Iron Overload Is Associated with Delayed Engraftment and Increased Nonrelapse Mortality in Recipients of Umbilical Cord Blood Hematopoietic Cell Transplantation.

The negative impact of iron overload (IO) on outcomes of allogeneic hematopoietic cell transplantation (HCT) is well recognized, but its impact on umbilical cord blood (UCB) transplant outcome is unknown. We retrospectively analyzed outcomes of 150 patients who received UCB-HCT at our institution, stratified by pre-HCT serum ferritin (SF) level of 2000 ng/mL. Two-year overall survival rate among patients with SF >2000 and ≤2000 ng/mL was 26.1% (95% CI, 10.6% to 44.7%) and 52.1% (95% CI, 40.1% to 62.8%), respectively; hazard ratio (HR) = 2.26 (95% CI, 1.28 to 4.00, P = .005). Two-year nonrelapse mortality rate was higher among patients with SF >2000 ng/mL (56.5%; 95% CI, 33.3% to 74.4%) compared to SF ≤2000 ng/mL (30.1%; 95% CI, 20.0% to 40.9%); HR = 2.18 (95% CI, 1.10 to 4.31, P = .025). Neutrophil engraftment at 42 days was 78.3% (95% CI, 53.5% to 90.8%) in patients with SF >2000 ng/mL versus 91.8% (95% CI, 82.1% to 96.4%) in patients with SF ≤2000 ng/mL; HR = 0.58 (95% CI, 0.35 to 0.96, P = .034). A significant difference in platelet engraftment at 3 months was also observed: 52.2% (95% CI, 29.4% to 70.8%) for SF >2000 ng/mL versus 80.8% (95% CI, 69.5% to 88.3%) for SF ≤2000 ng/mL; HR = 0.48 (95% CI, 0.23 to 0.98, P = .044). In conclusion, IO defined by SF of 2000 ng/mL is a strong adverse prognostic factor for UCB-HCT and should be considered when UCB is chosen as the graft source for patients without a fully matched donor.

Outcomes of Allogeneic Hematopoietic Cell Transplantation after Salvage Therapy with Blinatumomab in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia.

Historically, outcomes of adult patients with relapsed acute lymphoblastic leukemia (ALL) who fail to enter remission with conventional chemotherapy are very poor. Blinatumomab, a bispecific CD3/CD19 antibody, has shown remarkable activity in relapsed/refractory (r/r) ALL. Although allogeneic hematopoietic cell transplant (HCT) is the recommended consolidation therapy for patients with r/r ALL who respond to salvage therapy, HCT and toxicity outcomes for those who received blinatumomab salvage and HCT remain largely unknown. We treated 89 patients with r/r ALL with blinatumomab, of whom 43 patients (48%) achieved remission. Here we describe our single-center experience in the subset of patients who responded to blinatumomab salvage therapy for eradication of either gross (n = 24) or minimal residual disease (n = 11) before HCT. Overall survival at 1 and 2 years after allogeneic HCT was 77% and 52%, respectively. Leukemia-free survival at 1 and 2 years were 65% and 40%, respectively. Additionally, with blinatumomab administration pre-HCT, no unusual toxicities such as delayed neutrophil/platelet engraftment or graft failure were observed. Acute grades II to IV graft-versus-host disease (GVHD) at day +100 post-HCT was at 43% and 2-year chronic GVHD was 36%, both comparable with historic control subjects. Finally, results of our subset analysis based on pre-HCT minimal residual disease (MRD) status indicated no significant difference in survival outcomes among patients undergoing transplant in MRD-negative status and the entire cohort. In conclusion, based on results of this study, blinatumomab may be considered as a safe and effective agent for r/r ALL patients before HCT.

