In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m2/day on days -6 to -4 and i.v. fludarabine, 30 mg/m2/day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted.

A total of 21 patients with severe aplastic anemia (SAA) underwent marrow transplantation from HLA-identical siblings following a standard conditioning regimen with cyclophosphamide (50 mg/kg/day × 4 days) and horse antithymocyte globulin (30 mg/kg/day × 3 days). Post-grafting immunosuppression consisted of a short course of methotrexate (MTX) combined with cyclosporine (CSP). The transplant protocol tested the hypothesis that the incidence of chronic GvHD could be reduced by limiting the marrow grafts to ⩽2.5 × 108 nucleated marrow cells/kg. None of the patients rejected the graft, all had sustained engraftment and all are surviving at a median of 4 (range 1–8) years after transplantation. Chronic GvHD developed in 16% of patients given ⩽2.5 × 108 nucleated marrow cells/kg. Post-grafting immunosuppression has been discontinued in 20 of the 21 patients. In conclusion, limiting the number of transplanted marrow cells may have resulted in minimal improvement in the incidence and severity of chronic GvHD.

The 2005 NIH chronic GVHD (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0-3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were (i) not attributed to cGVHD or (ii) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities.

Recipient and donor age impact the risk of developing chronic GvHD in children after allogeneic hematopoietic transplant

Recent studies have reported that statin use may be associated with improved outcomes in patients with sepsis or respiratory viral infections. In the setting of allogeneic hematopoietic cell transplantation (HCT), it has been shown that donor and recipient statin use is associated with reduced risks of GVHD. We assessed in retrospective analysis whether donor or recipient statin use impacts infection risk after allogeneic HCT (n=1191). Although recipient statin use was associated with the increased incidence of Gram-negative bacteremia (adjusted hazard ratio (aHR) 2.22, (95% confidence interval (CI) 1.2–4.2), P=0.01) without affecting mortality, donor statin use was associated with an increased incidence of respiratory viral infections in recipients (aHR 2.84 (95% CI 1.3–6.0), P=0.007). The overall incidence of invasive fungal infections and CMV reactivation and CMV disease were not impacted by recipient or donor statin use. In conclusion, this study suggests that recipient or donor statin use may be associated with an increased incidence of some infections without adversely affecting mortality.

We hypothesized that clinical risk factors could be identified within 2 weeks of onset of severe (stage 3 or 4) acute gut GVHD for identifying a patient population with a very poor outcome. Among 1462 patients who had allogeneic hematopoietic cell transplantation (HCT) between January 2000 and December 2005, 116 (7.9%) developed stage 3–4 gut GVHD. The median time for onset of stage 3–4 gut GVHD was 35 (4–135) days after allogeneic HCT. Eighty-five of the 116 patients (73%) had corticosteroid resistance before or within 2 weeks after the onset of stage 3–4 gut GVHD. Significant risk factors for mortality included corticosteroid resistance (hazards ratio (HR)=2.93; P=0.0005), age >18 years (HR=4.95; P=0.0004), increased serum bilirubin (HR 2.53; P=0.0001) and overt gastrointestinal bleeding (HR 2.88; P=0.0004). Among patients with stage 3–4 gut GVHD, the subgroup with 0, 1 or 2 risk factors had a favorable prognosis, whereas the subgroup with 3 or 4 risk factors had a dismal prognosis. This information should be considered in designing future studies of severe gut GVHD and in counseling patients about prognosis.

Minimal residual disease (MRD) is associated with adverse outcome in acute myeloid leukemia (AML) after myeloablative (MA) hematopoietic cell transplantation (HCT). We compared this association with that seen after nonmyeloablative (NMA) conditioning in 241 adults receiving NMA (n=86) or MA (n=155) HCT for AML in first remission with pre-HCT bone marrow aspirates assessed by flow cytometry. NMA patients were older and had more comorbidities and secondary leukemias. Three-year relapse estimates were 28% and 57% for MRDneg and MRDpos NMA patients, and 22% and 63% for MA patients. Three-year overall survival (OS) estimates were 48% and 41% for MRDneg and MRDpos NMA patients and 76% and 25% for MA patients. This similar OS after NMA conditioning was largely accounted for by higher non-relapse mortality (NRM) in MRDneg (30%) compared with MRDpos (10%) patients, whereas the reverse was found for MRDneg (7%) and MRDpos (23%) MA patients. A statistically significant difference between MA and NMA patients in the association of MRD with OS (P<0.001) and NRM (P=0.002) but not relapse (P=0.17) was confirmed. After adjustment, the risk of relapse was 4.51 times (P<0.001) higher for MRDpos patients. These data indicate that the negative impact of MRD on relapse risk is similar after NMA and MA conditioning.

