Novel MAGIC composite scores using both clinical symptoms and biomarkers best predict treatment outcomes of acute GVHD.

Acute graft-vs-host disease (GVHD) grading systems that use only clinical symptoms at treatment initiation such as Minnesota risk identify standard and high risk categories but lack a low risk category suitable to minimize immunosuppressive strategies. We developed a new grading system that includes a low risk stratum based on clinical symptoms alone and determined whether the incorporation of biomarkers would improve the model's prognostic accuracy. We randomly divided 1863 patients in the Mount Sinai Acute GVHD International Consortium (MAGIC) who were treated for GVHD into training and validation cohorts. Patients in the training cohort were divided into 14 groups based on similarity of clinical symptoms and similar NRM; we used a classification and regression tree (CART) algorithm to create three Manhattan risk groups that produced a significantly higher area under the receiver operating characteristic curve (AUC) for 6-month NRM than the Minnesota risk classification (0.69 vs. 0.64, P=0.009) in the validation cohort. We integrated serum GVHD biomarker scores with Manhattan risk using patients with available serum samples and again used a CART algorithm to establish three MAGIC composite scores that significantly improved prediction of NRM compared to Manhattan risk (AUC, 0.76 vs. 0.70, P=0.010). Each increase in MAGIC composite score also corresponded to a significant decrease in day 28 treatment response (80% vs. 63% vs. 30%, P<0.001). We conclude that the MAGIC composite score more accurately predicts response to therapy and long term outcomes than systems based on clinical symptoms alone and may help guide clinical decisions and trial design.

Effective treatment of low-risk acute GVHD with itacitinib monotherapy.

The standard primary treatment for acute graft-versus-host disease (GVHD) requires prolonged, high-dose systemic corticosteroids (SCSs) that delay reconstitution of the immune system. We used validated clinical and biomarker staging criteria to identify a group of patients with low-risk (LR) GVHD that is very likely to respond to SCS. We hypothesized that itacitinib, a selective JAK1 inhibitor, would effectively treat LR GVHD without SCS. We treated 70 patients with LR GVHD in a multicenter, phase 2 trial (NCT03846479) with 28 days of itacitinib 200 mg/d (responders could receive a second 28-day cycle), and we compared their outcomes to those of 140 contemporaneous, matched control patients treated with SCSs. More patients responded to itacitinib within 7 days (81% vs 66%, P = .02), and response rates at day 28 were very high for both groups (89% vs 86%, P = .67), with few symptomatic flares (11% vs 12%, P = .88). Fewer itacitinib-treated patients developed a serious infection within 90 days (27% vs 42%, P = .04) due to fewer viral and fungal infections. Grade ≥3 cytopenias were similar between groups except for less severe leukopenia with itacitinib (16% vs 31%, P = .02). No other grade ≥3 adverse events occurred in >10% of itacitinib-treated patients. There were no significant differences between groups at 1 year for nonrelapse mortality (4% vs 11%, P = .21), relapse (18% vs 21%, P = .64), chronic GVHD (28% vs 33%, P = .33), or survival (88% vs 80%, P = .11). Itacitinib monotherapy seems to be a safe and effective alternative to SCS treatment for LR GVHD and deserves further investigation.

Dynamics of cytomegalovirus-specific T-cell recovery in allogeneic hematopoietic cell transplant recipients using a commercially available flow cytometry assay: A pilot study.