Melphalan-Based Reduced-Intensity Conditioning is Associated with Favorable Disease Control and Acceptable Toxicities in Patients Older Than 70 with Hematologic Malignancies Undergoing Allogeneic Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (alloHCT) is offered increasingly to elderly patients with hematologic malignancies. However, outcome data in those who are 70 years or older are limited, and no standard conditioning regimen has been established for this population. In this retrospective study we evaluated the outcome of 53 consecutive patients aged 70 years and older who underwent alloHCT with melphalan-based reduced-intensity conditioning (RIC) at City of Hope. Engraftment was prompt, with median time to neutrophil engraftment of 15 days. More than 95% of patients achieved complete donor chimerism within 6 weeks from HCT, consistent with the "semiablative" nature of this regimen. With a median follow-up of 31.1 months, the 2-year overall survival (OS), progression-free survival (PFS), and nonrelapse mortality (NRM) were 68.9%, 63.8%, and 17.0%, respectively. Cumulative incidence of relapse at 1 and 2 years was 17.0% and 19.3%, respectively. One hundred-day cumulative incidence of grades II to IV acute graft-versus-host disease was 37.7% (grades III to IV, 18.9%), and 2-year cumulative incidence of chronic graft-versus-host disease was 61.9% (extensive, 45.9%). The only significant predictor for poor OS was high/very high disease risk index. Transplant-related complications and morbidities observed here did not differ from the commonly expected in younger patients treated with RIC. In conclusion, alloHCT with a melphalan-based conditioning regimen is associated with acceptable toxicities and NRM, lower incidence of relapse, and favorable OS and PFS in patients aged 70 years or older.

Therapy-related acute lymphoblastic leukemia has distinct clinical and cytogenetic features compared to de novo acute lymphoblastic leukemia, but outcomes are comparable in transplanted patients.

Therapy-related acute lymphoblastic leukemia remains poorly defined due to a lack of large data sets recognizing the defining characteristics of this entity. We reviewed all consecutive cases of adult acute lymphoblastic leukemia treated at our institution between 2000 and 2017 and identified therapy-related cases - defined as acute lymphoblastic leukemia preceded by prior exposure to cytotoxic chemotherapy and/or radiation. Of 1022 patients with acute lymphoblastic leukemia, 93 (9.1%) were classified as therapy-related. The median latency for therapy-related acute lymphoblastic leukemia onset was 6.8 years from original diagnosis, and this was shorter for patients carrying the MLL gene rearrangement compared to those with other cytogenetics. When compared to de novo acute lymphoblastic leukemia, therapy-related patients were older (P<0.01), more often female (P<0.01), and had more MLL gene rearrangement (P<0.0001) and chromosomes 5/7 aberrations (P=0.02). Although therapy-related acute lymphoblastic leukemia was associated with inferior 2-year overall survival compared to de novo cases (46.0% vs 68.1%, P=0.001), prior exposure to cytotoxic therapy (therapy-related) did not independently impact survival in multivariate analysis (HR=1.32; 95% CI: 0.97-1.80, P=0.08). There was no survival difference (2-year = 53.4% vs 58.9%, P=0.68) between the two groups in patients who received allogenic hematopoietic cell transplantation. In conclusion, therapy-related acute lymphoblastic leukemia represents a significant proportion of adult acute lymphoblastic leukemia diagnoses, and a subset of cases carry clinical and cytogenetic abnormalities similar to therapy-related myeloid neoplasms. Although survival of therapy-related acute lymphoblastic leukemia was inferior to de novo cases, allogeneic hematopoietic cell transplantation outcomes were comparable for the two entities.

Hyperfractionated Cyclophosphamide, Vincristine, Doxorubicin, and Dexamethasone Chemotherapy in Mantle Cell Lymphoma Patients Is Associated with Higher Rates of Hematopoietic Progenitor Cell Mobilization Failure despite Plerixafor Rescue.

Induction regimens for mantle cell lymphoma (MCL) can be categorized into highly intensive regimens containing cytarabine and less intense regimens, such as rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) or rituximab with bendamustine (R-bendamustine). Prior publications have shown rituximab and hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyperCVAD) can be associated with stem cell mobilization failures. However, those studies did not include the use of plerixafor as rescue for stem cell mobilization failure. We examined our database of 181 consecutive MCL patients who received upfront therapy from 2005 to 2015 with either R-hyperCVAD or less intense chemotherapy (R-bendamustine and R-CHOP only) regimens to assess impact of frontline chemotherapy on collection of hematopoietic cell progenitors before autologous stem cell transplantation (ASCT). In the preplerixafor era (before August 16, 2009), a significant difference in peripheral blood stem cell (PBSC) collection failure between the R-hyperCVAD (12%) and other chemotherapy (11%) groups was not established. However, in the postplerixafor era, use of R-hyperCVAD chemotherapy was associated with significantly higher rates of hematopoietic progenitor cell collection failures (17%) compared with that observed in the other chemotherapy group (4%; P = .04). The rates of mobilization failure declined to 4% in the postplerixafor era from 11% in the preplerixafor era for patients receiving less intensive chemotherapy. Conversely, the rate of mobilization failure increased in the R-hyperCVAD group from 12% in the preplerixafor era to 17% in the postplerixafor era. Plerixafor does not overcome the negative impact of R-hyperCVAD on PBSC mobilization, and caution is warranted in using R-hyperCVAD in patients with newly diagnosed MCL who are candidates for ASCT.

