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This phase I/II study assessed the combination of brentuximab vedotin (BV) with ifosfamide-carboplatin-etoposide (ICE) as a second-line therapy in refractory/relapsed (R/R) classical Hodgkin lymphoma (cHL) patients. Phase I study was designed to determine the maximum tolerated dose (MTD) of BV (10 patients) and phase II evaluated the rate of complete metabolic response (CMR) after 2 cycles of BV-ICE (42 patients). There were no dose-limiting toxicities (DLT) during phase I recommending BV 1.8 mg/kg for phase II. Twenty-six patients (61.9%) achieved CMR after 2 cycles of BV-ICE and 37 patients (88%) were transplanted. With a median follow-up of 38 months, the 3-year progression free survival (PFS) and overall survival (OS) rate were 64.3% and 100%, respectively. Hematological toxicities (81%) and infections (21%) were the most frequent adverse event encountered BV-ICE regimen is feasible with manageable toxicities and could be an alternative to other salvage treatments. Trial Registration : ClinicalTrials.gov identifier: NCT02686346.

Purpose: The prospective, randomized AHL2011 trial demonstrated that the use of the doxorubicin, bleomycin, vinblastine, and dacarbazine regimen (ABVD) after two cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP escalated ) in early responders on the basis of a positron emission tomography (PET)-driven strategy was safe and minimized toxicity compared with standard 6 BEACOPP escalated cycles. This substudy investigated the benefit of this strategy in gonadal function and fertility in patients under 45 years old., Methods: Ovarian function was assessed by serum measurement of follicle-stimulating hormone (FSH), estradiol, and anti-müllerian hormone in women, and semen analysis, FSH, and testosterone levels were used to evaluate testicular function in men at baseline, end of treatment, and during 5 years of follow-up., Results: A total of 145 women and 424 men, enrolled between May 19, 2011, and April 29, 2014, were included. The risk of premature ovarian insufficiency (FSH > 24 IU/L) and of having a low ovarian reserve (anti-müllerian hormone < 0.5 ng/mL) was reduced after treatment in the PET-driven group (odds ratio [OR], 0.20; 95% CI, 0.08 to 0.50; P = .001 and OR, 0.15; 95% CI, 0.04 to 0.56, P = .005, respectively). Both parameters were correlated with age and dose of alkylating agents. However, no significant differences were observed in terms of pregnancy rates. Men in the PET-driven group had a higher recovery rate of sperm parameters after treatment compared with the standard BEACOPP escalated group, as well as a lower risk of severe testicular damage (OR, 0.26; 95% CI, 0.13 to 0.5; P < .0001) and a higher likelihood of achieving pregnancy (OR, 3.7; 95% CI, 1.4 to 9.3; P = .004)., Conclusion: Although both treatments affected ovarian reserve and spermatogenesis, the PET-driven strategy decreased the risk of gonadal dysfunction and infertility in advanced Hodgkin lymphoma., Competing Interests: Isabelle DemeestereConsulting or Advisory Role: RocheResearch Funding: Roche diagnosisTravel, Accommodations, Expenses: Ferring Jehan DupuisConsulting or Advisory Role: AstraZenecaTravel, Accommodations, Expenses: Gilead Sciences Franck MorschhauserConsulting or Advisory Role: Roche/Genentech, Gilead Sciences, Celgene, Bristol Myers Squibb, AbbVie, Epizyme, ServierSpeakers' Bureau: RocheExpert Testimony: Roche/Genentech Virginie De WildeConsulting or Advisory Role: Takeda, Janssen Oncology Julien LazaroviciTravel, Accommodations, Expenses: Roche, Novartis, Sandoz, Janssen-Cilag, Jazz Pharmaceuticals France, Daiichi Sankyo Oncology France, Mundipharma, Pfizer, AbbVie Hervé GhesquieresHonoraria: Gilead Sciences, Janssen, Celgene, RocheConsulting or Advisory Role: Gilead Sciences, Celgene, Roche, MundipharmaTravel, Accommodations, Expenses: Roche, Gilead Sciences, Celgene, Takeda Mohamed TouatiHonoraria: AmgenConsulting or Advisory Role: Janssen, Bristol Myers Squibb/Celgene David SibonConsulting or Advisory Role: Takeda, Iqone healthcare, Janssen, RocheTravel, Accommodations, Expenses: Takeda, Janssen Luc-Matthieu ForneckerConsulting or Advisory Role: Takeda, RocheTravel, Accommodations, Expenses: Takeda, Roche Marc AndréConsulting or Advisory Role: Takeda, BMSiResearch Funding: Takeda, RocheTravel, Accommodations, Expenses: Roche, Celgene, Gilead Sciences René-Olivier CasasnovasHonoraria: Roche/Genentech, Takeda, Gilead Sciences, Bristol Myers Squibb, Merck, AbbVie, Celgene, Janssen, AmgenConsulting or Advisory Role: Roche/Genentech, Takeda, Gilead Sciences, Bristol Myers Squibb, Merck, AbbVie, Celgene, Janssen, IncyteResearch Funding: Roche/Genentech, Gilead Sciences, TakedaTravel, Accommodations, Expenses: Roche/Genentech, Takeda, Gilead Sciences, JanssenNo other potential conflicts of interest were reported.

