Abstract 204
The NIH staging and response criteria offer for the first time the chance for uniform documentation of chronic graft-versus-host disease (cGVHD). Here we present the validation of the ...cGVHD staging criteria as part of an interim analysis of a prospective German/Austrian multicenter study on the NIH staging criteria in cGVHD. One hundred-seventeen patients (median age 44 years, range 21–72) after allogeneic hematopoietic stem cell transplantation (HSCT) were evaluated according to the NIH criteria based on cGVHD activity assessment including the NIH-cGVHD grading form, the physicians cGVHD activity assessment form, the NIH-cGVHD symptom self assessment form, and the Lee cGVHD symptom-scale (L-cGVHD-SC). Enrolment occurred a median of 443 (range, 100–4003) days after HSCT. The validation of the NIH staging criteria was performed using the first 3 surveys each one month apart. For the purpose of validity a second evaluation was performed including only patients with stable cGVHD (n=64) as judged by the physician (results in parentheses). The statistical significance p was <0.01 for all reported results. Severity of cGVHD was mild in 33 patients, moderate in 50, and severe in 34, respectively. For the global NIH cGVHD grading (mild, moderate, severe) the test-retest stability between the three evaluations showed a high correlation ranging from 0.67–0.75 (0.7–0.78). Interestingly, the physician′s severity grading using the 10 point scale demonstrated a higher correlation ranging from 0.82–0.87 (0.88–0.92). The test-retest stability was highest for skin: 0.82–0.85 (0.91–0.93), mouth: 0.7–0.75 (0.76–0.8) and joints: 0.75–0.79 (0.68–0.86) followed by liver: 0.58–0.76 (0.63), eye: 0.64–0.68 (0.6–0.62) and genital: 0.65–0.87 (0.83–0.95), while it was relatively low for gastrointestinal (GI): 0.43–0.44 (0.38) and lung manifestations: 0.46–0.49 (0.6) respectively. With regard to the patients' self assessment the test-retest stability ranged for the 10 point scale between 0.76–0.79 (0.8), and for the mild/moderate/severe grading from 0.68–0.75 (0.83–0.85). Mouth dryness was reported with a correlation of 0.74–0.79 (0.83–0.84), mouth pain with 0.68–0.79 (0.74–0.84) and mouth sensitivity with 0.77–0.80 (0.81–0.88). Eye complaints were reported with high stability: 0.82 (0.81–0.86). Comparison of physicians' organ grading with patients' organ specific self assessment of the NIH self assessment form and the L-cGVHD-SC organ scores revealed a moderate correlation of the physicians' skin grading with the skin L-cGVHD-SC subscale (r=0.55), the mouth grading with the mouth L-cGVHD-SC subscale (r=0.32), mouth dryness (r=0.42), mouth sensitivity (r=0.44), and mouth pain (r=0.5) of the NIH self assessment form. The physicians' eye grading correlated with the eye and mouth L-cGVHD-SC subscale (r=0.62) and eye complaints in the patients' NIH self assessment form (r=0.65). The lung grading correlated moderately with the breath subscale of the L-cGVHD-SC (r=0.5). While the joint grading correlated moderately only with the muscle and joint subscale of the L-cGVHD-SC, the GI grading did not correlate with the eating and digestion part of the L-cGVHD-SC. The results demonstrate a high test-retest stability for most of the organs and the global grading indicating its robustness in clinical use. The low test-retest correlation in the lung and GI grading including failure to correlate with the eating and digestion subscale of the L-cGVHD-SC may relate to the solely functional staging and the multifactorial pathogenesis of symptoms. This is supported by the correlation of lung symptoms in the L-cGVHD-SC breath subscale with lung grading.
No relevant conflicts of interest to declare.