BACKGROUND: Cytomegalovirus-specific T-cell-mediated immunity (CMV-CMI) protects from CMV infection in allogeneic hematopoietic cell transplantation (allo-HCT), but to date, there is no validated measure of CMV immunity for this population. METHODS: In this prospective, observational, pilot study, CMV T-cell responses were evaluated monthly and at onset of graft-versus-host disease (GVHD) or CMV infection in CMV-seropositive allo-HCT recipients using a commercial flow cytometry assay, the CMV inSIGHT T-Cell Immunity Panel (CMV-TCIP). The primary endpoint was the time to first positive CMV-TCIP, defined as percentage of interferon-γ-producing CD4+ or CD8+ CMV-specific T cells >0.2%. Letermovir was prescribed from day +10 to ≥100. RESULTS: Twenty-eight allo-HCT recipients were enrolled. The median time to first positive CMV-TCIP result was earlier for CD4+ (60 days [interquartile range, IQR 33‒148]) than for CD8+ T cells (96 days [IQR 33‒155]) and longer for haploidentical and mismatched transplant recipients (77 and 96 days, respectively) than for matched donors (45 and 33 days, respectively). CD4+ and CD8+ CMV-CMI recovery was sustained in 10/10 (100%) and 10/11 (91%) patients, respectively, without GVHD, whereas CD4+ and/or CD8+ CMV-CMI was lost in 4/6 and 2/6 patients, respectively, with GVHD requiring steroids. As a predictor of clinically significant CMV infection in patients with low-level CMV reactivation, the sensitivity and negative predictive value of CMV-TCIP were 90% and 87.5%, respectively, for CD4+ CMV-TCIP and 66.7% and 62.5%, respectively, for CD8+ CMV-TCIP. CONCLUSIONS: There was significant variability in time to CMV-CMI recovery post-HCT, with slower recovery after haploidentical and mismatched HCT. CD4+ CMV-CMI may protect against CS-CMVi, but immunity may be lost with GVHD diagnosis and treatment.

Children's Oncology Group's 2023 blueprint for research: Cellular therapy and stem cell transplantation.

Since the publication of the last Cellular Therapy and Stem Cell Transplant blueprint in 2013, Children's Oncology Group cellular therapy-based trials advanced the field and created new standards of care across a wide spectrum of pediatric cancer diagnoses. Key findings include that tandem autologous transplant improved survival for patients with neuroblastoma and atypical teratoid/rhabdoid brain tumors, one umbilical cord blood (UCB) donor was safer than two UCB donors, killer immunoglobulin receptor (KIR) mismatched donors did not improve survival for pediatric acute myeloid leukemia when in vivo T-cell depletion is used, and the depth of remission as measured by next-generation sequencing-based minimal residual disease assessment pretransplant was the best predictor of relapse for acute lymphoblastic leukemia. Plans for the next decade include optimizing donor selection for transplants for acute leukemia/myelodysplastic syndrome, using novel engineered cellular therapies to target a wide array of malignancies, and developing better treatments for cellular therapy toxicities such as viral infections and graft-vs-host disease.

Randomized multicenter trial of sirolimus vs prednisone as initial therapy for standard-risk acute GVHD: the BMT CTN 1501 trial.

Clinical- and biomarker-based tools may identify a lower-risk acute graft-versus-host disease (GVHD) population amenable to novel, reduced-intensity treatments. Previous data suggest sirolimus may rival standard of care prednisone. We conducted a National Heart, Lung, and Blood Institute/National Cancer Institute-funded Blood and Marrow Transplant Clinical Trials Network multicenter, open-label, randomized phase 2 trial to estimate the difference in day 28 complete response (CR)/partial response (PR) rates for sirolimus vs prednisone as initial treatment of patients with standard risk (SR) acute GVHD as defined by the Minnesota (MN) GVHD Risk Score and Ann Arbor (AA1/2) biomarker status. A total of 127 MN-SR patients were randomized (1:1), and 122 were AA1/2 (sirolimus, n = 58; prednisone, n = 64). Others were AA3 (n = 4), or AA status missing (n = 1). The day 28 CR/PR rates were similar for sirolimus 64.8% (90% confidence interval [CI], 54.1%-75.5%) vs 73% (90% CI, 63.8%-82.2%) for prednisone. The day 28 rate of CR/PR with prednisone ≤0.25 mg/kg/day was significantly higher for sirolimus than prednisone (66.7% vs 31.7%; P < .001). No differences were detected in steroid-refractory acute GVHD, disease-free survival, relapse, nonrelapse mortality, or overall survival. Sirolimus was associated with reduced steroid exposure and hyperglycemia, reduced grade 2 to 3 infections, improvement in immune suppression discontinuation and patient-reported quality of life, and increased risk for thrombotic microangiopathy. For patients with clinical- and biomarker-based SR acute GVHD, sirolimus demonstrates similar overall initial treatment efficacy as prednisone. In addition, sirolimus therapy spares steroid exposure and allied toxicity, does not compromise long-term survival outcomes, and is associated with improved patient-reported quality of life. This trial was registered at www.clinicaltrials.gov as #NCT02806947.

