Caribou: Other: Scientific Advisory Board; Virogin: Other: Scientific Advisory Board ; AvengeBio: Other: Scientific Advisory Board ; GSK: Other: Scientific Advisory Board ; Bayer: Other: Scientific Advisory Board ; Navan Technologies: Other: Scientific Advisory Board; GemoAb: Other: Scientific Advisory Board ; Takeda: Other: License agreement and research agreement, Patents & Royalties; Pharmacyclics: Other: Educational grant, Research Funding; Affimed: Other: License agreement and research agreement; education grant, Patents & Royalties, Research Funding. Qazilbash: Oncopeptides: Other: Advisory Board; Janssen: Research Funding; Bristol-Myers Squibb: Other: Advisory Board; NexImmune: Research Funding; Amgen: Research Funding; Angiocrine: Research Funding; Biolline: Research Funding. Shpall: Affimed: Patents & Royalties; Adaptimmune: Consultancy; Novartis: Consultancy; Magenta: Consultancy; Magenta: Honoraria; Axio: Consultancy; Takeda: Patents & Royalties; Navan: Consultancy; Novartis: Honoraria; Bayer HealthCare Pharmaceuticals: Honoraria.

Busulfan is used in myeloablative schemes for hematopoietic stem cell transplantation (HSCT), with monitoring of dosage through the area under the curve (AUC) of the drug plasma concentration (µMol min). In this study, we compared the complete pharmacokinetics of busulfan administered orally (Bu-Oral) and intravenously (Bu-IV). We evaluated 40 patients who underwent HSCT with different types of conditioning regimens. After one dose, in the Bu-Oral group (n = 21), the median AUC was 1174 µMol min (799-4000), reaching a median of 4440 µMol min (3428-7181.5) during conditioning in 24 h. In the Bu-IV group (n = 19), it was 1244.8 µMol min (1001.2-2021), reaching 5598.0 µMol min (3102-8818) during conditioning in 24 h. Measuring plasma concentration of Bu in patients undergoing HSCT is important, regardless of the formulation, and the inclusion of a pre-HSCT test can predict the optimal dose during conditioning. Pharmacokinetics of the oral administration of busulfan, as well as clearance, are extremely variable, and this can potentially compromise the clinical results of the treatment since it makes it difficult to predict clinical results.

Summary Background Retrospective studies suggest that conditioning therapy with busulfan plus melphalan could result in longer progression-free survival compared with melphalan alone in patients with multiple myeloma undergoing autologous haemopoietic cell transplantation (auto-HCT). We aimed to test this hypothesis in a randomised trial. Methods The primary objective of the study was to compare progression-free survival with conditioning of busulfan plus melphalan with melphalan alone in patients with multiple myeloma. Patients with newly diagnosed multiple myeloma who were eligible for cell transplantation, aged 70 years or younger, with at least stable disease, were randomly assigned (1:1) to treatment. Patients received either busulfan plus melphalan, with a test dose of busulfan 32 mg/m2 followed by pharmacokinetically adjusted doses on days −7, −6, −5, and −4 to achieve a target daily area under the curve (AUC) of 5000 mmol-minute and melphalan 70 mg/m2 per day on days −2 and −1 (total melphalan dose 140 mg/m2), or a melphalan dose of 200 mg/m2 on day −2. Randomisation was performed via a Clinical Trial Conduct Website at the University of Texas MD Anderson Cancer Center. The accrual is complete and final results are presented here. The study is registered with ClinicalTrials.gov , number NCT01413178 . Findings Between Oct 12, 2011, and March 22, 2017, 205 patients were assessed for eligibility and randomly assigned to treatment. The primary analysis of progression-free survival was measured in 202 patients who received treatment: 104 patients in the busulfan plus melphalan group and 98 patients in the melphalan alone group. 90 days after auto-HCT, 102 (98%) of 104 patients given busulfan plus melphalan and 95 (97%) of 98 patients given melphalan alone achieved partial response or better. The median follow-up in the busulfan plus melphalan group was 22·6 months (IQR 15·2–47·1) and 20·2 months (IQR 8·8–46·6) in the melphalan alone group. Median progression-free survival was 64·7 months (32·9–64·7) with busulfan plus melphalan versus 43·5 months (19·9–not estimated) with melphalan alone (hazard ratio 0·53 [95% CI 0·30–0·91]; p=0·022). There were no treatment-related deaths by day 100 in either group. Grade 2–3 mucositis was observed in 77 (74%) of 104 patients in the busulfan plus melphalan group versus 14 (14%) of 98 patients in the melphalan alone group. Interpretation These findings, if confirmed in other ongoing studies, suggest that busulfan plus melphalan could replace melphalan alone as the conditioning regimen for auto-HCT in patients with newly diagnosed myeloma. Funding This study was funded in part by the National Institutes of Health (NIH) through MD Anderson's Cancer Center Support Grant ( CA016672 ).

