Retrospective single center analysis of outcome, risk factors and therapy in steroid refractory graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute and chronic graft-vs.-host disease (aGvHD and cGvHD) are major complications after allogeneic hematopoietic cell transplantation (HCT) leading to substantial morbidity and mortality. This retrospective single-center study analyzes incidence, therapy, and outcome of GvHD in n = 721 patients ≥18 years having received allogeneic HCT 2004-2013 with a special focus on steroid refractory GvHD. Acute (n = 355/49.2%) and chronic (n = 269/37.3%) GvHD were mainly treated by steroids in first-line therapy. The proportion of steroid refractory aGvHD and cGvHD was 35.7% and 31.4%, respectively. As there is no standard therapy for steroid refractory GvHD, a range of different agents was used. In aGvHD, the overall response rate (ORR) of steroid refractory GvHD to second-line treatment was 27.4%. Mycophenolate mofetil (MMF) and mTOR inhibitors led to superior response rates (ORR 50.0% and 53.3%, respectively). In steroid refractory cGvHD therapy, ORR was 44.4%. Use of calcineurin inhibitors (CNI; n = 11/45.5%), MMF (n = 18/50.0%), mTOR inhibitors (n = 10/60.0%), and extracorporeal photophoresis (ECP; n = 16/56.3%) showed ORR above average. Targeted therapies lead to responses in 7.7% (n = 13). This data may help to improve the design of future prospective clinical studies in GvHD.

[Allogeneic stem cell transplantation : An option for autoimmune diseases?] / Allogene hämatopoetische Stammzelltransplantation : Eine Option bei Autoimmunerkrankungen?

According to experimental animal models and experiences of patients with coexisting autoimmune diseases, allogeneic stem cell transplantation has the potential to reestablish and maintain immunological tolerance. On the other hand, it is associated with significant treatment related mortality and may induce diverse immunological diseases by graft-versus-host reaction. Other than with severe aplastic anemia, it is not an established therapy for autoimmune diseases; it is under investigation in clinical trials and might be considered in severe, refractory immune cytopenia.

Allogeneic hematopoietic cell transplantation as curative therapy for non-transformed follicular lymphomas.

Allogeneic hematopoietic cell transplantation (HCT) offers the chance of cure for patients with non-transformed follicular lymphoma (FL), but is associated with the risk of non-relapse mortality (NRM). The aim of this study was to identify subgroups of FL patients who benefit from HCT. The European Society for Blood and Marrow Transplantation (EBMT) Minimum-Essential-A Data of 146 consecutive patients who received HCT for FL between 1998 and 2008 were extracted from the database of the German Registry 'DRST'. Diagnosis of FL was verified by contact with the reference pathologists. Estimated 1-, 2- and 5-year overall survivals (OS) were 67%, 60% and 53%, respectively. Day 100 NRM was 15%. Thirteen out of 33 patients (40%) with treatment-refractory disease (RD) at the time of transplantation survived long term. Univariate statistical analysis suggested limited chronic GvHD, donor age ⩽42 years and TBI-based conditioning in treatment refractory patients to correlate with favorable OS. Independent prognostic factors for OS were treatment-sensitive disease and limited chronic GvHD for the whole cohort, and additionally TBI-based conditioning for the treatment refractory subgroup. In contrast, patient age ⩾55 years had no impact on outcome. Thus, HCT for FL is associated with acceptable NRM, and offers a substantial chance of cure for patients with RD or advanced age. Donors ⩽42 years should be preferred if available.

Clofarabine salvage therapy before allogeneic hematopoietic stem cell transplantation in patients with relapsed or refractory AML: results of the BRIDGE trial.

In patients with relapsed or refractory (r/r) acute myeloid leukemia (AML), long-term disease control can only be achieved by allogeneic hematopoietic stem cell transplantation (HSCT). We studied the safety and efficacy of clofarabine-based salvage therapy. The study was designed as phase II, multicenter, intent-to-transplant (ITT) study. A total of 84 patients with r/r AML were enrolled. All patients received at least one cycle of CLARA (clofarabine 30 mg/m(2) and cytarabine 1 g/m(2), days 1-5). Chemo-responsive patients with a donor received HSCT in aplasia after first CLARA. Generally, HSCT was performed as soon as possible. The conditioning regimen consisted of clofarabine (4 × 30 mg/m(2)) and melphalan (140 mg/m(2)). The median patient age was 61 years (range 40-75). On day 15 after start of CLARA, 26% of patients were in a morphologically leukemia-free state and 79% exposed a reduction in bone marrow blasts. Overall, 67% of the patients received HSCT within the trial. The primary end point, defined as complete remission after HSCT, was achieved by 60% of the patients. According to the ITT, overall survival at 2 years was 43% (95% confidence interval (CI), 32-54%). The 2-year disease-free survival for transplanted patients was 52% (95% CI, 40-69%). Clofarabine-based salvage therapy combined with allogeneic HSCT in aplasia shows promising results in patients with r/r AML.