Long-Term Results of High-Dose Therapy and Autologous Stem Cell Transplantation for Mantle Cell Lymphoma: Effectiveness of Maintenance Rituximab.

High-dose therapy followed by autologous stem cell transplantation (ASCT) can improve outcomes for mantle cell lymphoma (MCL) but is associated with a high incidence of relapse. A retrospective study of 191 MCL patients who underwent ASCT at City of Hope was performed to examine prognostic factors for outcomes after ASCT. For all patients the 5-year overall survival (OS) was 71% (95% confidence interval [CI], 63% to 77%) and progression-free survival (PFS) was 53% (95% CI, 45% to 60%). The 5-year cumulative incidence of relapse was 41% (95% CI, 34% to 48%) with a continuous pattern of relapse events occurring at a median of 2.1 years (range, .2 to 13.4) after ASCT. In multivariate analysis, post-transplant maintenance rituximab was the factor most significantly associated with both OS (relative risk [RR], .17; 95% CI, .07 to .38) and PFS (RR, .25; 95% CI, .14 to .44). For the subset of patients who had positron emission tomography (PET) data available and were in a PET-negative first complete remission at ASCT (n = 105), maintenance rituximab was significantly associated with superior OS (RR, .17; 95% CI, .05 to .59) and PFS (RR, .20; 95% CI, .09 to .43). These results support a benefit with maintenance rituximab for all MCL patients treated with ASCT.

Favorable impact of allogeneic stem cell transplantation in patients with therapy-related myelodysplasia regardless of TP53 mutational status.

Therapy-related myelodysplastic syndrome is a long-term complication of cancer treatment in patients receiving cytotoxic therapy, characterized by high-risk genetics and poor outcomes. Allogeneic hematopoietic cell transplantation is the only potential cure for this disease, but the prognostic impact of pre-transplant genetics and clinical features has not yet been fully characterized. We report here the genetic and clinical characteristics and outcomes of a relatively large cohort of patients with therapy-related myelodysplastic syndrome (n=67) who underwent allogeneic transplantation, comparing these patients to similarly treated patients with de novo disease (n=199). The 5-year overall survival was not different between patients with therapy-related and de novo disease (49.9% versus 53.9%; P=0.61) despite a higher proportion of individuals with an Intermediate-2/High International Prognostic Scoring System classification (59.7% versus 43.7%; P=0.003) and high-risk karyotypes (61.2% versus 30.7%; P<0.01) among the patients with therapy-related disease. In mutational analysis, TP53 alteration was the most common abnormality in patients with therapy-related disease (n=18: 30%). Interestingly, the presence of mutations in TP53 or in any other of the high-risk genes (EZH2, ETV6, RUNX1, ASXL1: n=29: 48%) did not significantly affect either overall survival or relapse-free survival. Allogeneic stem-cell transplantation is, therefore, a curative treatment for patients with therapy-related myelodysplastic syndrome, conferring a similar long-term survival to that of patients with de novo disease despite higher-risk features. While TP53 alteration was the most common mutation in therapy-related myelodysplastic syndrome, the finding was not detrimental in our case-series.