Background: The tolerability and efficacy of high-dose dihydroxy-busulfane (Treosulfan Treo), a water-soluble bifunctional alkylating agent with profound stem cell toxicity, as the major myelotoxic ...component of the preparative regimen preceding allogeneic stem cell transplantation (alloSCT) in patients (pts) with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) has been recently demonstrated in phase II clinical trials. Since no prospective trials directly comparing Treo-based conditioning to a myeloablative total body irradiation (TBI) regimen will be available in the near future, the major clinical endpoints after Treo-based conditioning in comparison to a myeloablative TBI regimen were evaluated in adult pts with AML.
Methods: A total of 203 pts who underwent alloSCT between 1999 and 2005 were included in this bi-centre retrospective study, of whom 46 pts (23%) had received a Treo-based regimen (3 x 14 g/ m2), while 157 pts had been conditioned with TBI (4 x 2.5 Gy to 6 x 2 Gy), each combined with either fludarabine (5 x 30 mg/m2) or cyclophosphamide (2 x 60 mg/kg). Both cohorts were well comparable in terms of patient age, donor type, disease stage, cytogenetic risk category, and the hematopoietic cell transplantation comorbidity index (HCT-CI). The median follow-up time of all pts is 58 months (mo) (range 4 – 110 mo).
Results: For 125 pts transplanted in complete remission (CR)(CR1: 61 pts, CR2: 64 pts), non-relapse mortality (NRM) at 100 days, 1, and 3 years (yrs) after transplant was 6% (95% confidence limits CL: 0%–15%), 13% (95%-CL: 9%–24%), and 30% (95%-CL: 13%–30%) after Treo-compared to 10% (95%-CL: 4%–16%), 16% (95%-CL: 9%–24%), and 22% (95%-CL: 13%–30%) after the TBI-based regimen (ns). Similarly, no significant difference of NRM between the two regimens was detectable for the 78 pts in more advanced disease stages. Further, the post transplant risk of hematologic relapse (RR) was not influenced by the conditioning regimen: The RR for CR pts at 1 and 3 yrs was 13% (95%-CL: 1%–25%) and 16% (95%-CL: 3%–30%) after Treo-compared to 25% (95%-CL: 16%–34%) and 33% (95%-CL: 23%–43%) after TBI-based conditioning (ns). The corresponding figures for more advanced stages were 43% (95%-CL: 16%–70%) and 57% (95%-CL: 27%–87%) compared to 29% (95%-CL: 17%–40%) and 33% (95%-CL: 21%–46%), respectively (ns). Overall survival (OS) for all CR pts at 1 and 3 yrs was 77% (95%-CL: 63%–92%) and 54% (95%-CL: 36%–73%) after Treo-compared to 68% (95%-CL: 58%–67%) and 49% (95%-CL: 38%–60%) after TBI-based conditioning (ns). For pts transplanted in CR1, OS at 1 and 3 yrs reached 79% (95%-CL: 61%–97%) and 63% (95%-CL: 41%–85%) after Treo- and 70% (95%-CL: 58%–82%) and 53% (95%-CL: 39%–66%) after TBI-based conditioning (ns). In more advanced stages, OS at 1 and 3 years declined to 29% (95%-CL: 0%–7%) and 21% (95%-CL: 0%–50%) after Treo- and to 29% (95%-CL: 15%–44%) and 16% (95%-CL: 1%–32%) after TBI-based conditioning, respectively (ns). Major determinants of OS and RR were the disease stage (CR vs more advanced stages) and the cytogenetic risk category (low-intermediate vs high risk). The HCT-CI (stratified to <=2 or >2) had no apparent influence on NRM, RR, or OS in this analysis.
Conclusion: This retrospective long-term analysis supports that Treo-based conditioning leads to at least equivalent results regarding the major clinical endpoints of alloSCT when compared to a standard myeloablative TBI-based conditioning regimen in adult AML pts. An international prospective multicenter randomized trial has now been launched (EudraCT-No. 2008-002356-18) to compare Treosulfan-based conditioning with a reference reduced intensity conditioning regimen in AML and MDS pts.
