Malnutrition and clinical outcomes post alloSCT.

BACKGROUND: Malnutrition has been linked with higher risk of poor outcomes post-allogeneic stem cell transplantation (alloSCT); however, few studies have used a validated nutrition assessment tool such as the Patient Generated Subjective Global Assessment (i.e., PG-SGA) to measure nutritional status and investigate associations with long-term clinical outcomes. The present study aimed to assess the incidence of malnutrition prior to alloSCT and determine whether there was an association between nutritional status pre-transplant and post-transplant clinical outcomes including acute kidney injury, graft-versus-host disease, intensive care admission, need for haemodialysis and survival. METHODS: A retrospective analysis of 362 patients (213 males:149 females, mean ± SD age = 47.8 ± 14.1 years) who underwent alloSCT from 2008 to 2013 was conducted. Data on clinical outcomes were obtained for 5 years post-transplant. RESULTS: Fifteen percent (n = 56) of patients were identified as malnourished pre-admission. Malnutrition was associated with longer hospital stay (p = 0.007), increased requirement for haemodialysis (p = 0.016) and increased admissions to the intensive care unit (p = 0.003). There was no association between malnutrition and acute kidney injury, graft-versus-host disease or survival. Following multivariate analyses, malnutrition remained significantly associated with increased admission rates to the intensive care unit (odds ratio = 3.8, 95% confidence interval = 1.3-10.5, p = 0.011) and increased length of hospital stay > 30 days (odds ratio = 3.6. 95% confidence interval = 1.8-7.4, p ≤ 0.001). CONCLUSIONS: These findings add importance to the need for nutrition screening and assessment to be routinely undertaken for patients prior to alloSCT and throughout hospitalisation to provide early nutrition intervention for the prevention of malnutrition, poor clinical outcomes and increased healthcare costs.

The improvement in overall survival from unrelated donor transplantation in Australia and New Zealand is driven by a reduction in non-relapse mortality: A study from the ABMTRR.

Unrelated donors (UDs) are the commonest source for allogeneic transplantation (alloSCT), with higher non-relapse mortality (NRM) than siblings. We analyzed data from the Australasian Bone Marrow Transplant Recipient Registry from adults receiving a first UD alloSCT during 2001-2015, to determine whether and how NRM has changed. Predictors of outcome were determined using cox regression, accounting for time-interactions and competing risks. A total of 2308 patients met inclusion criteria. Changes over time included increasing age, utilization of peripheral blood cells, reduced intensity conditioning, and T-cell depletion. Three-year OS increased significantly from 44% in 2001-2005 to 58% in 2011-2015 (p < 0.001). This was attributed to a reduction in NRM from 35% to 24% (p < 0.001) with no change in relapse. Factors associated with increased NRM included age, male sex, CMV seropositivity, HLA mismatch, transplant more than 6 months from diagnosis, and T-cell depletion when administered during 2001-2005. Survival following UD SCT has improved by almost 15% over the past decade, driven by improvements in NRM. This has occurred despite increasing recipient age and appears to be due to better donor selection, reduced delays to transplantation, and improved prevention and management of GVHD.

A phase 3 double-blind study of the addition of tocilizumab vs placebo to cyclosporin/methotrexate GVHD prophylaxis.

We determined the efficacy of tocilizumab (TCZ) in preventing grade 2-4 acute graft-versus-host disease (aGVHD) in patients with acute leukemia or myelodysplasia undergoing matched sibling donor (MSD) or volunteer unrelated donor (VUD) allogeneic stem cell transplantation after myeloablative or reduced-intensity conditioning across 5 Australian centers. A total of 145 patients (50 MSD, 95 VUD) were randomly assigned to placebo or TCZ on day -1. All patients received T-cell-replete peripheral blood stem cell grafts and graft-versus-host disease (GVHD) prophylaxis with cyclosporin/methotrexate. A planned substudy analyzed the VUD cohort. With a median follow-up of 746 days, the incidence of grade 2-4 aGVHD at day 100 for the entire cohort was 36% for placebo vs 27% for TCZ (hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.38-1.26; P = .23) and 45% vs 32% (HR, 0.61; 95% CI, 0.31-1.22; P = .16) for the VUD subgroup. The incidence of grade 2-4 aGVHD at day 180 for the entire cohort was 40% for placebo vs 29% for TCZ (HR, 0.68; 95% CI, 0.38-1.22; P = .19) and 48% vs 32% (HR, 0.59; 95% CI, 0.30-1.16; P = .13) for the VUD subgroup. Reductions in aGVHD were predominantly in grade 2 disease. For the entire cohort, transplant-related mortality occurred in 8% vs 11% of placebo-treated vs TCZ-treated patients, respectively (P = .56), and overall survival was 79% vs 71% (P = .27). Median day to neutrophil and platelet engraftment was delayed by 2 to 3 days in TCZ-treated patients, whereas liver toxicity and infectious complications were similar between groups. In this phase 3 randomized double-blind trial, TCZ showed nonsignificant trends toward reduced incidence of grade 2-4 aGVHD in recipients from HLA-matched VUDs but no improvements in long term-survival.