Summary Allogeneic stem cell transplantation is now part of standard care for acute leukaemia. To reduce toxicity of the pretransplant conditioning regimen, intravenous busulfan is usually used as a preparative regimen for acute leukaemia patients undergoing allogeneic stem cell transplantation. Systemic busulfan exposure, characterized by the area under the plasma concentration versus time curve, AUC, is strongly associated with clinical outcome. An AUC that is too high is associated with severe toxicities, whereas an AUC that is too low carries increased risks of recurrence of disease and failure to engraft. Consequently, an optimal AUC-interval needs to be determined for therapeutic use. To address the possibility that busulfan pharmacokinetics and pharmacodynamics vary significantly with patients’ characteristics, we propose a tailored approach to determine optimal covariate-specific AUC-intervals. To estimate these personalized AUC-intervals, we apply a flexible Bayesian non-parametric regression model based on a dependent Dirichlet process and Gaussian process. Our analyses of a data set of 151 patients identified optimal therapeutic intervals for AUC that varied substantively with age and whether the patient was in complete remission or had active disease at transplant. Extensive simulations to evaluate the dependent Dirichlet process–Gaussian process model in similar settings showed that its performance compares favourably with alternative methods. We provide an R package, DDPGPSurv, that implements the dependent Dirichlet process–Gaussian process model for a broad range of survival regression analyses.

PURPOSE BK virus-associated hemorrhagic cystitis (BKV-HC) is a common complication of allogenic hematopoietic stem cell transplantation (AHSCT), particularly in recipients of alternative donor transplants, which are being performed in increasing numbers. BKV-HC typically results in painful hematuria, urinary obstruction, and renal dysfunction, without a definitive therapeutic option. METHODS We performed a clinical trial (ClinicalTrials.gov identifier: NCT02479698 ) to assess the feasibility, safety, and efficacy of administering most closely HLA-matched third-party BKV-specific cytotoxic T lymphocytes (CTLs), generated from 26 healthy donors and banked for off-the-shelf use. The cells were infused into 59 patients who developed BKV-HC following AHSCT. Comprehensive clinical assessments and correlative studies were performed. RESULTS Response to BKV-CTL infusion was rapid; the day 14 overall response rate was 67.7% (40 of 59 evaluable patients), which increased to 81.6% among evaluable patients at day 45 (40 of 49 evaluable patients). No patient lost a previously achieved response. There were no cases of de novo grade 3 or 4 graft-versus-host disease, graft failure, or infusion-related toxicities. BKV-CTLs were identified in patient blood samples up to 3 months postinfusion and their in vivo expansion predicted for clinical response. A matched-pair analysis revealed that, compared with standard of care, after accounting for prognostic covariate effects, treatment with BKV-CTLs resulted in higher probabilities of response at all follow-up timepoints as well as significantly lower transfusion requirement. CONCLUSION Off-the-shelf BKV-CTLs are a safe and effective therapy for the management of patients with BKV-HC after AHSCT.