Mesenchymal stromal cell therapy for acute respiratory distress syndrome due to coronavirus disease 2019.

BACKGROUND AIMS: The acute respiratory distress syndrome (ARDS) resulting from coronavirus disease 2019 (COVID-19) is associated with a massive release of inflammatory cytokines and high mortality. Mesenchymal stromal cells (MSCs) have anti-inflammatory properties and have shown activity in treating acute lung injury. Here the authors report a case series of 11 patients with COVID-19-associated ARDS (CARDS) requiring mechanical ventilation who were treated with remestemcel-L, an allogeneic MSC product, under individual patient emergency investigational new drug applications. METHODS: Patients were eligible if they were mechanically ventilated for less than 72 h prior to the first infusion. Patients with pre-existing lung disease requiring supplemental oxygen or severe liver or kidney injury were excluded. Each patient received two infusions of remestemcel-L at a dose of 2 million cells/kg per infusion given 48-120 h apart. RESULTS: Remestemcel-L infusions were well tolerated in all 11 patients. At the end of the 28-day follow-up period, 10 (91%, 95% confidence interval [CI], 59-100%) patients were extubated, nine (82%, 95% CI, 48-97%) patients remained liberated from mechanical ventilation and were discharged from the intensive care unit and two (18%, 95 CI%, 2-52%) patients died. The median time to extubation was 10 days. Eight (73%, 95% CI, 34-100%) patients were discharged from the hospital. C-reactive protein levels significantly declined within 5 days of MSC infusion. CONCLUSIONS: The authors demonstrate in this case series that remestemcel-L infusions to treat moderate to severe CARDS were safe and well tolerated and resulted in improved clinical outcomes.

Results of a phase 2, multicenter, single-arm, open-label study of lenalidomide in pediatric patients with relapsed or refractory acute myeloid leukemia.

BACKGROUND: Outcomes after relapse remain poor in pediatric patients with acute myeloid leukemia (AML), and new therapeutic approaches are needed. Lenalidomide has demonstrated activity in adults with lower risk myelodysplastic syndromes and older adults with relapsed or refractory (R/R) AML. METHODS: In this phase 2 study (NCT02538965), pediatric patients with R/R AML who received two or more prior therapies were treated with lenalidomide (starting dose 2 mg/kg/day on days 1-21 of each 28-day cycle) for a maximum of 12 cycles. The primary endpoint was rate of complete response (CR) and CR with incomplete blood count recovery (CRi) within the first four cycles. RESULTS: Seventeen patients enrolled and received one or more dose of lenalidomide. Median age was 12 years (range 5-18 years), median white blood cell count was 3.7 × 109 /L, and median peripheral blood blast count was 1.0 × 109 /L. One patient (5.9%) with a complex karyotype including del(5q) achieved CRi after two cycles of lenalidomide. This responder proceeded to a second hematopoietic stem cell transplantation and has remained without evidence of disease for 3 years. All patients experienced one or more of grades 3-4 treatment-emergent adverse event (TEAE). The most common grades 3-4 TEAEs were thrombocytopenia (58.8%), febrile neutropenia (47.1%), anemia (41.2%), and hypokalemia (41.2%). CONCLUSIONS: In this population of pediatric patients with R/R AML, safety data were consistent with the known safety profile of lenalidomide. As only one patient responded, further evaluation of lenalidomide at the dose and schedule studied is not warranted in pediatric AML, with the possible exception of patients with del(5q).