Pegylated interferon-2α invokes graft-versus-leukemia effects in patients relapsing after allogeneic stem cell transplantation.

Allogeneic stem cell transplantation (SCT) is a curative therapy for patients with hematological malignancies related largely to an immunological graft-versus-leukemia (GVL) effect mediated by donor T cells and natural killer cells. Relapse of disease after SCT represents failure of GVL and is now the major cause of treatment failure. We sought to augment GVL effects in patients (n = 29) relapsing after SCT in a prospective phase I/II clinical trial of dose-escalated pegylated interferon-2α (peg-IFNα). The administration of peg-IFNα after reinduction chemotherapy, with or without subsequent donor lymphocyte infusion (DLI), resulted in a 2-year overall survival (OS) of 31% (95% confidence interval, 17.3%-49.2%), which rejects the null hypothesis of 7% generated by observations in an institutional historical cohort. As expected, peg-IFNα was associated with graft-versus-host disease (GVHD) and hematological toxicity, which was manageable with scheduled dose modifications. Progression-free survival (PFS) was greatest in patients who experienced GVHD, although the majority of those patients still eventually progressed. Higher PFS and OS were associated with pretreatment proportions of immune cell populations with regulatory function, including mucosal invariant T cells, regulatory T cells, and plasmacytoid dendritic cells, independent of any association with GVHD. Peg-IFNα administration after relapse thus constitutes a logical strategy to invoke GVL effects and should be studied in a larger, multicenter cohort. This trial was registered at www.anzctr.org.au as #ACTRN12612000728831.

Effect of plasmapheresis on ATG (Thymoglobulin) clearance prior to adoptive T cell transfer.

The effect of anti-thymocyte globulin (ATG) on the outcome of hematopoietic stem cell transplantation (SCT) is dependent on formulation, dose and exposure. However, ATG levels are not routinely measured and therapeutic levels are not well defined. In ex vivo T cell-deplete SCT, the potential effect of residual ATG has important implications on the timing of adoptive T cell transfer. Here we measured active rabbit ATG concentration using a flow cytometry-based method that can be implemented in any laboratory. Three adult patients received 6 mg/kg Thymoglobulin over 4 days, leading to peak plasma active ATG concentration of 20.8 ± 1.4 µg/mL, suggesting volume of distribution of 16-19 L. The half-life of active ATG was 6.1 ± 0.7 days and plasmapheresis at Day 25 ± 1 post-transplant reduced mean plasma concentration from 1.25 to 0.61 µg/mL. Total ATG and active ATG do not have a constant relationship because of differences in volumes of distribution and half-lives. Thymoglobulin can mediate antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro at concentrations as low as 0.03 µg/mL, with a log-linear relationship between ATG concentration and ADCC. Plasmapheresis can remove ATG but likely has modest biological impact when performed 4 weeks after 6 mg/kg ATG.

Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells.

PURPOSE: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. PATIENTS AND METHODS: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. RESULTS: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/µL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/µL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. CONCLUSIONS: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse.