Implications and Management of Central Nervous System Involvement before Allogeneic Hematopoietic Cell Transplantation in Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) with a history of central nervous system (CNS) involvement, either at diagnosis or relapse, poses challenges when the decision is made to proceed with allogeneic hematopoietic cell transplantation (alloHCT), as there is no evidence-based consensus on the best peri-transplantation approach to reduce subsequent CNS relapse risk. Here, we retrospectively analyzed outcomes of 87 patients with ALL and a history of CNS involvement who later underwent alloHCT. Patients with pretransplantation CNS involvement had higher risk of CNS relapse after transplantation (2-year CNS relapse: 9.6% versus 1.4%, P < .0001), inferior event-free survival (EFS) (hazard ratio [HR], 1.52; P = .003), and worse overall survival (OS) (HR, 1.55; P = .003) compared with patients without pretransplantation CNS involvement (n = 543). There was no difference in post-transplantation CNS relapse, EFS, or OS among patients presenting with CNS involvement at diagnosis, those with isolated CNS relapse, and those with combined bone marrow and CNS relapse before HCT. Interestingly, neither pretransplantation cranial irradiation, use of total body irradiation-based conditioning, nor post-transplantation prophylactic intrathecal chemotherapy were associated with a reduction of CNS relapse risk after transplantation. Thus, among the patients in the cohort studied, there was no clear benefit of CNS-directed therapy in the peri-transplantation period among patients who had prior CNS involvement and underwent subsequent alloHCT.

Cytomegalovirus sinusitis complicated by orbital apex syndrome in an immunocompromised host.

Sinusitis in immunocompromised patients can be caused by a wide variety of pathogens, primarily bacterial and fungal in nature. Tissue invasion can extend into the orbital apex and result in ophthalmoplegia and blindness. We report the first histologically proven case, to our knowledge, caused by cytomegalovirus infection.

Impact of Additional Cytogenetic Abnormalities in Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation.

The occurrence of additional cytogenetic abnormalities (ACAs) is common in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) but is of unknown significance in the tyrosine kinase inhibitor (TKI) era. We retrospectively analyzed data from a consecutive case series of adults with Ph+ ALL who had undergone allogeneic hematopoietic cell transplantation (alloHCT) at City of Hope between 2003 and 2014. Among 130 adults with Ph+ ALL who had TKI therapy before alloHCT, 78 patients had available data on conventional cytogenetics at diagnosis and were eligible for outcomes analysis. ACAs were observed in 41 patients (53%). There were no statistically significant differences in median age, median initial WBC count, post-HCT TKI maintenance, or disease status at the time of transplant between the Ph-only and ACA cohorts; however, the Ph-only cohort had a higher rate of minimal residual disease positivity at the time of HCT. Three-year leukemia-free survival (79.8% versus 39.5%, P = .01) and 3-year overall survival (83% versus 45.6%, P = .02) were superior in the Ph-only cohort compared with the ACA cohort, respectively. Monosomy 7 was the most common additional aberration observed in our ACA cohort (n = 12). Thus, when TKI therapy and alloHCT are used as part of adult Ph+ ALL therapy, the presence of ACAs appears to have a significant deleterious effect on outcomes post-HCT.

Pathways analysis of differential gene expression induced by engrafting doses of total body irradiation for allogeneic bone marrow transplantation in mice.

A major challenge in allogeneic bone marrow (BM) transplantation is overcoming engraftment resistance to avoid the clinical problem of graft rejection. Identifying gene pathways that regulate BM engraftment may reveal molecular targets for overcoming engraftment barriers. Previously, we developed a mouse model of BM transplantation that utilizes recipient conditioning with non-myeloablative total body irradiation (TBI). We defined TBI doses that lead to graft rejection, that conversely are permissive for engraftment, and mouse strain variation with regards to the permissive TBI dose. We now report gene expression analysis, using Agilent Mouse 8x60K microarrays, in spleens of mice conditioned with varied TBI doses for correlation to the expected engraftment phenotype. The spleens of mice given engrafting doses of TBI, compared with non-engrafting TBI doses, demonstrated substantially broader gene expression changes, significant at the multiple testing-corrected P <0.05 level and with fold change ≥2. Functional analysis revealed significant enrichment for a down-regulated canonical pathway involving B-cell development. Genes enriched in this pathway suggest that suppressing donor antigen processing and presentation may be pivotal effects conferred by TBI to enable engraftment. Regardless of TBI dose and recipient mouse strain, pervasive genomic changes related to inflammation was observed and reflected by significant enrichment for canonical pathways and association with upstream regulators. These gene expression changes suggest that macrophage and complement pathways may be targeted to overcome engraftment barriers. These exploratory results highlight gene pathways that may be important in mediating BM engraftment resistance.