Priorities for Improving Outcomes for Nonmalignant Blood Diseases: A Report from the Blood and Marrow Transplant Clinical Trials Network.

Nonmalignant blood diseases such as bone marrow failure disorders, immune dysregulation disorders, and hemoglobinopathies often lead to shortened life spans and poor quality of life. Many of these diseases can be cured with allogeneic hematopoietic cell transplantation, but patients are often not offered the procedure because of perceived insufficient efficacy and/or excess toxicity. In 2018, the Blood and Marrow Transplant Clinical Trials Network convened a task force to identify the most urgently needed yet feasible clinical trials with potential to improve the outcomes for patients with nonmalignant diseases. This report summarizes the task force discussions and specifies the network plans for clinical trial development for nonmalignant blood diseases.

MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

Phase I/II Trial of a Combination of Anti-CD3/CD7 Immunotoxins for Steroid-Refractory Acute Graft-versus-Host Disease.

Effective therapies for treating patients with steroid-refractory acute graft-versus-host-disease (SR-aGVHD), particularly strategies that reduce the duration of immunosuppression following remission, are urgently needed. The investigated immunotoxin combination consists of a mixture of anti-CD3 and anti-CD7 antibodies separately conjugated to recombinant ricin A (CD3/CD7-IT), which induces in vivo depletion of T cells and natural killer (NK) cells and suppresses T cell receptor activation. We conducted a phase I/II trial to examine the safety and efficacy of CD3/CD7-IT in 20 patients with SR-aGVHD; 17 of these patients (85%) had severe SR-aGVHD, and all 20 patients had visceral organ involvement, including 18 (90%) with gastrointestinal (GI) involvement and 5 (25%) with liver involvement. A validated 2-biomarker algorithm classified the majority of patients (11 of 20) as high risk. On day 28 after the start of CD3/CD7-IT therapy, the overall response rate was 60% (12 of 20), with 10 patients (50%) achieving a complete response. The 6-month overall survival rate was 60% (12 of 20), including 64% (7 of 11) classified as high risk by biomarkers. The 1-week course of treatment with CD3/CD7-IT caused profound but transient depletion of T cells and NK cells, followed by rapid recovery of the immune system with a diverse TCR Vß repertoire, and preservation of Epstein-Barr virus- and cytomegalovirus-specific T cell clones. Furthermore, our results indicate that CD3/CD7-IT appeared to be safe and well tolerated, with a relatively low prevalence of manageable and reversible adverse events, primarily worsening of hypoalbuminemia, microangiopathy, and thrombocytopenia. These encouraging results suggest that CD3/CD7-IT may improve patient outcomes in patients with SR-aGVHD.

Blood and Marrow Transplant Clinical Trials Network Report on the Development of Novel Endpoints and Selection of Promising Approaches for Graft-versus-Host Disease Prevention Trials.

Graft-versus-host disease (GVHD) is a common complication after hematopoietic cell transplantation (HCT) and associated with significant morbidity and mortality. Preventing GVHD without chronic therapy or increasing relapse is a desired goal. Here we report a benchmark analysis to evaluate the performance of 6 GVHD prevention strategies tested at single institutions compared with a large multicenter outcomes database as a control. Each intervention was compared with the control for the incidence of acute and chronic GVHD and overall survival and against novel composite endpoints: acute and chronic GVHD, relapse-free survival (GRFS), and chronic GVHD, relapse-free survival (CRFS). Modeling GRFS and CRFS using the benchmark analysis further informed the design of 2 clinical trials testing GVHD prophylaxis interventions. This study demonstrates the potential benefit of using an outcomes database to select promising interventions for multicenter clinical trials and proposes novel composite endpoints for use in GVHD prevention trials.