Objective Stable mixed hematopoietic chimerism can be established in a canine stem cell transplantation model using a conditioning consisting of total body irradiation (TBI; 2 Gy) and postgrafting ...immunosuppression with mycophenolate mofetil (MMF) and cyclosporin (CSA). Reduction of TBI had resulted previously in graft rejection in this model. We investigated whether postgrafting stimulation of donor T cells against recipient's hematopoietic antigens or graft augmentation with donor monocyte-derived dendritic cells (MoDC) promote engraftment following 1 Gy TBI. Materials and Methods All dogs received dog leukocyte-antigen−identical bone marrow transplantation. Dogs were conditioned with either 2 Gy TBI (group 1) or 1 Gy TBI, followed by repetitive recipient hematopoietic cell lysate vaccinations (group 2) or graft augmentation with MoDC (group 3). Immunosuppression consisted of CSA and MMF. Results In group 1, four animals remained stable chimeras for >110 weeks, and three rejected their grafts (week 10, week 14, week 16). All dogs in groups 2 and 3 rejected their graft (median: week 10 and 11, respectively). Peak chimerism and engraftment duration was shorter in the 1-Gy groups ( p < 0.05) compared to group 1. Conclusion Neither postgrafting vaccination nor graft augmentation with MoDC were effective in supporting durable engraftment. Additional modifications are necessary to improve potential strategies aimed at establishment of early tissue specific graft-vs-host reactions.
•First-line treatment is applied relatively homogeniously among German, Austrian, and Swiss transplant centers except initial treatment of progressive onset.•Second-line treatment varies considerably ...with new agents entering clinic through the last 10 years.•Even in the presence of evidence clinical practice in treatment of lung manifestations varies considerably.
Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeated 7 questions on first-line treatment and 3 questions on second-line scenarios followed by an updated survey on all current systemic treatment options known and applied, with 29 of 66 centers (43%) responding. In summary, the results show a large overlap of first-line treatment practice between centers and the 2 surveys because of a lack of new data that changes practice, except significant heterogeneity of treatment of cGVHD progressive onset type, which can be explained by the lack of trials focusing on this high-risk entity. In contrast, treatment options applied to second-line therapy vary considerably, with new agents like ibrutinib and ruxolitinib entering clinical practice. Moreover, treatment of bronchiolitis obliterans syndrome demonstrates heterogeneity in applied therapeutic options and sequence because of a lack of controlled data and different conclusions from already existing evidence. In summary, the survey results demonstrate an increasing number of treatment options applied to cGVHD accompanied by a significant heterogeneity in second-line treatment and underline the urgent need for clinical trials and registry analyses on rare entities with high mortality like progressive onset type and lung involvement of cGVHD.
The NIH staging and response criteria offer for the first time the chance for uniform documentation and evaluation of physical functioning and quality of life (QoL) aspects of chronic ...graft-versus-host disease (cGVHD). Here we present the results of an interim analysis of a prospective German multicenter study on the NIH staging criteria in cGVHD.
Hundred-thirty-eight patients (median age 46 years, range 19–64) after allogeneic hematopoietic stem cell transplantation (HSCT) for hematologic malignancies were evaluated according to the NIH criteria based cGVHD activity assessment, the Lee Chronic GVHD Symptom-Scale (L-cGVHD-SC), FACT-BMT, Human Activity Profile (HAP), SF36, Berlin Social Support Scale (BSSS), 24 Item Adjective Measure (24–AM), Hospital Anxiety and Depression Scale (HADS), and the NCCN-Distress-Thermometer. Enrolment occurred between day 100 and 1 year after HSCT or in the presence of active cGVHD also at later time points. Follow-up surveys were conducted at 1, 2, 3, 5, 8, 12 and 18 months after baseline survey. At all time points disease status, comorbidities and medication were documented. Additionally the NIH-Symptom-Scale was applied for clinician rating of cGVHD symptoms.