Fine mapping of the Bmgr5 quantitative trait locus for allogeneic bone marrow engraftment in mice.

To identify novel mechanisms regulating allogeneic hematopoietic cell engraftment, we used forward genetics and previously described identification, in mice, of a bone marrow (BM) engraftment quantitative trait locus (QTL), termed Bmgr5. This QTL confers dominant and large allele effects for engraftment susceptibility. It was localized to chromosome 16 by quantitative genetic techniques in a segregating backcross bred from susceptible BALB.K and resistant B10.BR mice. We now report verification of the Bmgr5 QTL using reciprocal chromosome 16 consomic strains. The BM engraftment phenotype in these consomic mice shows that Bmgr5 susceptibility alleles are not only sufficient but also indispensable for conferring permissiveness for allogeneic BM engraftment. Using panels of congenic mice, we resolved the Bmgr5 QTL into two separate subloci, termed Bmgr5a (Chr16:14.6-15.8 Mb) and Bmgr5b (Chr16:15.8-17.6 Mb), each conferring permissiveness for the engraftment phenotype and both fine mapped to an interval amenable to positional cloning. Candidate Bmgr5 genes were then prioritized using whole exome DNA sequencing and microarray gene expression data. Further studies are warranted to elucidate the genetic interaction between the Bmgr5a and Bmgr5b QTL and identify causative genes and underlying gene variants. This may lead to new approaches for overcoming the problem of graft rejection in clinical hematopoietic cell transplantation.

Outpatient antibiotic prescribing for acute respiratory infections in Vietnamese primary care settings by the WHO AWaRe (Access, Watch and Reserve) classification: An analysis using routinely collected electronic prescription data.

Background: This study aims to investigate patterns of antibiotic prescribing and to determine patient-specific factors associated with the choice of antibiotics by the World Health Organization's Access-Watch-Reserve (WHO AWaRe) class for acute respiratory infections (ARIs) in rural primary care settings in northern Vietnam. Methods: We retrospectively reviewed health records for outpatients who were registered with the Vietnamese Health Insurance Scheme, visited one of 112 commune health centres in 6 rural districts of Nam Dinh province, Vietnam during 2019, and were diagnosed with ARIs. Patient-level prescription data were collected from the electronic patient databases. We used descriptive statistics to investigate patterns of antibiotic prescribing, with the primary outcomes including total antibiotic prescriptions and prescriptions by WHO AWaRe group. We identified patient-specific factors associated with watch-group antibiotic prescribing through multivariable logistic regression analysis. Findings: Among 193,010 outpatient visits for ARIs observed in this study, 187,144 (97.0%) resulted in an antibiotic prescription, of which 172,976 (92.5%) were access-antibiotics, 10,765 (5.6%) were watch-antibiotics, 3366 (1.8%) were not-recommended antibiotics. No patients were treated with reserve-antibiotics. The proportion of watch-antibiotic prescription was highest amongst children under 5-years old (18.1%, compared to 9.5% for 5-17-years, 4.9% for 18-49-years, 4.3% for 50-64-years, and 3.7% for 65-and-above-years). In multivariable logistic regression, children, district, ARI-type, comobid chronic respiratory illness, and follow-up visit were associated with higher likelihood of prescribing watch-group antibiotics. Interpretation: The alarmingly high proportion of antibiotic prescriptions for ARIs in primary care, and the frequent use of watch-antibiotics for children, heighten concerns around antibiotic overuse at the community level. Antimicrobial stewardship interventions and policy attention are needed in primary care settings to tackle the growing threat of antibiotic resistance. Funding: This work was supported through Australian government and UK aid from the UK government funding to FIND (Foundation for Innovative New Diagnostics) grant number FO17-0015, in addition to a Wellcome Trust grant (213920/Z/18/Z), and an Oxford University Clinical Research Unit internal grant from the Wellcome Trust Africa Asia Programme core grant in Vietnam (106680/Z/14/Z).

Brentuximab vedotin plus nivolumab after autologous haematopoietic stem-cell transplantation for adult patients with high-risk classic Hodgkin lymphoma: a multicentre, phase 2 trial.