BACKGROUND/AIMS: We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft-versus-host disease (GVHD) on OSR. METHODS: Data on 386 patients from nine Australian centres with relapsed AML post-alloHSCT were collected retrospectively. OSR was calculated using the Kaplan-Meier method. Univariate and multivariate analyses were conducted using the log-rank test and proportional hazards modelling, respectively and a prognostic index for OSR was derived from multivariate modelling. RESULTS: On multivariate analysis, relapse within 6 months (hazard ratio (HR) 2.4, P < 0.001) and grade 3-4 acute GVHD preceding relapse (HR 2.0, P = 0.004), were associated with inferior OSR. Patients with 1-2 factors had inferior OSR compared to those with zero factors (all patients: HR 2.3, P < 0.001, patients given salvage: HR 1.8, P < 0.001). The first salvage therapy used post-relapse was donor cell therapy (DCT) (second alloHSCT or donor lymphocyte infusion) in 75, re-induction chemotherapy (CT) in 103, radiotherapy in 8 and interferon-α in 6. Although re-induction CT death rate was low (2%), survival after CT was inferior to DCT (HR 1.9, P < 0.001). No survival benefit was seen for patients who developed GVHD following salvage therapy (P = 0.405). CONCLUSION: Patients with AML who relapse beyond 6 months from alloHSCT without prior grade 3-4 acute GVHD have a better outcome from salvage therapy. Salvage treatments employing DCT as the initial treatment of AML relapse confer a survival advantage over CT.

Use of brentuximab vedotin as salvage therapy pre-allogeneic stem cell transplantation in relapsed/refractory CD30 positive lympho-proliferative disorders: a single centre experience.

BACKGROUND: The role of brentuximab peri-allogeneic transplantation in patients with relapsed and/or refractory CD30 positive lymphomas remains poorly defined. AIM: To assess the outcome of use of brentuximab as a bridge to allogeneic stem cell transplantation (SCT) in patient with relapsed/refractory CD30+ classic Hodgkin lymphoma cHL and anaplastic large cell lymphoma (ALCL). METHODS: Outcomes of consecutive patients with relapsed/refractory cHL/ALCL treated with brentuximab as a bridge to SCT were determined by retrospective review of individual medical records. Survival analysis was measured from start of brentuximab treatment. RESULTS: A total of 12 patients (10 cHL, 2 ALCL) had received brentuximab as a planned bridge to allogeneic SCT. Median age was 27 years (range 20-54 years); median prior lines of therapy was 4 (range 3-6) and all except one patient had undergone prior autologous SCT (92%). Patients received at median of 3 brentuximab doses pre-allogeneic SCT (range 1-4), with an overall response rate of 66.7%. At a median follow up of 30 months (range 6-52 months), 2 years progression free survival and overall survival post-allogeneic SCT is 58 and 92% respectively. Incidence of non-relapse mortality, grade 3-4 acute graft versus host disease and extensive stage chronic graft versus host disease is 8, 17 and 18% respectively. Of five patients who subsequently relapsed post-SCT, four remain alive with disease control post manipulation of immune-suppression. CONCLUSION: Our experience suggests that brentuximab use pre-allogeneic SCT is not associated with any significant post-transplant toxicity, and is associated with a rapid response in a majority of patients with relapsed/refractory CD30 positive lymphomas. Brentuximab may thus provide a non-toxic bridge to allogeneic SCT for patients with relapsed/refractory CD30 positive cHL or ALCL.

A randomized trial of olanzapine versus palonosetron versus infused ondansetron for the treatment of breakthrough chemotherapy-induced nausea and vomiting in patients undergoing hematopoietic stem cell transplantation.

PURPOSE: The primary aim of this study was to compare the effectiveness of olanzapine, palonosetron and ondansetron infusion (standard of care) for the treatment of breakthrough chemotherapy-induced nausea and vomiting (CINV) in patients undergoing hematopoietic stem cell transplantation (HSCT). METHOD: It was a randomized open-label prospective study. Sixty-two patients were randomized to receive either ondansetron 32-mg infusion over 24 h, or olanzapine wafer 10 mg once daily in addition to ondansetron 8 mg IV three times a day or a single dose of palonosetron 0.25 mg IV instead of ondansetron. All groups were allowed rescue antiemetics. The primary endpoint was a composite outcome of no emesis, no use of rescue medication, and nausea score reduction of ≥50 %. The secondary endpoint was nausea score reduction of ≥50 %. Both endpoints were measured at 24 and 48 h after initiation of the study treatment. Statistical analysis was conducted using a double-sided Fisher's exact test. RESULT: The primary endpoint was achieved in 6, 45, and 18 %, and 6, 64, and 18 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. The secondary outcome was observed in 17, 60, and 62 %, and 35, 71, and 43 % of ondansetron versus olanzapine versus palonosetron patient groups at 24 and 48 h, respectively. Serious adverse drug reactions were not reported in any arms. Time to engraftment was not significantly different between the arms. CONCLUSIONS: Olanzapine was an effective treatment of breakthrough CINV. A single dose of palonosetron significantly reduced nausea up to 24 h.

Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial.

BACKGROUND: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD. METHODS: We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853. FINDINGS: Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways. INTERPRETATION: Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted. FUNDING: National Health and Medical Research Council and Queensland Health.

A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia.

This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid- and post- each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 µg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

Is extramedullary relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation associated with improved survival?

AIMS: Recent reports have suggested that extramedullary (EM) relapse of acute myeloid leukemia (AML) post-hematopoietic stem cell transplantation (HSCT), unlike isolated bone marrow (BM) relapse, is associated with improved prognosis. We reviewed the outcomes of relapsed AML post-HSCT at our institution to determine whether survival for patients with EM relapse was truly improved in comparison to patients suffering BM relapses treated in a similar (active) way. METHODS: Outcomes of all 274 allogeneic HSCT performed for adult AML between 2000 and 2010 at our institution were retrospectively reviewed. RESULTS: As of January 2011, 72 relapses post-HSCT had occurred, including 64 BM relapses (89%), two concomitant BM and EM relapses (3%), and six EM relapses alone (8%). EM relapses occurred significantly later post-HSCT than BM relapses (median 25.2 vs 3.9 months, respectively; P = 0.001). Patients suffering an EM relapse were significantly more likely to receive active therapy at relapse (7/8; 88%) than those suffering a BM relapse alone (28/64; 44%; P = 0.026). When survival analysis was restricted to outcomes of patients treated actively (i.e., with curative intent), no difference in outcome between EM and BM relapses was observed (median survival 13.5 vs 8 months for EM vs BM relapses, respectively, P = 0.44). CONCLUSIONS: Our results suggest that EM relapse post-HSCT has similar outcomes to BM relapses treated in a similar way. Furthermore, choice of therapy at relapse appears related to the time post-HSCT that the relapse occurs, with BM relapses occurring significantly earlier post-HSCT than relapses at EM sites.

Outcomes after major or bidirectional ABO-mismatched allogeneic hematopoietic progenitor cell transplantation after pretransplant isoagglutinin reduction with donor-type secretor plasma with or without plasma exchange.

BACKGROUND: Major ABO mismatch in hematopoietic progenitor cell transplantation (HPCT) is associated with a range of immunohematologic consequences including progenitor cell infusion (PCI)-related hemolysis, delayed red blood cell engraftment, and pure red cell aplasia (PRCA). Although pretransplant (recipient) isoagglutinin reduction may be associated with decreased immunohematologic complications in this setting, there is no consensus with respect to strategies for isoagglutinin reduction. STUDY DESIGN AND METHODS: This observational study assessed the efficacy of a standardized pretransplant isoagglutinin reduction strategy incorporating donor-type secretor plasma infusions with or without plasma exchange to prevent PCI-associated hemolysis and PRCA in major or bidirectional ABO-mismatched peripheral blood HPCT. All major or bidirectional ABO-mismatched HPCTs performed between 1999 and 2010 were identified from an institutional database. Immunohematologic outcomes were determined retrospectively by review of individual medical records. RESULTS: In total 110 major or bidirectional ABO-mismatched HPCTs had been performed. No patient developed hemolysis after PCI. With respect to PRCA incidence, 16 patients (15%) were excluded due to early mortality and three (3%) due to incomplete data; of the remaining 91 patients, five (5%) developed PRCA. Patients with PRCA had significantly higher pretransplant isoagglutinin titers (p = 0.0001) compared to those who did not develop PRCA. CONCLUSIONS: Use of a standardized pretransplant isoagglutinin reduction strategy including donor-type secretor plasma infusions is both safe and efficient in preventing PCI-associated hemolysis and is associated with low rates of posttransplant PRCA.