Ninety-one patients had cGVHD (mild n=29, moderate n=38, severe n=24) while 47 patients had no cGVHD. The cGVHD NIH consensus grading correlated with impairment of the activity profile (r=0.29, p<0.01), and the FACT-G total score (r=0.29, p=0.04). Pain highly correlated with impairment of QoL (FACT-G total score) (r=0.71, p<0.01), and impairment of the activity profile (r=0.30, p<0.01) and was associated with depression (r=0.29, p<0.01). In addition, the activity profile correlated with QoL (FACT-G total score) (r=0.41, p<0.01), anxiety (r=0.20, p=0.02), and mental health (r=0.38, p<0.01). Multiple regression analysis revealed that severity of cGVHD (β=0.27, p=0.01), grade of distress measured by the distress thermometer (β=0.28, p<0.01) and extraverted personality (β= −0.27, p<0.01) significantly predicted QoL as measured by the FACT-BMT. In contrast to the FACT-BMT, the SF36 total score was not predicted from severity of cGVHD in a multiple regression analysis; the only factors that predicted the SF36 total score were comorbid diabetes mellitus (β=0.22, p=0.01) and patients age (β=0.26, p=0.01). Moreover, a multiple regression analysis including the FACT-BMT (β= −0.29, p<0.01), L-cGVHD-SC (β= −0.19, p=0.01), and SF36 showed that the SF36 (β=0.12, p=0.1) did not contribute a significant additional information in the prediction of the HAP-maximum activity score. Using a multiple regression model the HAP-maximum activity score correlated inversely with severity of cGVHD (β= −0.25, p=0.015). Male sex (β=0.24, p=0.02) as well a diligent personality (β=0.24, p=0.02) had a significant positive impact on the HAP-maximum activity score.
The results demonstrate, that severity of cGVHD as assessed by the NIH consensus grading correlates with impairment of physical functioning as well as QoL. Gender as well as personality are significant modifiers of the activity profile and QoL. While the FACT-BMT correlated with severity of cGVHD the SF36 failed to detect cGVHD related impairment of QoL and the activity profile in this cohort of patients in a multiple regression analysis.
The treatment of refractory or relapsed non-Hodgkin lymphoma (NHL) remains challenging. In this retrospective study, 88 patients with refractory or relapsed NHL received treosulfan and fludarabine as ...a reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Of the 88 intensely pre-treated patients, 73 experienced a relapse, with 18 of the 88 patients experiencing an early relapse (ER; <6 months from the last chemotherapy). At the time of allo-HSCT, 26 patients were in complete remission (CR) and 43 in partial remission (PR), 12 patients had progressive disease (PD) and 7 had stable disease (SD). A total of 47 patients received an autologous graft followed by allo-HSCT. Following allo-HSCT, 69 of the 88 patients were in CR and 7 were in PR, resulting in an overall response rate of 86.4% (76/88). A total of 33 patients achieved a CR from PR, as did 6 patients from PD and 5 from SD. Of the 88 patients, 43 (49%) were alive at the end of the follow-up period. The patients who directly underwent allo-HSCT without prior auto-HSCT exhibited a better disease-free survival (DFS; P=0.038) with a tendency (P=0.077) for a better overall survival (OS). The patients with ER exhibited a probability of OS of 0.35±0.12 after 3 and 7 years. Chronic graft-versus-host disease (cGvHD) exerted a positive effect on OS and DFS (for limited cGvHD vs. no cGvHD, P=0.002 and 0.004, respectively). In conclusion, allogeneic stem cell transplantation following conditioning with treosufan and fludarabine constitutes a viable therapeutic option for patients with refractory or relapsed NHL and should be considered early during the course of salvage treatment.
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is often performed in cases of advanced hematological diseases, but because of the associated mortality and a high risk of relapse it is ...life prolonging only in some patients.
A retrospective multi-center analysis of 401 patients was conducted to analyze the variables associated with outcome after alloHSCT in advanced hematological diseases. The Cox proportional hazards model was used to assess the independence of overall survival (OS) and disease-free survival (DFS) from prognostic factors in a multivariate model.