BACKGROUND: After autologous haematopoietic stem-cell transplantation (HSCT), consolidation with brentuximab vedotin in patients with high-risk relapsed or refractory classic Hodgkin lymphoma has been shown to improve progression-free survival compared with placebo. Brentuximab vedotin plus nivolumab is a safe and effective treatment for relapsed or refractory classic Hodgkin lymphoma; therefore, we aimed to evaluate the safety and activity of this drug combination post-autologous HSCT consolidation in patients with high-risk relapsed or refractory classic Hodgkin lymphoma. METHODS: We did a multicentre phase 2 trial at five centres in the USA. Eligible patients were aged 18 years or older with high-risk relapsed or refractory classic Hodgkin lymphoma, had an ECOG performance status of 0-2, and had adequate organ and bone marrow function. Enrolled patients received brentuximab vedotin (1·8 mg/kg) and nivolumab (3 mg/kg) intravenously starting 30-60 days after autologous HSCT on day 1 of each 21-day cycle for up to 8 cycles. Nivolumab dose reduction was not allowed. Brentuximab vedotin dose reduction to 1·2 mg/kg was permitted. If one drug was discontinued because of a toxic effect, the other could be continued. The primary endpoint was 18-month progression-free survival in all treated patients. This study is registered with ClinicalTrials.gov, number NCT03057795. FINDINGS: Between May 3, 2017, and July 13, 2019, 59 patients were enrolled and received the study therapy. Patients initiated brentuximab vedotin plus nivolumab for a median of 54 days (IQR 46-58) after autologous HSCT and received a median of 8 cycles (8-8). 34 (58%) of 59 patients were male, 29 (49%) completed 8 cycles of brentuximab vedotin plus nivolumab, and 45 (76%) completed 8 cycles of at least one drug. The median follow-up time was 29·9 months (IQR 24·6-34·8). The 18-month progression-free survival in all 59 patients was 94% (95% CI 84-98). The most common adverse events were sensory peripheral neuropathy (31 [53%] of 59) and neutropenia (25 [42%]), and immune-related adverse events requiring corticosteroids occurred in 17 (29%) of 59 patients. No treatment-related deaths were observed. INTERPRETATION: Brentuximab vedotin plus nivolumab was highly active post-autologous HSCT consolidation for patients with high-risk relapsed or refractory classic Hodgkin lymphoma, most of whom had previous exposure to either brentuximab vedotin or PD-1 blockade. Combination immunotherapy in this setting should be further studied in patients with classic Hodgkin lymphoma with further refinement of the regimen to mitigate toxic effects, particularly in high-risk patients in whom more intensive therapy to prevent relapse is warranted. FUNDING: Bristol Myers Squibb, Leukemia and Lymphoma Society, Lymphoma Research Foundation, and National Cancer Institute of the National Institutes of Health.

Role of Salvage Radiation Treatment of Relapses in Relapsed/Refractory Diffuse Large B Cell Lymphoma Post-Autologous Stem Cell Transplant.

PURPOSE: Approximately 50% of patients with relapsed/refractory diffuse large B cell lymphoma (R/R DLBCL) will relapse post-autologous stem cell transplant (ASCT), and the role of salvage therapy is not well defined. We examined radiation therapy (RT) as salvage treatment in this patient population. MATERIALS AND METHODS: A retrospective review of patients with DLBCL who had an ASCT during 2004 to 2016 and subsequently relapsed was performed. Clinical and pathologic characteristics were collected, including detailed information regarding post-ASCT treatment. Response rates were tabulated and survival analysis was performed, stratified by salvage modality. RESULTS: A total of 165 patients with R/R DLBCL who relapsed after ASCT were identified; 91 of these patients received salvage chemotherapy as their first line of relapse therapy, and 14 received salvage radiation. Median salvage RT dose was 36 Gy (range, 24-50). The objective response rate with salvage chemotherapy and RT was 53.0% and 78.5%, respectively (P = 0.07), and the complete response rate was 31.3% and 57.1%, respectively (P = 0.06). Median follow-up among living patients was 48.9 months (range, 4.8-136.17). Among patients with one site of relapse post-ASCT, median overall survival in patients who received salvage RT was significantly improved (P = 0.008) relative to chemotherapy (not reached [95% confidence interval {CI}, 8.4-not reached] versus 10.0 months [95% CI, 5.3-17.8]). Median progression-free survival in patients who received salvage RT was not significantly different (P = 0.16) relative to chemotherapy (8.4 months [95% CI, 2.5-47.7] versus 3.9 months [95% CI, 2.4-8.5]). CONCLUSIONS: Patients who received RT as first salvage therapy post-ASCT, particularly with localized disease, had favorable oncologic outcomes. Future studies are needed to understand which patients with R/R DLBCL who relapse after ASCT may benefit from early salvage RT versus chemotherapy.

