This study was aimed at ascertaining whether extracorporeal photopheresis (ECP) is an effective treatment for pediatric patients with steroid resistant graft versus host disease (GvHD). Fifteen patients with acute GvHD (aGvHD) and 10 patients with chronic GvHD (cGvHD) were enrolled in the study. At the start of the ECP protocol, aGvHD was staged as II (n=7), III (n=4), and IV (n=4). The response rate was 100% for aGvHD II, 75% for aGvHD III, and finally 0% for aGvHD IV (P=0.02). In multivariate analysis, the strongest predictor for ECP response was the aGvHD severity: aGvHD II 100%, aGvHD III-IV 30% [relative risk (RR) 5.071, confidence interval (CI) 95% 2.2-5.5, P=0.0016], this translates in a higher risk of transplant-related mortality for ECP nonresponders (RR 5.26, CI 95% 3.4-6.2, P=0.02). cGvHD was diagnosed as limited n=3, and extensive n=7; the response rate was 100% and 28% for limited or extensive cGvHD, respectively (P=0.03). For cGvHD the strongest predictor for ECP response was the absence of visceral organ involvement (RR 5.17, CI 95% 2-4.9, P=0.001), and the highest risk of transplant-related mortality was among patients not responding to ECP (RR 12.4, CI 95%, P=0.02). Our results suggest that ECP can rescue good-risk GvHD-patients, whereas for advanced, poor-risk GvHD patients, new therapies are required.
10517 Background: The prognosis of patients with metastatic Ewing sarcoma remains poor. The primary aim of the ISG/AIEOP EW2 Study (EUDRACT# 2009-011197-15) was to evaluate the feasibility and efficacy of maintenance therapy with oral cyclophosphamide plus celecoxib. Methods: From June 1st 2009 to Nov 22nd 2019, 112 patients with metastatic Ewing sarcoma at onset entered the ISG/AIEOP EW2 study, consisting of induction chemotherapy, radiotherapy and/or surgery at the site of the primary tumor, a consolidation phase with high-dose busulphan/melphalan + autologous stem cell rescue, whole-lung irradiation (12-15Gy), and a maintenance phase of 180 days with cyclophosphamide 50 mg daily (35 mg/mq daily if age < 14 years) plus celecoxib 400 mg twice daily (250 mg/mq twice daily if age < 14 years). Exclusion criteria from the maintenance phase were disease progression, cardiac or gastro-intestinal comorbidity. For CTCAE v4.0 grade 3-4 toxicities a temporary interruption was planned. Results: Seventy-one patients were eligible and entered the maintenance phase. Median age was 16 years (range 13-41); sites of metastases were lung or single bone (n = 56) and multicentric metastatic spread (n = 15). Sixty-one patients terminated the maintenance phase, 4 patients are still on treatment, 1 patient interrupted the treatment due to auto-immune thrombocytopenia at 4 months, 5 patients were withdrawn throughout maintenance due to disease progression/relapse. The duration of maintenance therapy was 89% of the scheduled days, with a median suspension length of 12 days (range 1-44 days). Causes of temporary suspension were hematological toxicity (19 episodes), infections (12 episodes), gastrointestinal disorders (9 episodes), fluid retention/distal oedema (3 episodes), renal disorders (3 episodes). Median follow-up was 42 months. The 3-year EFS of patients who entered the maintenance phase was 0.79 ± 0.09 for lung or single bone, and 0.19 ± 0.11 for those with multicentric metastatic spread. Conclusions: This schedule of maintenance phase is feasible, despite previous intensive treatment. A longer follow-up is needed to monitor side effects and to evaluate clinical outcome of patients with lung or single bone metastases, while the outcome remains dismal for multicentric metastatic Ewing sarcoma. Clinical trial information: NCT02727387.