Developing a preclinical canine model that predicts outcomes for hematopoietic cell transplantation in humans requires a model that mimics the degree of matching between human donor and recipient major histocompatibility complex (MHC) genes. The polymorphic class I and class II genes in mammals are typically located in a single chromosome as part of the MHC complex. However, a divergent class I gene in dogs, designated dog leukocyte antigen-79 (DLA-79), is located on chromosome 18 while other MHC genes are on chromosome 12. This gene is not taken into account while DLA matching for transplantation. Though divergent, this gene shares significant similarity in sequence and exon-intron architecture with other class I genes, and is transcribed. Little is known about the polymorphisms of DLA-79 and their potential role in transplantation. This study was aimed at exploring the reason for high rate of rejection seen in DLA-matched dogs given reduced intensity conditioning, in particular, the possibility that DLA-79 allele mismatches may be the cause. We found that about 82% of 407 dogs typed were homozygous for a single, reference allele. Owing to the high prevalence of a single allele, 87 of the 108 dogs (∼80%) transplanted were matched for DLA-79 with their donor. In conclusion, we have developed an efficient method to type alleles of a divergent MHC gene in dogs and identified two new alleles. We did not find any statistical correlation between DLA-79 allele disparity and graft rejection or graft-versus-host disease, among our transplant dogs.

Chronic GVHD (cGVHD) is associated with mortality, disability and impaired quality of life. Understanding the role of comorbidity in patients with cGVHD is important both for prognostication and potentially for tailoring treatments based on mortality risks. In a prospective cohort study of patients with cGVHD (n=239), we examined the performance of two comorbidity scales, the Functional Comorbidity Index (FCI) and the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Both scales detected a higher number of comorbidities at cGVHD cohort enrollment than pre-hematopoietic cell transplant (HCT) (P<0.001). Higher HCT-CI scores at the time of cGVHD cohort enrollment were associated with higher non-relapse mortality (HR: 1.21:1.04–1.42, P=0.01). For overall mortality, we detected an interaction with platelet count. Higher HCT-CI scores at enrollment were associated with an increased risk of overall mortality when the platelet count was ⩽100 000/μL (HR: 2.01:1.20–3.35, P=0.01), but not when it was >100 000/μL (HR: 1.05:0.90–1.22, P=0.53). Comorbidity scoring may help better to predict survival outcomes in patients with cGVHD. Further studies to understand vulnerability unrelated to cGVHD activity in this patient population are needed.

We examined whether overlap subtype of chronic GVHD was associated with different prognosis, functional limitations, or patient reported outcomes compared to "classic" chronic GVHD. Prospective data were collected from 427 patients from nine centers in an observational cohort study conducted by the Chronic GVHD Consortium. Patients were classified as overlap (n = 352) or classic chronic GVHD (n = 75) based on organ involvement. Among 352 overlap subjects, skin erythema or maculopapular rash was present in 189 (54%), GI involvement in 129 (37%), and liver involvement in 216 (62%); 198 (56%) met criteria with acute features in only one organ, 126 (36%) with acute features in two organs, and 28 (8%) with acute features in all three organs. Overlap patients were more likely to be incident cases (59% vs 35%, p<.001), to have a shorter median time from transplant to enrollment (11.9 months vs. 19.8 months, p = 0.01), and to have lower platelet count at chronic GVHD onset (p < 0.001). Those with overlap had significantly higher functional impairment by 2 minute walk test (p<0.001), higher symptom burden (Lee Chronic GVHD Symptoms Scale) and lower Human Activity Profile scores (p<0.001). Quality of life was similar, except overlap had worse SF-36 social functioning. The median follow-up time after enrollment for overlap patients was 17.1 months, and 19.0 months for classic chronic GVHD patients. Two year OS was 77% and 94%, and two year NRM was 20% and 3% for overlap and classic chronic GVHD patients, respectively. Multivariable analyses in which overlap and classic were treated as time-varying covariates demonstrated that overlap was associated with worse overall survival (HR 2.1, 95% CI 1.1 – 4.7; p = 0.03) and higher non-relapse mortality (HR 2.8, 95% CI 1.2 – 8.3; p = 0.02) than classic chronic GVHD. Among other considered covariates in the OS analysis, platelet count < 100K (HR 3.4, 95% CI 1.9 – 6, p < 0.001), KPS < 80 (HR 2.4, 95% CI 1.4 – 4.1, p = 0.002), and severe NIH global severity score (HR 5.1, 95% CI 1.5 – 32.1, p = 0.03) were associated with OS. In the analysis of NRM, platelet < 100K (HR 3.1, 95% CI 1.6 – 5.9, p < 0.001), and KPS < 80 (HR 2.2, 95% CI 1.2 – 4.2, p = 0.01) were associated with NRM. These findings suggest that the presence of acute features in patients with chronic GVHD is a marker for adverse prognosis, greater functional impairment, and higher symptom burden. Further study is needed to define optimal therapy for these patients.