Treosulfan, Fludarabine, and Low-Dose Total Body Irradiation for Children and Young Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome Undergoing Allogeneic Hematopoietic Cell Transplantation: Prospective Phase II Trial of the Pediatric Blood and Marrow Transplant Consortium.

This multicenter study evaluated a treosulfan-based regimen in children and young adults with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplant (HCT). Forty patients with median age 11 years (range, 1 to 19) underwent allogeneic HCT for AML in first (n = 18), second (n = 11), and third or greater remission (n = 3) or MDS (n = 8) using bone marrow (n = 25), peripheral blood stem cells (n = 5), or cord blood (n = 9). The regimen consisted of body surface area (BSA)-based treosulfan 10 g/m2/day (BSA ≤ .5 m2), 12 g/m2/day (BSA > .5 to 1.0 m2), or 14 g/m2/day (BSA > 1.0 m2) on days -6 to -4; fludarabine 30 mg/m2/day on days -6 to -2; and a single fraction of 200 cGy total body irradiation on day -1. Graft-versus-host disease (GVHD) prophylaxis included tacrolimus and methotrexate for marrow and peripheral blood stem cell and cyclosporine/mycophenolate mofetil for cord blood. One-year overall survival, disease-free survival, and nonrelapse mortality were 80%, 73%, and 3%, respectively. One-year relapse was 38% for AML and 13% for MDS. No serious organ toxicities were observed. All 37 assessable patients engrafted. Cumulative incidences of grades II to IV acute GVHD and chronic GVHD were 22% and 40%, respectively. BSA-based treosulfan dosing resulted in predictable area under the curve and maximum concentration, which is required for dosing without measuring individual pharmacokinetic parameters. Observed differences in pharmacokinetics did not impact disease control or regimen toxicity. This BSA-based treosulfan regimen resulted in excellent engraftment and disease-free survival and minimal toxicity and transplant-related mortality (3%) in children and young adults with AML and MDS.

A trial of unrelated donor marrow transplantation for children with severe sickle cell disease.

Children with sickle cell disease experience organ damage, impaired quality of life, and premature mortality. Allogeneic bone marrow transplant from an HLA-matched sibling can halt disease progression but is limited by donor availability. A Blood and Marrow Transplant Clinical Trials Network (BMT CTN) phase 2 trial conducted from 2008 to 2014 enrolled 30 children aged 4 to 19 years; 29 were eligible for evaluation. The primary objective was 1-year event-free survival (EFS) after HLA allele-matched (at HLA-A, -B, -C, and -DRB1 loci) unrelated donor transplant. The conditioning regimen included alemtuzumab, fludarabine, and melphalan. Graft-versus-host disease (GVHD) prophylaxis included calcineurin inhibitor, short-course methotrexate, and methylprednisolone. Transplant indications included stroke (n = 12), transcranial Doppler velocity >200 cm/s (n = 2), ≥3 vaso-occlusive pain crises per year (n = 12), or ≥2 acute chest syndrome episodes (n = 4) in the 2 years preceding enrollment. Median follow-up was 26 months (range, 12-62 months); graft rejection was 10%. The 1- and 2-year EFS rates were 76% and 69%, respectively. The corresponding rates for overall survival were 86% and 79%. The day 100 incidence rate of grade II-IV acute GVHD was 28%, and the 1-year incidence rate of chronic GVHD was 62%; 38% classified as extensive. There were 7 GVHD-related deaths. A 34% incidence of posterior reversible encephalopathy syndrome was noted in the first 6 months. Although the 1-year EFS met the prespecified target of ≥75%, this regimen cannot be considered sufficiently safe for widespread adoption without modifications to achieve more effective GVHD prophylaxis. The BMT CTN #0601 trial was registered at www.clinicaltrials.gov as #NCT00745420.