Noninfectious Generalized Bronchiolitis in the Setting of Allogeneic Stem Cell Transplantation: A Potential Mimic of Lower Respiratory Tract Infection.

RATIONALE AND OBJECTIVES: To describe a little-known therapy-related small-airway phenomenon presumably caused by mucosal irritation in patients undergoing allogeneic stem cell transplantation (allo-SCT). MATERIALS AND METHODS: Retrospective database search at our institution identified 739 hematologic patients who underwent chemotherapy + allo-SCT between September 2004 and March 2014. After infectious pulmonary complications were excluded, 75 patients (female = 24; male = 51; median age = 47 years) with signs of generalized bronchiolitis (GB) on chest high-resolution computed tomography were identified. Computed tomography (CT) was performed proximate to chemotherapy onset; 92% had follow-up CT (mean, 1.9 weeks). The presence of centrilobular nodules, bronchial wall thickening (BWT), tree-in-bud (distributed diffuse vs. focal), ground-glass opacity, airspace opacification, luminal impactions, and air trapping was correlated with occurrence and duration of oral mucositis and therapy characteristics. Intensity of tree-in-bud and centrilobular nodules was graded absent (grade = 0), moderate (grade = 1), or marked (grade = 2). RESULTS: Overall incidence of GB among allo-SCT patients was 10.14%. GB was diagnosed at the time point of transplantation with a mean duration of CT findings of 4 weeks (±2.7). Tree-in-bud (17% [grade 2] and 83% [grade 1]) and BWT were present in 100% of the patients. Centrilobular nodules diffusely distributed were found in 45.5% of patients (20% [grade 2], 24% [grade 1], and 56% [none]). Air trapping and mosaic pattern were found in 13% and 16% of the patients, respectively. Resolution of GB was spontaneous. GB and its severity correlated with the temporal course and grade of oral mucositis; frequency and degree were not significantly influenced by the chemotherapy regimen. The incidence of GB in high-resolution computed tomography was statistically and significantly higher in patients with oral mucositis (P < 0.035). CONCLUSIONS: GB is frequent during chemotherapy for allo-SCT and is characterized by an even distribution of tree-in-bud, BWT, centrilobular nodules, mild clinical symptoms, and spontaneous resolution.

Allogeneic stem cell transplantation after conditioning with treosulfan, etoposide and cyclophosphamide for patients with ALL: a phase II-study on behalf of the German Cooperative Transplant Study Group and ALL Study Group (GMALL).

TBI-based preparative regimens are considered as standard conditioning therapy for allogeneic stem cell transplantation (AHSC) in patients with ALL. We investigated toxicity and efficacy of a non-TBI-based regimen consisting of treosulfan, etoposide and cyclophosphamide for ALL within a prospective study. Major inclusion criteria were CR and non-eligibility for TBI. Fifty patients with a median age of 46.5 years (range, 18-64) were included. Donors were HLA-identical sibling (n=8), matched (n=42) or mismatched (n=10) unrelated. The toxicity was moderate, resulting in a cumulative incidence of non-relapse mortality (NRM) at 1 year of 8% (90% confidence interval: 2-15%). Acute GvHD grade II-IV and grade III/IV was noted in 53% and 14%, respectively. Chronic GvHD at one year was seen in 41%. After a median follow-up of 24 months the cumulative incidence of relapse was 36% (90% confidence interval: 24-48) and 51% (90% confidence interval: 37-65) at 1 and 2 years, respectively. The estimated 2-year disease-free and overall survivals were 36 and 48%, respectively. Treosulfan, etoposide and cyclophosphamide followed by AHSC has a favorable toxicity profile with low NRM and therefore represents a potential alternative regimen for ALL in 1. CR (NCT00682305).