Context Fractionated busulfan/fludarabine (Bu-Flu) myeloablative conditioning yields low non-relapse mortality (NRM) in older patients and those with comorbidities after matched sibling (MSD) or unrelated (MUD) donor transplant (HCT). [Popat et al, Lancet Haematology 2018]. This has not been tested in haploidentical patients, and safety of post-transplant cyclophosphamide (PTCy) GVHD prophylaxis with this approach is unknown; both aims were assessed in the current trial. Objective Primary objective/endpoints were safety/NRM. Design Open label, non-randomized, phase II. Participants Eligibility criteria included any hematologic malignancy, age Interventions Patients received busulfan 80 mg/m2 i.v. either on days -13 and -12 (n=45) or with further fractionation (days -20 and -13; n=10) and fludarabine 40 mg/m2 i.v. plus busulfan (days -6 to -2) dosed to achieve target AUC 20,000 pmol/min per pharmacokinetic studies. Haploidentical patients received thiotepa 5 mg/kg i.v on day -7. GVHD prophylaxis included PTCy 50 mg/kg i.v. and tacrolimus. Haploidentical and later MUD recipients also received mycophenolate mofetil. Results Fifty-five patients were enrolled between 08/2016 and06/2018; median follow-up was 37.6 months (range, 25.3–47.8). Diagnoses were AML/MDS (n=30), CML/MPN (n=9), ALL (n=6), and lymphoma/myeloma (n=10). Donors were haploidentical (n=26, 47%), MUD (n=18, 33%), or MSD (n=11, 20%) with PB (n=33, 60%) or BM graft. DRI was intermediate/high (n=50, 91%); 40% (n=22) had HCT-CI >3. There was no graft failure. Median time to neutrophil and platelet engraftment was 17 days (range, 13–39) and 25 days (range, 11–167). Day 100 NRM was 16.4% (95% CI 6.5–26.2%) and 24.6% (12.6–36.6%) at 3-years. Day 100 grade II–IV and III–IV acute GVHD was 38.2% (95% CI 25.2–51.2%) and 9.1% (95% CI 1.4–16.8%), 3-year chronic GVHD (all extensive) was 15.2% (95% CI 5.3–25.1%). Relapse was 25.5% (95% CI 13.8–37.1%), PFS 50% (95% CI 38.1–65.6%), OS 60.7% (95% CI 48.7–75.6%). Conclusions Myeloablative fractionated Bu-Flu with PTCy is safe and effective in MSD, MUD, and haploidentical HCT. It appears to reduce the severe acute/chronic GVHD without an apparent increase in relapse.

The cell of origin (COO) classification into germinal center B cell (GCB) and non-GCB types has been shown to predict survival outcomes in newly diagnosed diffuse large B cell lymphoma (DLBCL). In the relapsed/refractory (R/R) setting, there is building evidence that COO does not predict prognosis after high-dose chemotherapy and autologous stem cell transplantation (auto-SCT). The present analysis aimed to compare survival outcomes based on COO classification in R/R DLBCL patients who underwent auto-SCT. This retrospective study included adult patients with R/R DLBCL who underwent auto-SCT at MD Anderson Cancer Center between January 2007 and December 2016. The Hans algorithm using CD10, BCL6, and MUM1 markers was used to classify patients by COO. A total of 122 patients with DLBCL (71 GCB, 51 non-GCB) were included in the analysis. There were no significant differences in patient characteristics between the 2 groups, except for older median age in the GCB cohort (64 years versus 58 years; P.004). The median overall survival (OS) time was 68.5 (95% confidence interval [CI], 51.3 to not reached) months for the total population, 68.5 (95% CI, 44.8 to not reached) for GCB, and not reached for non-GCB. The 3-year OS rate was 0.659 (95% CI, 0.575 to 0.755) for the total population, 0.653 (95% CI, 0.547 to 0.779) for GCB, and 0.666 (95% CI, 0.537 to 0.824) for non-GCB. When adjusted for age and other factors of interest, no statistically significant associations for OS or progression-free survival were observed between the 2 cohorts. Our results confirm that COO loses its prognostic potential in patients with R/R DLBCL who receive high-dose chemotherapy followed by auto-SCT and both GCB and non-GCB types of DLBCL derive similar benefit from auto-SCT. Younger age, female sex, and pretransplantation disease status were associated with better OS.