Late acute graft-versus-host disease: a prospective analysis of clinical outcomes and circulating angiogenic factors.

Late acute (LA) graft-versus-host disease (GVHD) is persistent, recurrent, or new-onset acute GVHD symptoms occurring >100 days after allogeneic hematopoietic cell transplantation (HCT). The aim of this analysis is to describe the onset, course, morbidity, and mortality of and examine angiogenic factors associated with LA GVHD. A prospective cohort of patients (n = 909) was enrolled as part of an observational study within the Chronic GVHD Consortium. Eighty-three patients (11%) developed LA GVHD at a median of 160 (interquartile range, 128-204) days after HCT. Although 51 out of 83 (61%) achieved complete or partial response to initial therapy by 28 days, median failure-free survival was only 7.1 months (95% confidence interval, 3.4-19.1 months), and estimated overall survival (OS) at 2 years was 56%. Given recently described alterations of circulating angiogenic factors in classic acute GVHD, we examined whether alterations in such factors could be identified in LA GVHD. We first tested cases (n = 55) and controls (n = 50) from the Chronic GVHD Consortium and then validated the findings in 37 cases from Mount Sinai Acute GVHD International Consortium. Plasma amphiregulin (AREG; an epidermal growth factor [EGF] receptor ligand) was elevated, and an AREG/EGF ratio at or above the median was associated with inferior OS and increased nonrelapse mortality in both cohorts. Elevation of AREG was detected in classic acute GVHD, but not chronic GVHD. These prospective data characterize the clinical course of LA GVHD and demonstrate alterations in angiogenic factors that make LA GVHD biologically distinct from chronic GVHD.

In vivo IL-12/IL-23p40 neutralization blocks Th1/Th17 response after allogeneic hematopoietic cell transplantation.

T-helper 1 and T-helper 17 lymphocytes mediate acute graft-versus-host disease (GvHD). Interleukin 12 is critical for T-helper 1 differentiation and interleukin 23 for T-helper 17 maintenance. Interleukin 12 and 23 are heterodimeric cytokines that share the p40 subunit (IL-12/IL-23p40). In a randomized, blinded, placebo-controlled trial, we examined the biological impact and clinical outcomes following IL-12/IL-23p40 neutralization using ustekinumab. Thirty patients received peripheral blood mobilized hematopoietic cell transplantation (HCT) from HLA-matched sibling or unrelated donors, received sirolimus plus tacrolimus as GvHD prophylaxis, and were randomized to ustekinumab versus placebo with 1:1 allocation after stratification by donor type. The primary end point of the trial was the mean percentage (%) T-regulatory (Treg) cells on day 30 post HCT. Ustekinumab was delivered by subcutaneous injection on day -1 and day +20 after transplantation. On day 30 post transplant, no significant difference in % Treg was observed. Ustekinumab suppressed serum IL-12/IL-23p40 levels. Host-reactive donor alloresponse at days 30 and 90 after transplantation was polarized with significant reduction in IL-17 and IFN-α production and increase in IL-4. No toxicity attributed to ustekinumab was observed. Overall survival and National Institute of Health moderate/severe chronic GvHD-free, relapse-free survival were significantly improved among ustekinumab-treated patients. No significant improvements were observed in acute or chronic GvHD, relapse, or non-relapse mortality. These data provide first evidence that IL-12/IL-23p40 neutralization can polarize donor anti-host alloresponse in vivo and provide initial clinical efficacy evidence to be tested in subsequent trials. (Trial registered at clinicaltrials.gov identifier: 01713400).

Infectious Risk after Allogeneic Hematopoietic Cell Transplantation Complicated by Acute Graft-versus-Host Disease.