Influence of age on outcome after allogeneic hematopoietic cell transplantation: a single center study in patients aged ⩾60.

Reduced intensity conditioning regimens lead to an increasing use of allogeneic hematopoietic cell transplantation (HCT) in elderly patients. We retrospectively analyzed 151 patients aged ⩾60 receiving allogeneic HCT 2000-2012 at our center. Median age was 66 years. Kaplan-Meier estimated 3-year OS was 42% with a median follow-up of 38 months. Cumulative incidences of progression and non-relapse mortality after 3 years were 38 and 24%. OS was better in the group of patients >65 years with a Kaplan-Meier estimated OS of 50% vs 34%, P=0.060. We observed a significant influence of donor age (<50 years: 53% vs >50 years: 30%, P=0.017) and gender match (matched: 57% vs mismatched: 32%, P=0.007) on outcome. The use of a matched related donor was inferior compared with a matched or mismatched unrelated donor (19% vs 47%, P=0.015). On multivariate analysis there was an increased hazard ratio for a non-gender-matched HLA-matched-related donor (hazard ratio 3.23, 95% confidence interval 1.55-6.74, P=0.002). Age had no significant impact on OS (P=0.414). In conclusion, the data suggest that older age alone has no negative impact on the outcome of allogeneic HCT. Transplant decision should be tailored to disease risk and patient performance status rather than age.

Extracorporeal photopheresis combined with pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent GVHD.

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects. We evaluated the use of these treatment modalities to prevent GVHD in a canine model of unrelated dog leukocyte Ag-mismatched hematopoietic cell transplantation, after conditioning with 920 cGy TBI. We have shown previously in this model that 36/40 dogs given MTX alone as postgrafting immunosuppression engrafted and that 25 of 40 dogs had severe GVHD and median survival of 21 days. In the current study, nine dogs received conditioning with 920 cGy TBI and postgrafting MTX either with ECP on days -2 to -1 alone (n=5) or ECP on days -6 and -5 combined with two doses of pentostatin (days -4 to -3) (n=4). Seven of nine dogs achieved engraftment. Six dogs developed severe acute GVHD (four in the group with ECP alone and two with pentostatin and ECP). We failed to demonstrate a positive impact of ECP and pentostatin for the prevention of GVHD compared with historical control dogs.

Extracorporeal photopheresis increases neutrophilic myeloid-derived suppressor cells in patients with GvHD.

Extracorporeal photopheresis (ECP) is beneficial in patients with T-cell-mediated disorders, including GvHD, but the underlying immunological mechanisms are incompletely understood. Myeloid-derived suppressor cells (MDSCs) are innate immune cells characterized by their capacity to suppress T-cell proliferation. We quantified MDSCs by flow cytometry in peripheral blood from patients after BMT with GvHD before and after ECP treatment, patients after BMT but without GvHD and age-matched healthy controls. MDSC functionality was analyzed using T-cell proliferation, cytokine release and arginase activity. GvHD patients showed increased baseline percentages of neutrophilic MDSCs (PMN-MDSCs) compared with healthy controls and patients after BMT without GvHD. ECP treatment in GvHD patients rapidly increased circulating percentages of PMN-MDSCs. Functionally, PMN-MDSCs efficiently dampened Th1 and Th17 responses and were paralleled by an increase of cellular and extracellular arginase activity. Following ECP longitudinally over 16 weeks, two GvHD responder subgroups were identified, with group one continuously increasing PMN-MDSCs and group two with stable or decreasing PMN-MDSCs over time. This study demonstrates for the first time that ECP increases T-cell-dampening PMN-MDSCs in GvHD patients, a finding that should be confirmed in larger series of GvHD patients.

Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia.

Minimal residual disease (MRD) after allogeneic stem cell transplantation (SCT) for Ph+ acute lymphoblastic leukemia (ALL) is predictive of relapse. Imatinib administration subsequent to SCT may prevent relapse, but the role of scheduling and its impact on outcome are not known. In a prospective, randomized multicenter trial, we compared the tolerability and efficacy of post-transplant imatinib administered either prophylactically (arm A; n=26) or following detection of MRD (arm B; n=29). Prophylactic imatinib significantly reduced the incidence of molecular recurrence after SCT compared with MRD-triggered imatinib (40% vs 69%; P=0.046). Median duration of PCR negativity was 26.5 and 6.8 months, respectively (P=0.065). Five-year survival in both interventional groups was high (80 and 74.5%), despite premature discontinuation of imatinib in the majority of patients because of poor tolerability. Relapse probability was significantly higher in patients who became MRD positive (P=0.017). In conclusion, post-transplant imatinib results in a low relapse rate, durable remissions and excellent long-term outcome in patients with BCR-ABL1-positive ALL irrespective of whether it is given prophylactically or MRD-triggered. Reappearance of BCR-ABL1 transcripts early after SCT or at higher levels identifies a small subset of patients who do not benefit sufficiently from imatinib, and in whom alternative approaches should be explored.

Allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia and pulmonary mucormycosis.

Mucormycosis is a serious invasive fungal infection in immunocompromised patients. Patients undergoing treatment for hematologic malignancies are predominantly prone to the pulmonary manifestation of mucormycosis. Historically, allogeneic hematopoietic cell transplantation (HCT) in patients suffering from pulmonary mucormycosis (PM) was considered contraindicated owing to mortality rates up to 90%. We present 3 patients with acute myeloid leukemia and PM who were treated with radical surgical debridement combined with high-dose liposomal amphotericin B (LAB), and subsequently underwent successful allogeneic HCT. To date, all 3 patients are in complete remission and show no signs of mucormycosis. Allogeneic HCT in patients with PM seems feasible provided that the infectious focus is completely removed surgically and adequate antifungal pharmacotherapy, such as high-dose LAB or posaconazole, is established.

Dose-escalated radioimmunotherapy as part of reduced intensity conditioning for allogeneic transplantation in patients with advanced high-grade non-Hodgkin lymphoma.

A total of 20 patients enrolled in a multicenter phase II dose escalation study of radioimmunotherapy (RIT) using yttrium-90-ibritumomab tiuxetan at two dose levels (22 and 30 MBq/kg) in 10 patients, combined with reduced intensity conditioning (RIC) using fludarabine, melphalan and alemtuzumab followed by allogeneic hematopoietic cell transplantation (HCT) from either matched-related (n=5) or matched-unrelated donors (n=15). Postgrafting immunosuppression with cyclosporine was administered. Diagnoses were diffuse large B-cell lymphoma (n=13), transformed CLL (n=4), blastic mantle cell lymphoma (n=2) and follicular lymphoma grade 3 (n=1). Median age was 51 (range, 29-69) years. All patients were high risk with relapsed/refractory disease or relapse after preceding autologous HCT. Median follow-up of patients alive was 1115 (range, 1006-1252) days. No directly RIT-related toxicities were observed. The cumulative incidence of non-relapse mortality was 30%. Incidences of grade II-IV acute and chronic GvHD was 45% and 70%, respectively. Kaplan-Meier estimated 3-year OS and EFS were 20% for both dose levels. In conclusion, dose escalation of RIT and combined use with RIC is feasible with no additional toxicity due to dose escalation. This study is registered on http://clinicaltrials.gov as NCT00302757.

[Allogeneic stem cell transplantation for acute myeloid leukemia and HIV infection--case 3/2012]. / Allogene Stammzelltransplantation bei Akuter Myeloischer Leukämie und HIV-Infektion--Fall 3/2012.

HISTORY AND ADMISSION FINDINGS: A 27-year-old male patient with a past medical history of HIV presented with acute myeloid leukemia for allogeneic hematopoietic stem cell transplantation (HSCT). Highly active anti-retroviral therapy suppressed the viral load below detection threshold. INVESTIGATIONS: There were no contraindications for allogeneic HSCT. TREATMENT AND COURSE: Myeloablative conditioning consisted of total body irradiation and cyclophosphamide. Anti-thymocyte globulin, tacrolimus and mycophenolate mofetil were used for immunosuppression. Combined anti-retroviral therapy (nucleoside and nucleotide analog reverse-transcriptase inhibitor, boostered protease inhibitor, maraviroc and raltegravir) was maintained for allogeneic HSCT and viral load remained below detection threshold. No graft-versus-host disease or serious infectious complications occurred. The patient showed good graft function with stable hematopoiesis. Localized Kaposi's sarcoma was diagnosed six months after allogeneic HSCT and treated successfully with surgical excision and reduction of immunosuppression. Almost one year after allogeneic HSCT, the CD4+ cell count is rising and viral load remains below detection threshold with combined anti-retroviral therapy. CONCLUSION: Allogeneic HSCT can be safely performed in HIV positive patients. Kaposi's sarcoma is a rare event after allogeneic HSCT and linked to strong immunosuppression.