Despite low nonrelapse mortality (NRM) at day 100 after allogeneic hematopoietic cell transplantation (HCT), NRM at 1 year remains substantial. In this study, we retrospectively analyzed 199 patients who were treated on a phase II clinical trial assessing safety and efficacy of myeloablative fractionated busulfan and fludarabine conditioning regimen for hematologic malignancies. The goal of the study was to identify factors associated with NRM occurring between days 101 and 365 post-HCT and generate a hypothesis for future studies to reduce the risk of NRM at 1 year. We found that a vast majority (83%) of patients who experienced NRM between days 101 and 365 had prior grade II-IV acute graft-versus-host disease (GVHD), which was the leading cause of death either by itself (33.3%) or complicated by infections (37.5%). In multivariate analysis, grade II-IV acute GVHD (hazard ratio (HR) 2.9, 95% confidence interval (CI) 1.3-6.6, p = 0.01) was the only significant predictor of NRM between days 101 and 365. Measures to reduce the risk of acute GVHD could lower the risk of NRM at 1 year and improve overall survival.

Background ACTolog (IMA101) is a personalized multi-target adoptive cell therapy (ACT) approach in which autologous T-cell products are redirected against multiple novel defined peptide-HLA (pHLA) cancer targets identified by the target discovery platform XPRESIDENT®. The primary endpoint was to assess the safety of ACTolog. Secondary endpoints were to assess the in vivo persistence of transferred T-cells and antitumor activity (www.clinicaltrials.gov NCT02876510). Methods HLA-A*02:01 positive patients with relapsed/refractory solid tumors whose tumor expressed ≥1 cancer target underwent leukapheresis and endogenous T-cells specific for up to 4 targets were primed and expanded in vitro. Patients received lymphodepletion (fludarabine 40 mg/m² and cyclophosphamide 500 mg/m² on days -6 to -3) followed by up to 4 × 1010 cells (day 0), and IL-2 (1 × 106 IU/m² SC twice daily, 14 days) (Cohort 1). In addition, cohort 2 received atezolizumab (1200 mg IV) every 21 days upon hematologic recovery. Infused T-cells were tracked in patients‘ blood via flow cytometry-based immunomonitoring as well as TCRβ sequencing. TCRs from target specific T-cells were identified from patients‘ T-cell products and characterized. Results From 07/2017–03/2020, 214 patients were screened, and 14 heavily pre-treated patients with various tumor types were infused with 1–3 T-cell products each (table 1). The treatment was generally well tolerated. The most common adverse events observed to date were expected cytopenias, mostly attributed to the lymphodepleting regimen, and Grade 1–2 cytokine release syndrome. Prolonged disease stabilization was noted in three patients for 12 months, 12+ months, and 7 months. High frequencies of target-specific T-cells up to 78.7% of CD8+ cells were detected in the blood of treated patients, persisted for >1 year and were detected in post-treatment tumor biopsies. Characterization of individual TCRs contained in T-cell products showed a broad variation of TCR avidities with the majority of TCRs being of low avidity. High-avidity TCRs were identified from products of some patients, including a patient with 26% decrease in tumor measurements 6 weeks post-treatment. Tracking the respective T-cell clonotypes in patients‘ blood and tumor provides insights into the mechanism of tumor control. Six-month data will be presented at the conference. Conclusions This is the first reported trial demonstrating the feasibility and tolerability of a personalized ACT approach using multiple defined T-cell products directed to multiple precisely defined pHLA cancer targets. These results support further exploration of a multi-target ACT approach, particularly in the context of T-cells expressing high-avidity TCRs to such defined pHLA targets. Trial Registration https://clinicaltrials.gov/ct2/show/NCT02876510 Ethics Approval The study was approved by WCG WIRB, IRB tracking number 20162235. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All the study participants provided written informed consent before enrollment. Consent Patient consent for publication is not required. Patients consented to participate in the study.