The occurrence of infections after allogeneic hematopoietic stem cell transplantation (HCT) is nearly universal. However, the relationship between infections and graft-versus-host disease (GVHD) is complex and attribution of infectious-related mortality is highly inconsistent, making comparison of infectious complication rates across allogeneic HCT clinical studies difficult. We categorized infectious complications from diagnosis or 1 year before HCT (whichever occurred later) through 2 years after HCT according to timing, frequency, causative organism, severity, and contribution to mortality for 431 consecutive patients who underwent allogeneic HCT from 2008 to 2011. We then assessed the contribution of risk factors, such as the frequency of pre-HCT infections and post-HCT GVHD, on post-HCT infection frequency and severity. We found that each pre-HCT bacterial infection/year leads to an additional 2.15 post-HCT bacterial infection/year (P = .004). Pre-HCT viral and fungal infections were not predictors for post-HCT infections. Acute GVHD (aGVHD) significantly increased the risk of developing life-threatening (hazard ratio [HR], 1.97; 95% confidence interval [CI], 1.33 to 2.90) and fatal (HR, 2.8; 95% CI, 1.10 to 7.08) infections. Furthermore, patients who develop aGVHD experienced ~60% more infections than patients who never develop aGVHD. Quantification of infection frequency and severity for patients with and without GVHD may facilitate comparison of infectious outcomes across allogeneic HCT trials.

Combination Therapy for Graft-versus-Host Disease Prophylaxis with Etanercept and Extracorporeal Photopheresis: Results of a Phase II Clinical Trial.

Reduced-intensity conditioning (RIC) regimens minimize early toxicity after allogeneic hematopoietic cell transplantation (HCT) by placing greater reliance on establishing a graft-versus-leukemia effect (GVL). Because graft-versus-host disease (GVHD) and GVL are tightly linked, inhibition of T cell populations that cause GVHD may lead to an unintended increased risk of relapse in the RIC setting. Although not completely understood, etanercept and extracorporeal photopheresis (ECP) are thought to ameliorate GVHD without direct T cell inhibition. We hypothesized that adding these 2 agents to a standard GVHD prophylaxis regimen of tacrolimus and mycophenolate mofetil (MMF) would improve survival by reducing GVHD-related mortality without increasing relapse rates. Therefore, we conducted a prospective phase II clinical trial that incorporated tacrolimus, MMF, etanercept, and ECP as GVHD prophylaxis in 48 patients undergoing RIC unrelated donor transplantation. The preferred RIC was fludarabine 160 mg/m(2) + busulfan 6.4 mg/kg to 12.8 mg/kg ± total body irradiation 200 cGy. Etanercept .4 mg/kg (maximum dose, 25 mg) was given subcutaneously twice weekly for 8 weeks after HCT and ECP was given for 12 treatments, starting weekly on day 28 weekly and tapering off by day 180. The median age of the study patients was 60 (range, 18 to 71) years. Donors were 7/8 (n = 14, 29%) or 8/8 (n = 34, 71%) HLA matched. All patients engrafted neutrophils at a median of 12 days. The cumulative incidence of grades II to IV acute GVHD at day 100 was 46%, but it was typically sensitive to initial steroid treatment (84% day 56 complete response/partial response rate). Overall survival at 1 year in this older, frequently mismatched unrelated donor setting was excellent (73%) because of low rates of nonrelapse mortality (21%) and relapse (19%). However, this strategy was not effective at preventing a high incidence of chronic GVHD and late deaths led to a drop in 2-year survival, declining to 56%, reflecting a high incidence of chronic GVHD.

Reducing Treatment-Related Mortality Did Not Improve Outcomes of Allogeneic Myeloablative Hematopoietic Cell Transplantation for High-Risk Multiple Myeloma: A University of Michigan Prospective Series.