In this era of growing health care costs, the decision to proceed with a second allogeneic transplant has financial as well as clinical implications. We analyzed all medical costs for the transplant process from the beginning of conditioning to 100 days after the transplant for 55 patients who underwent second allogeneic transplants from 1/19/05 to 4/9/10 at the University of Washington/Seattle Cancer Care Alliance. Clinical information was obtained from the institutional database. Multiple linear regression was used to analyze the patient and transplant characteristics that are associated with total costs. Median age was 50 years (range 21 to 69 years), and 62% patients were male. Seventy eight percent transplants were for acute leukemia/MDS. Reasons for second transplant were graft failure (25%), relapse of original disease (65%) and other causes e.g. secondary MDS/aplasia (10%). 73% of relapsed patients were in remission at the time of the second transplant. Non-myeloablative conditioning was more common in the second allografts (75%) than in first allografts (30%) and a higher proportion of second allografts were from unrelated donors (76% vs. 43%). In the first 100 days, relapse occurred in 25% patients and 64% experienced ≥ grade II acute GVHD. Survival was 78% at 100 days and 49% at one year after transplant. Regimen related toxicity accounted for 75% of deaths within the first 100 days. The median total cost in 2010 dollars was $137,600 ($4,500 - $434,200) for the first 100 days, with approximately $135,600 (0 - $432,200) for inpatient and $4,100 (0 - $17,200) for outpatient costs. The median length of hospital stay was 22 days (range 0 to 77 days). Myeloablative conditioning, unrelated donors and pulmonary complications post-transplant were significant predictors of higher costs for the second transplants.Table 1Predictors of costs for second allogeneic transplantVariableCost multiplier95%CIp valuePre-transplant factorsAge <501 >500.890.53-1.470.64Disease Acute leukemia/MDS1 Lymphoma0.650.28-1.480.31 Others3.180.90-11.20.08Diseases status Remission1 Relapse0.760.38-1.490.43Graft source PBSC1 BM0.970.26-3.660.97 cord blood0.830.35-1.940.67Conditioning myeloablative1 Non-myeloablative0.450.23-0.860.02Year of transplant Per year0.880.73-1.060.18Reason for transplant Relapse1 Graft rejection1.180.64-2.190.6 Others1.480.45-4.950.52Donor type Related1 Unrelated2.391.34-4.250.006CMV serostatus negative1 positive0.830.50-1.370.48Post-transplant complications within 100 days Death (n = 12)0.90.37-2.200.82 Relapse (n = 14)1.150.64-2.070.65 GVHD (II-IV) (n = 35)1.590.96-2.640.08 VOD (n = 10)∗Veno-occlusive disease1.160.52-2.580.72 Pulmonary (n = 5)2.081.05-4.120.04 Renal (n = 9)1.580.59-4.180.37 Infection (n = 29)1.620.96-2.730.08∗ Veno-occlusive disease Open table in a new tab Short-term costs of second transplants appear comparable to those of first transplants especially since a majority of them are non-myeloablative/reduced intensity regimens. Additional work is needed with larger numbers of patients to confirm these results and identify additional characteristics that would predict the group with the best clinical and economic outcomes.

Allogeneic stem cell transplant for multiple myeloma (MM) is one treatment associated with long-term disease-free survival. The high incidence of treatment-related mortality and relapses, however, are important reasons for controversy about the role of allografting in the management of MM. We reviewed our results of allografting for MM spanning a period of 34 years in order to better define long-term outcomes and identify areas of progress as well as areas requiring improvement. A total of 278 patients received allogeneic marrow or PBSCs after high-dose myeloablative (N=144) or reduced intensity, non-myeloablative (N=134) regimens. In multivariable analysis, adjusting for differences in patient groups, reduced intensity/non-myeloablative transplants were associated with significantly less acute GVHD, lower transplant mortality, better PFS and overall survival. There were no significant differences in relapse, progression or chronic GVHD, when adjusted. In multivariable analysis of patients receiving only non-myeloablative transplants, decreased overall survival and PFS were associated with relapse after a prior autograft and a β2 microglobulin >4.0. Transplant mortality was reduced and only influenced by a prior tandem autograft.