BACKGROUND BK polymavirus (BKPyV), a member of the family Polyomaviridae, is associated with increased morbidity and mortality in allogeneic stem cell transplant recipients. METHODS In our previous retrospective study of 2477 stem cell transplant patients, BKPyV replication independently predicted chronic kidney disease and poor survival. In this study, using the same cohort, we derived and validated a risk grading system to identify patients at risk of BKPyV replication after transplantation in a user-friendly modality. We used 3 baseline variables (conditioning regimen, HLA match status, and underlying cancer diagnosis) that significantly predicted BKPyV replication in our initial study in a subdistribution hazard model with death as a competing risk. We also developed a nomogram of the hazard model as a visual aid. The AUC of the ROC of the risk-score-only model was 0.65. We further stratified the patients on the basis of risk score into low-, moderate-, and high-risk groups. RESULTS The total risk score was significantly associated with BKPyV replication (P

Relapse is the major cause of mortality in patients with acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Effective preventive intervention in high-risk AML may be crucial. In this study, we investigated the clinical efficacy and safety of low dose decitabine (DAC) as part of a modified Busulfan-Cyclophosphamide (Bu-Cy) regimen for high-risk AML patients undergoing allo-HSCT to reduce relapse rate. Fifty-nine patients received DAC (20 mg/m2/d, i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A matched-pair control (CON) group of 177 patients (matched 1:3) received modified Bu-Cy only. The differences were more substantial among patients with active disease: 2-year OS, 80.7% (DAC) versus 43.5% (CON), P = 0.011 and 2-year LFS, 64.9% (DAC) versus 39.2% (CON), P = 0.024. Median time to relapse was 8 months (DAC) versus 5 months (CON) for the entire groups and 6.5 months (DAC) versus 3.5 months (CON) for patients with active disease. In summary, our data indicated that the conditioning regimen containing low dose DAC may confer a survival advantage in high-risk AML patients with active disease undergoing allo-HSCT, and a prospective randomized trial is warranted to confirm these observations.

BACKGROUND: Optimal conditioning regimen for older patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation (HCT) is not known. Likewise, role of dose intensity is not clear. METHODS: We conducted a non-randomized prospective phase II trial using low-dose, later escalated to high-dose (MAC) busulfan with fludarabine (Bu-Flu) in myelofibrosis patients up to 74 years. First 15 patients received intravenous busulfan 130 mg/m(2)/day on days −3 and −2 (“low dose”); 31 received high dose – either 100 mg/m(2)/day (days −5 to −2; n=4) or pharmacokinetic-guided area under the curve of 4,000 μmol.min (days −5 to −2; n=27). Primary endpoint was day 100 non-relapse mortality (NRM). FINDINGS: Median age was 58 years (interquartile range (IQR) 53–63). Dynamic international prognostic scoring system (DIPSS)-plus was intermediate (n=28) or high (n=18). Donors were related (n=19) or unrelated (n=27). Cumulative incidence of NRM was 9.7% (95% confidence interval (CI) 0-20.3) at day 100 and at 3 years in the high dose, while it was 0% in the low dose group at day 100, and increased to 20% (95% CI 0-41.9) at 3 years. With a median follow up of 5.1 years (IQR 3.8–6), 3-year relapse was 32.3% (95% CI 15.4-49.1) in high dose versus 53.3% (95% CI 26.6-80.1) in low dose; event-free survival was 58% (95% CI 43-78%) versus 27% (95% CI 12-62%), and overall survival was 74% (95% CI 60-91%) versus 60% (95% CI 40-91%) respectively. In multivariate analysis, high dose busulfan had a trend towards lower relapse (Hazard ratio (HR) 0.44, 95% CI, 0.18-1.07, p=0.07), with no impact on NRM. INTERPRETATION: Intensifying Bu-Flu regimen using pharmacokinetic-monitoring appears promising in reducing relapse without increasing non-relapse mortality. FUNDING: The study was supported partly by Otsuka pharmaceutical and partly by the Cancer Center Support Grant (NCI Grant P30 CA016672). TRIAL REGISTRATION: ClinicalTrials NCT00475020