Despite the ongoing advent of more effective immunomodulators and proteasome inhibitors, multiple myeloma (MM) remains incurable and no effective therapy is available for advanced aggressive disease. Although allogeneic (Allo) hematopoietic cell transplantation (HCT) has a curative potential, the outcomes remain poor because of high treatment-related mortality (TRM), mostly due to regimen-related toxicities and graft-versus-host disease (GVHD) in case of myeloablative conditionings, high relapse rate in case of reduced-intensity or nonmyeloablative regimens, and possibly other unknown MM-specific issues. In an attempt to improve TRM, without compromising conditioning intensity, we prospectively explored the feasibility and efficacy of a myeloablative but reduced-toxicity conditioning regimen, consisting of fludarabine and busulfan (FluBu4; fludarabine 40 mg/m(2)/day and busulfan 3.2 mg/kg/day i.v. × 4 days) in 22 patients with high-risk or advanced refractory MM. The majority (14 of 22, 64%) had prior autologous HCT. The median HCT-specific comorbidity index score was 3 (range, 0 to 6), with 46% having a Karnofsky performance score < 80%. Ten patients had unrelated donors, 3 of whom were 7/8 HLA-loci matched. GVHD prophylaxis was tacrolimus and methotrexate in 20 (91%). Most patients had active MM at transplantation, with a partial response in 12 of 22 (46%) and stable disease in 1 of 22 (4.5%). All 22 patients tolerated the FluBu4 conditioning well, without early toxic deaths or graft failure. Common regimen-related toxicities included mild to moderate mucositis (18 of 22, 82%) and mild transient liver function abnormality (9 of 22, 41%). There were no grade 4 toxicities but grade 3 mucositis occurred in 7 of 22 patients (32%). The cumulative incidence of severe, grades III and IV acute GVHD at day 180 was 23% (95% confidence interval [CI], 10% to 47%) and that of chronic GVHD was 68% (95% CI, 46% to 88%). The cumulative incidences of TRM at 100 days, 1 year, and 3 years were 9% (95% CI, 2% to 33%), 19% (95% CI, 7% to 44%), and 29% (95% CI, 13% to 55%), respectively. Two TRMs were due to idiopathic pneumonia syndrome and 1 was due to cirrhosis. They all had decreased pre-HCT corresponding organ function, with HCT-specific comorbidity index scores of > 3. With a median follow-up of 58.7 (range, 39 to 82) months, the cumulative incidences of relapse at 1 and 3 years were 37% (95% CI, 20% to 61%) and 50% (95% CI, 29% to 75%); those for 1-year and 3-year overall survival (OS) were 58% (95% CI, 40% to 83%) and 29% (95% CI, 15% to 57%), respectively, and those for the 1-year and 3-year progression-free survivals (PFS) were 40% (95% CI, 23% to 67%) and 15% (95% CI, 5% to 42%), respectively. In summary, the use of the myeloablative FluBu4 conditioning Allo-HCT for high-risk MM resulted in decreased TRM, compared with that of Allo-HCT using conventional myeloablative regimens; however, the relapse rate was high, including in those developing moderate-to-severe chronic GVHD. This suggested a less robust graft-versus-myeloma effect against high-risk MM, thus resulting in poor PFS and OS. Nonetheless, the FluBu4 regimen may be used as a lower-TRM platform to combine with other strategies, eg, addition of an MM-targeted agent and/or maintenance therapy with these agents, to decrease relapse or progression in patients with high-risk MM.

International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International Consortium.

Acute graft-versus-host disease (GVHD) remains a leading cause of morbidity and nonrelapse mortality after allogeneic hematopoietic cell transplantation. The clinical staging of GVHD varies greatly between transplant centers and is frequently not agreed on by independent reviewers. The lack of standardized approaches to handle common sources of discrepancy in GVHD grading likely contributes to why promising GVHD treatments reported from single centers have failed to show benefit in randomized multicenter clinical trials. We developed guidelines through international expert consensus opinion to standardize the diagnosis and clinical staging of GVHD for use in a large international GVHD research consortium. During the first year of use, the guidance followed discussion of complex clinical phenotypes by experienced transplant physicians and data managers. These guidelines increase the uniformity of GVHD symptom capture, which may improve the reproducibility of GVHD clinical trials after further prospective validation.