Nearly 50% of patients with chronic graft-versus-host disease (GVHD) require secondary systemic treatment to control the disease. Outcomes after secondary treatment and the associated prognostic factors have not been examined well. This retrospective study had 3 goals; (1) to establish a benchmark that could be used to evaluate the efficacy of secondary treatment in future trials, (2) to elucidate prognostic factors associated with outcomes, and (3) to test the hypothesis that a composite of response and steroid dose at 6 months correlates with long-term outcomes, similar to results observed in a trial of primary treatment for chronic GVHD (BBMT 2011;17:124). The study included 289 consecutive relapse-free patients who had high-intensity conditioning and required secondary treatment for chronic GVHD due to worsening or persistence of GVHD. Failure was defined as third-line systemic treatment or death, with recurrent malignancy considered a competing risk. Platelet count, serum bilirubin concentration and prednisone dose were assessed at start of secondary treatment. Response was assessed at 6 months among 174 patients without prior failure or relapse, and was defined as complete response in any organ, prednisone dose <0.25 mg/kg, or the combination. Cox regressions were used to evaluate potential risk factors for failure at the beginning of secondary treatment, and to evaluate the risk of subsequent failure associated with the 3 response definitions at 6 months. Median age of the patients was 44 (1-70) years. The single agents most commonly used for secondary treatment included MMF (n = 83), tacrolimus (n = 73) and sirolimus (n = 51); 16 received multiple new agents at start of secondary treatment. The cumulative incidence of failure was 48% (95% CI, 42-53%) at 1 year. Cox models revealed that the risk of failure was increased in patients treated with multiple agents and in those with thrombocytopenia, hyperbilirubinemia or oral involvement at the beginning of secondary treatment. None of the 3 response definitions showed strong correlation with the risk of subsequent failure (Table).TableCorrelation of response after secondary treatment with subsequent failureResponse definitionResponse at 6 monthsNCumulative incidence of failure∗At 2 years after the beginning of secondary treatment.PCR in any organY10337%0.66N6543%Prednisone dose <0.25 mg/kg/dayY10435%0.05N6647%CR in any organ and prednisone dose <0.25 mg/kg/dayY6434%0.25N10343%∗ At 2 years after the beginning of secondary treatment. Open table in a new tab Secondary treatment for chronic GVHD is associated with a 48% failure rate at one year, with failure predicted by thrombocytopenia, hyperbilirubinemia or oral involvement. Unlike the results reported for primary treatment, a composite of response and steroid dose would not perform well as a surrogate endpoint in secondary treatment studies.

Latent CMV infection is known to have a life long effect on the distribution of T cell subsets, but little is known about the impact on cell function. We performed a gene expression analysis in purified CD4+ T cells from 68 hematopoietic cell transplant (HCT) recipients (median age 48; range 20-65) studied on average 5 years after HCT (median 4.75; range 1-20 years). The study population included 38 patients with active chronic GVHD (cGVHD) and 30 tolerant (TOL) patients. Tolerance was defined by absence of signs, symptoms of cGVHD and immunosuppressive therapy (IST) for 3 months. Gene expression was measured on Illumina bead arrays. CMV status was defined by pre-transplant recipient CMV serology (by ELISA). There was no recorded evidence of CMV reactivation at the time of study. Nine of 93 candidate genes associated with immune function and inflammation were found to be associated CMV serostatus in cGVHD patients at a significance threshold of p<0.05, but only four genes (ITK; CD86; PLCG1; PIK3CB) were associated with CMV serostatus in TOL patients. A multivariate analysis including: acute GVHD, conditioning regimen, marrow vs. PBSC; related vs. unrelated donor, matched vs. mismatched donor, recipient age and time post-HCT was performed Table 1. cGVHD patients had a profile consistent with T effector cell activation that was not present in TOL. The characteristic inflammatory environment, increased cytokine production, immunosuppressive therapy and impaired T cell immune reconstitution observed in cGVHD, may increase the risk of CMV reactivation and subsequent upregulation of genes related to T cell activation and effector functions. In contrast, tolerant patients may have achieved greater immune reconstitution and more effective CMV surveillance and control. T cell activation during cGVHD is a complex process that appears to be influenced by latent CMV.Tabled 1Table 1. Multivariate analysisActive cGVHDTolerantCMV+ (n = 17) vs CMV-(n = 21)CMV+ (n = 11) vs CMV-(n = 19)ITK0.023↑upregulated geneCD860.034↑PLCG10.033↑PIK3CB0.005↑GZMB0.024↑INFg0.015↑IL4R0.025↓downregulated genePTPN70.000↑PRF10.000↑GZMA0.003↑PDCD10.008↑IL12RB1a0.016↑IL12RB1b0.000↑↓ downregulated gene↑ upregulated gene Open table in a new tab