Incubation of umbilical cord blood (UCB) derived regulatory T-cells (Tregs) with fucosyltransferase enzyme improves their ability to home to the target tissue to prevent graft vs. host disease (GVHD). We report results of 5 patients (Double UCB Transplant, n=2; Peripheral Blood Matched Unrelated Donor Transplant, n=3) who received UCB-Tregs (Dose level = 1×106/kg), infused one day prior to the donor graft. All patients received their designated UCB-Treg dose without any infusion reaction. The ratio of conventional T-cells in donor graft was at least 10 times higher than infused UCB-Tregs (ratio range, 12-356). All patients engrafted at median of 13 days (range, 8-17 days). One patient died due to brain hemorrhage on day 45. A bi-modal increase of plasma IL-10 level occurred on day 7 and day 21 and notably, plasma IL-2 level dropped significantly in all patients at Day 7. All evaluable patients developed ≥grade II acute GVHD and at 1 year follow up, all were alive and without evidence of disease relapse. No increase in the chronic GVHD biomarkers (REG3a and Elafin) was observed at day 7. At the time of last follow up, all evaluable patients were off immune-suppression. Stage 2 of this clinical trial examining UCB-Treg at dose level= 1×107/kg is currently underway.

Summary Background Haemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities. Methods This non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 μmol/min (16K group) or 20 000 μmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m2 for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662. Findings Between April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54–67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0–10) in the 16K group and 6% (0–13) in the 20K group (p=0·65). Infection was the most common grade 3–5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group. Interpretation Myeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse. Funding Cancer Center Support Grant (US National Cancer Institute, National Institutes of Health).

Outcomes after allogeneic stem-cell transplantation (AHSCT) are influenced by both disease- and patient-related factors. Here, we developed a novel prognostic model, hematopoietic cell transplant-composite risk (HCT-CR), by combining the refined disease risk index (DRI-R) and hematopoietic stem-cell transplant comorbidity/age index (HCT-CI/Age) to predict post-transplant survival for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The analysis included 942 AML/MDS patients treated with AHSCT. Patients were stratified into 4 HCT-CR risk groups: Low-risk—patients with low/intermediate DRI-R and HCT-CI/Age ≤3 (N = 272); Intermediate-risk—patients with low/intermediate DRI-R and HCT-CI/Age >3 (N = 168); High-risk—patients with high/very high DRI-R and HCT-CI/Age ≤3 (N = 284); and Very high-risk—patients with high/very high DRI-R and HCT-CI/Age >3 (N = 184). Compared with the low-risk group, intermediate, high, and very high-risk groups had a significantly increased risk of death [adjusted HR of 1.37 (P

We studied if the inclusion of early post–stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment—combined with pre-SCT MRD assessment, ELN risk category, and age—improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.

In this study, we compared transplantation outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS) who received a CD34+ cell-selected and those who received an unmodified allograft. This analysis initially included 181 patients, 60 who received a CD34+ cell-selected transplant and 121 who received an unmodified transplant. Owing to significant differences in disease characteristics, the analysis was limited to patients with