e23564 Background: Activity of temozolomide (TEM) and irinotecan (IRI) in recurrent Ewing sarcoma (EWS) was demonstrated. Few data are available on TEMIRI use upfront. Biological predictive factors are lacking. Methods: This multi-institutional retrospective study (NCT03542097) included 59 patients with EWS. 8 patients with very high risk (HR) EWS (multivisceral ± bone marrow) received TEMIRI (TEM 100 mg/m2/day oral, and IRI 40 mg/m2/day intravenous, days 1-5, every 21 days) upfront, 51 patients after relapse (28% in 1st line, 72% ≥ 2nd line). Overall response rate (ORR: CR+PR), SD, and PD, progression-free (PFS) and overall survival (OS) were assessed. The relationship between pre-treatment expression of MGMT and ABCG2 (when FFPE tissue available) with ORR, PFS and OS was evaluated. Results: Median age was 27 years (range 4-62 years): 47 patients (80%) were adults (≥18 years), 35 (61%) had ECOG 0 and 42 (71%) presented with multivisceral disease (+ bone marrow in 5). MGMT was positive in 16/30 (53%), ABCG2 in 4/33 (12%). ORR for upfront TEMIRI (n = 8) was 50% (CR + PR = 1 + 3), with SD 50%, while in recurrent EWS (n = 49, 2 patients no measurable by RECIST) ORR was 31% (CR + PR = 4 + 11), SD 38%, and PD 31%. A better ORR was observed in adult (p = 0.008) & ECOG 0 (p = 0.001) patients; MGMT & ABCG2 expression did not influence ORR. 6-mos PFS was 87% after TEMIRI upfront, 43% at recurrence (p = 0.06), and 65% vs 28% (p = 0.02) for ECOG 0 vs ECOG 1-2, respectively. 6-mos PFS was 62% in MGMT+ vs 33% in MGMT- (p = 0.4) and 75% in ABCG2+ vs 50% in ABCG2- (p = 0.7). Median time to progression (TTP) with upfront TEMIRI was 9 months (range 5-28 months), with 1 patient with ongoing CR at 56 months; median TTP at relapse was 3 months (1-29 months). MGMT and ABCG2 expression did not influence 1-yr OS, whereas ECOG (0 vs 1-2) did (88% vs 31% p < 0.001). Grade 3-4 diarrhea, neutropenia, and thrombocytopenia incidence was < 5%, 1 patient with recurrent kidney EWS died of acute liver failure. Conclusions: TEMIRI showed promising activity in a very unfavorable cohort of EWS patients, with manageable toxicity. Performance status correlated with 6-month PFS & OS whereas MGMT & ABCG2 did not. Clinical trial information: NCT03542097 .
10516 Background: The prognosis of patients with primary multifocal metastatic Ewing sarcoma (PMES) remains dismal. So far, combination with temozolomide and irinotecan (TEMIRI) was tested in patients with refractory or relapsed disease. This study evaluates the activity and the tolerability of TEMIRI as front-line treatment in PMES. Methods: In the study-period 2012-2018, a front-line window therapy with 2 courses TEMIRI (temozolomide 100 mg/sqm/day + irinotecan 50 mg/sqm/day for 5 days every three weeks) was introduced as amendment to the ISG/AIEOP EW-2 protocol ( EUDRACT#2009-011197-15, Vers. 1.02 ) for patients with PMES. Main objective was to test the activity of TEMIRI evaluated by RECIST 1.1 criteria, with centralized revision of the radiological response. Secondary objectives included assessment of the toxicity profile and clinical benefit of the combination. A two-step study design by Simon was planned. Results: Thirty-four patients were enrolled. Median age at diagnosis was 19 years (range 3-55); males/females ratio was 2.4. Primary axial tumour was present in 24 (70%). After TEMIRI, RECIST response was as follows: partial response -20 (59%), stable disease -11 (32%), progression disease -3 (9%). After TEMIRI, amelioration in ECOG/Lansky score was achieved in 25/34 (73,5%), and reduction or disappearance of pain was observed in 31/34 patients (91%). TEMIRI toxicity was manageable: incidence of grade 3-4 nonhaematological and haematological toxicity was 3% and 3%, respectively (67/68 evaluable courses). At the time of the present analysis, 11 patients are alive; 7 of them are in complete remission and completed their treatment program (5-drug standard chemotherapy). With a median follow-up of 31 months (range 23-75), the 3-year survival estimate is 36,5%±0.09. Conclusions: Upfront TEMIRI x 2 courses showed an encouraging activity, with response rate 59% and deserves further evaluation combined with conventional treatments also in non-metastatic patients. In PMES new treatment strategies are urgently needed. Clinical trial information: NCT02727387.
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