Tacrolimus initial steady state level in post-transplant cyclophosphamide-based GvHD prophylaxis regimens.

Post-transplant cyclophosphamide (PTCy) combined with tacrolimus (TAC) as graft-versus-host disease (GvHD) prophylaxis post-hematopoietic cell transplantation (HCT) is safe and effective. Optimal serum levels of TAC in this combination remain undetermined. We hypothesized that TAC at initial steady state (TISS) of <10 ng/mL could promote optimal transplant outcomes and prevent TAC-associated toxicities. We retrospectively analyzed a consecutive case series of 210 patients who received PTCy/TAC-based prophylaxis post-HCT from 1/2013-6/2018. Patients received HCT from haploidentical (n = 172) or mismatched donors (n = 38), and flat dose (FD) or weight-based dose (WBD) TAC. Twenty-four-month overall survival (OS), disease free survival (DFS), and relapse rate (RR) were 61%, 56%, and 22%, respectively, in TISS < 10 ng/mL cohort (n = 176), and 50%, 43%, and 35%, respectively, in TISS ≥ 10 ng/mL cohort (n = 34) (OS, P = 0.71; DFS, P = 0.097; RR, P = 0.031). OS, DFS, RR, non-relapse mortality, acute GvHD grade II-IV, grade III-IV or chronic GvHD by TISS were similar in multivariable analysis. TISS ≥ 10 ng/mL conferred increased risk of viral infection (P = 0.003). More patients receiving FD vs. WBD had TISS < 10 ng/mL (P = 0.001). Overall, TISS < 10 ng/mL early post HCT conferred similar survival outcomes and lowered risk of viral infection and toxicities compared to TISS ≥ 10 ng/mL.

Total marrow and lymphoid irradiation as conditioning in haploidentical transplant with posttransplant cyclophosphamide.

Posttransplant cyclophosphamide (PTCy) platform has shown low rates of graft-versus-host disease (GVHD) and nonrelapse mortality (NRM) after haploidentical hematopoietic cell transplantation (HaploHCT). However, because of the limited disease control, relapse rate remains a major cause of treatment failure in high-risk patients. Total marrow and lymphoid irradiation (TMLI) allows for delivery of high radiation to bone marrow and other targeted structures, without increasing off-target radiation exposure and toxicity to end organs. In this phase 1 trial, 31 patients with high-risk and/or active primary refractory leukemias or myelodysplastic syndrome underwent peripheral blood stem cell HaploHCT with TMLI, fludarabine, and cyclophosphamide as the conditioning regimen. Radiation dose was escalated in increments of 200 cGy (1200-2000 cGy). GVHD prophylaxis was PTCy with tacrolimus/mycophenolate mofetil. Grade 2 toxicities by the Bearman scale were mucositis (n = 1), hepatic (n = 3), gastrointestinal (n = 5), and cardiac (n = 2). One patient (1800 cGy) experienced grade 3 pulmonary toxicity (dose-limiting toxicity). At a follow-up duration of 23.9 months for the whole cohort; 2-year NRM was 13%. Cumulative incidence of day 100 grade 2 to 4 and 3 to 4 acute GVHD was 52% and 6%, respectively. Chronic GVHD at 2 years was 35%. For patients treated with 2000 cGy, with a median follow-up duration of 12.3 months, 1-year relapse/progression, progression-free survival, and overall survival rates were 17%, 74%, and 83%, respectively. In conclusion, HaploHCT-TMLI with PTCy was safe and feasible in our high-risk patient population with promising outcomes.

Inappropriate supply of antibiotics for common viral infections by community pharmacies in Vietnam: A standardised patient survey.