Background: Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP escalated ) improves progression-free survival in patients with advanced Hodgkin lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPP escalated to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring., Methods: AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16-60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPP escalated given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPP escalated , after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPP escalated induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPP escalated and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPP escalated ). BEACOPP escalated consisted of bleomycin 10 mg/m 2 and vincristine 1·4 mg/m 2 intravenously on day 8, etoposide 200 mg/m 2 intravenously on days 1-3, doxorubicin 35 mg/m 2 and cyclophosphamide 1250 mg/m 2 intravenously on day 1, 100 mg/m 2 oral procarbazine on days 1-7, and 40 mg/m 2 oral prednisone on days 1-14. ABVD was given every 28 days (doxorubicin 25 mg/m 2 , bleomycin 10 mg/m 2 , vinblastine 6 mg/m 2 , and dacarbazine 375 mg/m 2 intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747., Findings: From May 19, 2011, to April 29, 2014, 823 patients were enrolled-413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPP escalated after PET2. With a median follow-up of 50·4 months (IQR 42·9-59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6-89·8 in the standard treatment group versus 85·7%, 81·4-89·1 in the PET-driven treatment group (hazard ratio [HR] 1·084, 95% CI 0·737-1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9-90·3 and 85·4%, 80·7-89·0, respectively (HR 1·144, 0·758-1·726; p=0·74). The most common grade 3-4 adverse events were leucopenia (381 [92%] in the standard treatment group and 387 [95%] in the PET-driven treatment group), neutropenia (359 [87%] and 366 [90%]), anaemia (286 [69%] vs 114 [28%]), thrombocytopenia (271 [66%] and 163 [40%]), febrile neutropenia (145 [35%] and 93 [23%]), infections (88 [22%] and 47 [11%]), and gastrointestinal disorders (49 [11%] and 48 [11%]). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 [20%] of 412 vs 50 [12%] of 407) and febrile neutropenia (21 [5%] vs 23 [6%]). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukaemia)., Interpretation: PET after two cycles of induction BEACOPP escalated chemotherapy safely guided treatment in patients with advanced Hodgkin lymphoma and allowed the use of ABVD in early responders without impairing disease control and reduced toxicities. PET staging allowed accurate monitoring of treatment in this trial and could be considered as a strategy for the routine management of patients with advanced Hodgkin lymphoma., Funding: Programme Hospitalier de Recherche Clinique., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

The prognosis of refractory/relapsed acute myeloid leukemia (AML) remains poor. The complete response (CR) rate after relapse is around 25%, with 11% of patients still alive after 5 years. The efficacy and toxicity of fractionated gemtuzumab ozogamicin (fGO; 3 mg/m2, days 1, 4, 7) in combination with intensive chemotherapy were retrospectively evaluated in patients with refractory/relapsed AML. Thirty-six patients (median age 54 years) were included. European LeukemiaNet classification was as follows: favorable (n=6), intermediate-I (n=13), intermediate-II (n=8), adverse (n=9). Median CR duration was 7.16 months (1.63-96.8). The overall response rate was 38.8%, with CR in eight patients (22.2%) and CR with incomplete platelet recovery (CRp) in six patients (16.7%). Two-year overall survival was 26% (95% confidence interval [CI]: 12-42) and 2-year relapse free-survival was 18.5% (95% CI: 6.6-35.0). Salvage therapy with fractionated GO in patients with very high-risk disease produced a 38.8% response rate and may be considered as a bridge therapy to transplant.