CLL pts who are fludarabine-refractory or possess unfavorable cytogenetics have short survivals with conventional therapies. Nonmyeloablative allogeneic HCT may provide long-term disease control. Disease progression is the major risk within the first year after HCT (median 3.3 months), until development of graft-versus-leukemia (GVL) effects. Treatment with anti-CD20 monoclonal antibody (rituximab) in the early post-transplant period could improve disease control: 1) directly by antibody-dependent cytotoxicity and 2) indirectly by promoting cross-presentation of cell-derived peptides causing earlier and/or more robust GVL effects. To date, 20 pts have been enrolled on a phase II trial comprising fludarabine, 30 mg/m2 (days -4, -3, and -2) and 2 Gy total body irradiation (day -1) together with rituximab, 375 mg/m2 (days -3, +10, +24, and +38). Grafts were from HLA-matched related (n = 6) or unrelated (n = 14) donors. Median age was 61 (range 37-74) years. Pts were older, had higher comorbidity scores, more frequently received unrelated grafts, and more frequently had unfavorable cytogenetics compared to a historical control group of 128 pts treated with the same regimen except for peri-transplant rituximab (Table).TableComparison of Pre-transplant Characteristics Among Pts Treated with Nonmyeloablative Conditioning and Allogeneic HCT Either With (n = 20) or Without (n = 128) RituximabNo Rituximab (n = 128), n (%)Rituximab (n = 20), n (%)pAge, years≥6032 (26%)14 (70%)0.0001051 (32%)2 (10%)HCT-CI scores1-242 (37%)7 (35%)0.05≥335 (31%)11 (55%)Response to last treatment prior to HCTRelapse/refractory73 (57%)12 (60%)0.80CR or PR55 (43%)8 (40%)Fludarabine-refractoryYes117 (91%)20 (100%)0.17Lymph node size ≥5 cmYes33 (26%)6 (30%)0.69Campath within 12 months prior to HCTYes30 (23%)5 (25%)0.88Donor typeUnrelated55 (43%)14 (70%)0.02Chromosomal abnormalitiesUnfavorable∗50 (64%)19 (95%)0.0002Favorable†78 (36%)1 (5%)∗Includes deletion 17p, P53 mutation, deletion 11q23, or more than 3 cytogenetic abnormalities.†Includes deletion 13q, normal chromosomes, and triosomy 12. Open table in a new tab ∗Includes deletion 17p, P53 mutation, deletion 11q23, or more than 3 cytogenetic abnormalities.†Includes deletion 13q, normal chromosomes, and triosomy 12. After a median follow up of 13.6 (range: 3.4-26.5) months following HCT, none of the 20 pts have experienced progression or relapse. Five pts have died (median 9 months), 2 from graft-versus-host disease (GVHD), 2 infections, and 1 elected Hospice care after experiencing renal failure. Last disease responses were complete remission (n = 8), partial remission (n = 6), stable disease (n = 5), not-evaluated (n = 1). The incidences of grades II and III-IV acute GVHD were 60% and 15% respectively, and chronic GVHD was 46% at 1-year. Estimated 1-year rate of non-relapse mortality (NRM), relapse, progression-free (PFS), and overall survivals (OS) were 33%, 0%, 67%, and 67% respectively. Patients receiving peri-HCT rituximab had lower HR for relapse (HR:0, p = 0.001), comparable HR for NRM (HR:1, p = 0.9) and OS (HR:0.7, p = 0.45), and a trend for lower HR for PFS (HR:0.5, p = 0.07) compared to the historical control group. At day 84, median CD3 chimerisms were 99% vs 95% (p = 0.08), respectively. After adjusting for the previous 4 significant covariates, PFS was better (HR:0.4, p = 0.04) among the rituximab group. Peri-transplant rituximab is a promising addition to nonmyeloablative HCT and may decrease early disease progression by allowing the generation of potent GVL effects.