Background: This study aimed to evaluate the appropriateness of antibiotic dispensing of private pharmacies in Vietnam. Methods: Standardised patient surveys were conducted in randomly selected community pharmacies across 40 districts in Vietnam. Four clinical scenarios were represented by patient actors: (a) an adult requesting treatment for a sibling with a viral upper respiratory tract infection (URTI), (b) a parent requesting treatment for a child with acute diarrhoea, (c) an adult making a direct antibiotic request, and (d) an adult presenting with an antibiotic prescription. We calculated the proportion of interactions that resulted in inappropriate supply of antibiotics and patient advice. Predictors of inappropriate antibiotic supply were assessed. Findings: Patient actors attended 949 pharmacies, resulting in 1266 clinical interactions. Antibiotics were inappropriately supplied to 92% (291/316) of adults requesting treatment for URTI symptoms, 43% (135/316) for children with acute diarrhoea symptoms and to 84% (267/317) of direct request for antibiotics. Only 49% of pharmacies advised patients regarding their antibiotic use. Female actors were more likely to be given antibiotics than male actors for URTI (aOR 2·71, 1·12-6·60) but not for diarrhoeal disease. Pharmacies in northern Vietnam were more likely than those in southern Vietnam to supply antibiotics without a prescription: for adult URTI (aOR=5·8, 95% CI: 2·2-14·9) and childhood diarrhoea (aOR=3·5, 95% CI: 2·0-6·0) symptoms, but less likely to dispense for direct antibiotics request. Interpretation: Inappropriate antibiotic supply was common in Vietnamese private pharmacies. Multifaceted measures are urgently needed to achieve WHO's global action plan for the optimal use of antimicrobials. Funding: This study was funded by a grant from the Australian Department of Foreign Affairs and Trade.

A chromosome 16 quantitative trait locus regulates allogeneic bone marrow engraftment in nonmyeloablated mice.

Identifying genes that regulate bone marrow (BM) engraftment may reveal molecular targets for overcoming engraftment barriers. To achieve this aim, we applied a forward genetic approach in a mouse model of nonmyeloablative BM transplantation. We evaluated engraftment of allogeneic and syngeneic BM in BALB.K and B10.BR recipients. This allowed us to partition engraftment resistance into its intermediate phenotypes, which are firstly the immune-mediated resistance and secondly the nonimmune rejection of donor BM cells. We observed that BALB.K and B10.BR mice differed with regard to each of these resistance mechanisms, thereby providing evidence that both are under genetic control. We then generated a segregating backcross (n = 200) between the BALB.K and B10.BR strains to analyze for genetic linkage to the allogeneic BM engraftment phenotype using a 127-marker genome scan. This analysis identified a novel quantitative trait locus (QTL) on chromosome 16, termed Bmgr5 (logarithm of odds 6.4, at 11.1 cM). The QTL encodes susceptibility alleles, from the BALB.K strain, that are permissive for allogeneic BM engraftment. Further identification of Bmgr5 genes by positional cloning may reveal new and effective approaches for overcoming BM engraftment obstacles.

Identification of a major susceptibility locus for lethal graft-versus-host disease in MHC-matched mice.

Graft-vs-host disease (GVHD) is the major cause of morbidity and mortality after allogeneic hemopoietic cell transplantation. From a genetic perspective, GVHD is a complex phenotypic trait. Although it is understood that susceptibility results from interacting polymorphisms of genes encoding histocompatibility Ags and immune regulatory molecules, a detailed and integrative understanding of the genetic background underlying GVHD remains lacking. To gain insight regarding these issues, we performed a forward genetic study. A MHC-matched mouse model was used in which irradiated recipient BALB.K and B10.BR mice demonstrate differential susceptibility to lethal GHVD when transplanted using AKR/J donors. Assessment of GVHD in (B10.BR x BALB.K)F(1) mice revealed that susceptibility is a dominant trait and conferred by deleterious alleles from the BALB.K strain. To identify the alleles responsible for GVHD susceptibility, a genome-scanning approach was taken using (B10.BR x BALB.K)F(1) x B10.BR backcross mice as recipients. A major susceptibility locus, termed the Gvh1 locus, was identified on chromosome 16 using linkage analysis (logarithm of the odds, 9.1). A second locus was found on chromosome 13, named Gvh2, which had additive but protective effects. Further identification of Gvh genes by positional cloning may yield new insight into genetic control mechanisms regulating GVHD and potentially reveal novel approaches for effective GVHD therapy.