The 5-year OS and DFS were 27.3 and 21.1% respectively. Multivariate analysis showed that the underlying malignancy had a significant influence on OS and DFS (p < 0.001 and p < 0.011, respectively), whereas development of severe acute graft versus host disease (GvHD) had a negative impact on OS (p < 0.001). Development of chronic GvHD showed a trend to a better OS (p = 0.085) and DFS (p = 0.199). No impact was seen for the intensity of conditioning.
Development of chronic GvHD but not the conditioning regimen improved the outcome after alloHSCT for advanced malignancies, underlining the importance of immunological rather than cytotoxic effects.
Background: Viral infections contribute significantly to morbidity and mortality following allogeneic HSCT. Whereas incidences and risk factors for CMV infections are well studied data for other ...viral infections are more limited. Here, we present data on 202 alloHSCT recipients that received predominantly reduced intensity conditioning (RIC).
Patients and Methods: Data of 202 consecutive patients (pts) who received HSCT during 1/1999 to 12/2006 were retrospectively analysed with regards to viral infections caused by adenovirus (AdV), herpes simplex virus (HSV), varicella zoster virus (VZV), human herpesvirus 6 (HHV6), epstein-barr virus (EBV) and BK-virus (BKV). Other factors included were gender, age, underlying disease, disease status, year of diagnosis, year of HSCT, time from diagnosis to HSCT, donor type, gender-matching between donor and recipient, stem cell source, conditioning-regimen, T-cell-depletion, prior autologous HSCT, acute and chronic GvHD, prior fungal infection, and viral serostatus of the recipients.
Results: Median follow-up was 9.2mths (mean 21.7mths, range 8days to 95.3mths). Median pt. age was 45yrs (range 15 to 69yrs). Underlying diseases were ALL (n=20), AML (n=63), CLL (n=7), CML (n=32), MDS (n=21), MM (n=17), NHL (n=28), OMF (n=5), others (n=9). 137 pts received RIC most commonly based on treosulfan/fludarabine (n=112). 65 pts received myeloablative conditioning mainly based on 12Gy TBI containing regimen (n=48). GvHD-prophylaxis consisted of CSA/MTX (n=106), other CSA based regimen (n=83) or other (n=13). The overall infection incidences of AdV were 4.0%, of HSV 7.4%, of VZV 5.9%, of HHV6 8.9%, of EBV 4.5% and of BKV 5.4%. Median time of onset of AdV infections were 64 days after HSCT, of HSV 34 days, of VZV 542 days, of HHV6 97 days, of EBV 83 days, of BKV 50 days. Pts with AdV or HHV6 infections had a inferior survival compared to pts w/o the according viral infection (p=0.024 and p=0.048, respectively). 3/8 pts (37%) with AdV and 5/18 pts (28%) with HHV6 infections died within 30 days after infection diagnosis. Pts with EBV or BKV infections tended to have an inferior survival compared to pts w/o the according infection (p=0.084, p=0.152, respectively). 4/9 pts (44%) with EBV and 2/11 pts (18%) with BKV infection died within 30 days after infection diagnosis. Whereas pts with HSV infections had a similar survival compared to pts w/o infections, mean survival for pts with VZV infections was significantly better compared to pts w/o VZV infections (p=0.003). In multivariate analyses VZV infections remained to be associated with better survival (p=0.046, HR 0.132, CI 0.018–0.962). The other viral infections did not remain significant risk factors when analysed adjusted for competing risk factors. In order to determine the influence of late viral infections we performed an additional multivariate analyses solely including pts surviving beyond day 90. EBV infections (p=0.024, HR 2.807, CI 1.147–6.873) and HHV6 infections (p=0.013, HR 2.594, CI 1.227- 5.484) were significant risk factors for inferior survival besides unrelated donor HSCT (p=0.013), acute GvHD III/IV (p=0.001) and fungal infection prior to HSCT (p=0.005).
Conclusion: Non-CMV viral infections are commonly observed following myeloablative and RIC alloHSCT. Since they are associated with significant mortality early broad viral screening seems advisable if virus infections are clinically suspected.
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