Extracorporeal photopheresis in addition to pentostatin in conditioning for canine hematopoietic cell transplantation: role in engraftment.

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects, but have not been evaluated for their ability to enhance engraftment of hematopoietic stem cells. We evaluated, in a canine model of dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT), whether ECP in combination with pentostatin could enhance engraftment using a nonmyeloablative regimen consisting of 100 cGy TBI and postgrafting immunosuppression with mycophenolate mofetil and CYA. We have shown previously that with 100 cGy TBI alone as conditioning, all of the six dogs rejected their grafts 2-12 weeks after HCT. With the addition of pentostatin to 100 cGy TBI, 6 of 10 dogs rejected their graft. We now tested the additional use of ECP alone (n=2) or ECP and 3-6 doses of pentostatin (n=7) before 100 cGy TBI and HCT. Eight out of nine dogs rejected their grafts within 6-11 weeks after HCT. Compared with data without ECP, we failed to demonstrate a positive impact of the use of either ECP or pentostatin for prevention of rejection.

Immune reconstitution after haploidentical hematopoietic cell transplantation: impact of reduced intensity conditioning and CD3/CD19 depleted grafts.

Haploidentical hematopoietic cell transplantation (HHCT) using CD34 selected grafts is complicated by slow engraftment and immune reconstitution. Engraftment and immune reconstitution might be improved using CD3/CD19-depleted grafts and reduced intensity conditioning (RIC). We report on 28 patients after HHCT with CD3/CD19-depleted grafts using RIC, which were prospectively evaluated for engraftment and immune reconstitution. Engraftment was rapid with full chimerism reached on day +15 after HHCT. T-cell reconstitution was delayed with a median of 205 CD3+ cells/µl, 70 CD3+CD4+ cells/µl and 66 CD3+ CD8+ cells/µl on day +100, respectively. A skewed T-cell receptor-Vß repertoire with oligoclonal T-cell expansions to day +100 and normalization after day +200 was observed. B-cell reconstitution was slow with a median of 100 CD19+ CD20+ cells/µl on day +150. Natural killer (NK) cell engraftment was fast reaching normal values on day +20. An increased natural cytotoxicity receptor and NKG2A, but decreased NKG2D and KIR expressions were observed on NK cells until day +100. We observed a positive impact of donor lymphocyte infusions on immune reconstitution. In conclusion, after HHCT, using CD3/CD19-depleted grafts and RIC, T- and B-cell reconstitution is delayed, whereas NK-cell reconstitution occurs early and fast.

CT-analysis of the course of gastrointestinal graft-versus-host disease--patterns of involvement.

OBJECTIVE: To describe the main patterns of distribution of gastrointestinal graft-versus-host disease (GVHD) and their chronological course. METHODS: Twenty-five adult patients (17 men, 8 women, mean age 47 years) were enrolled from 11/2003 to 11/2007. All patients underwent abdominopelvic CT shortly after onset of GVHD-related symptoms and also at follow up. The mean number of CT examinations per patient was 3.2±2.7 with a total of 81 in a median time period of 97 days after HCT. The gastrointestinal tract was divided into 7 segments. Gastrointestinal abnormalities were defined as follows: presence of wall thickening (>4mm), increased mucosal enhancement, bowel dilatation (>3 cm for the small bowel, >8 cm for the colon), fluid-filled loops of the bowel, bowel loop separation and double-halo sign. RESULTS: 40% (10/25) of the patients presented a classical pattern of evolution of involved segments by GI-GVHD. In these cases, especially the small bowel was initially involved showing a retreat with time towards the terminal ileum with longer length of stay in this location. 28% (7/25) of the patients presented with a nonclassical permanently migratory involvement of the GI jumping from one GI segment to another. Other 32% (8/25) of our patients revealed a nonclassical persistent, unchanged involvement pattern of GI involvement by GVHD at time. CONCLUSION: Contrary to existing reports, our data collected in 25 patients diagnosed with GI-GVHD after allogeneic hematopoietic stem cell transplantation suggest the presence of three different courses (classical, nonclassical migratory and nonclassical persistent) of this disorder. Awareness of this knowledge enables more accurate risk stratification.