ALBERT

Description: Background: Treating relapsed/refractory non-Hodgkin and Hodgkin lymphoma in fit young and elderly patients represents a considerable challenge for clinicians. Combined cytotoxic agents are rapidly ineffective, especially when relapse occurs after autologous stem cell transplantation (ASCT). Alternative regimens are often sparse. In the era of personalized medicine, phase I clinical trials offer an alternative therapeutic option through a multitude of immunotherapy and targeted drugs in development. Phase I trials aim to determine the recommended phase II dose (RP2D) through toxicity and pharmacokinetic assessments. Documenting signal of activity is also a major objective, underlying the importance of including patients susceptible to remain on study until first lymphoma response evaluation (usually 6 weeks, 2 cycles). We aimed to assess a simple scoring system that could identify patients who will discontinue phase I studies before 6 weeks. Patients and Methods: Data from all lymphoma patients treated within a phase I trial in Gustave Roussy (GR) Cancer Center were retrospectively collected. 83 consecutive patients were enrolled in 17 phase I trials at GR between January 2008 and May 2014. All patients had progressive lymphoma at time of enrollment, after a median of 3 prior therapeutic lines (range 1;13). 37 patients (45%) received an ASCT prior to phase I inclusion. Median age was 67 years (range: 23-92) and WHO performance status (PS) was 0 in 36 patients (43%), 1 in 43 patients (52%) and 2 in 4 patients (5%). Median time from lymphoma diagnosis to phase I inclusion was 47 months. Lymphoma histological subtypes were represented as follows: 21% Hodgkin lymphoma, 36% aggressive non-Hodgkin lymphoma (83% diffuse large B cell lymphoma, 17% T cell lymphoma), 24% indolent non-Hodgkin lymphoma (70% follicular lymphoma, 25% marginal zone lymphoma, 5% Waldenström macroglobulinemia) and 19% mantle cell lymphoma. Univariate analysis on this cohort allowed identifying simple factors significantly associated with overall survival (OS). A simple scoring system, predictive for OS was pre-established and validated through a multivariate analysis in 2 large cohorts of various hematological malignancies by our group. Statistical tests were conducted on this relapsed/refractory lymphoma cohort, to evaluate this score's OS and early study discontinuation predictive ability. Results: Within a median follow up of 19 months, median OS and progression free survival (PFS) were respectively 18 (CI95%: 12; 37) and 3 (CI95%: 1.7; 3.6) months. Best overall response rate (ORR) and disease control rate (DCR: objective response and stable disease rates) were respectively 18% and 61%. Thirty-four patients (41%) experienced grade 3 or 4 adverse events and 7 patients (8%) a dose limiting toxicity (DLT). WHO performance status (PS) 〉 0 at inclusion, baseline albumin ≤ 35 g/l and baseline LDH ≥ 250 UI/L were significantly associated with poorer OS. The predefined GR prognostic score combined 2 simple variables, PS and baseline serum albumin (+1 if PS 0, +1 if albumin≤ 35 g/l). In our lymphoma cohort, patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months vs 17 months vs 9 months; p = 0.007). This simple score, distinguishes patients most likely to remain on study for more than 6 weeks, considered as the minimum required period for response and toxicity evaluation (classical DLT and targeted therapies associated long term toxicities). Among patients prematurely withdrawn from clinical trials, 91% had a GR score ≥ 1 (p=0,007). Main study discontinuation reason was progressive disease (77%), drug related toxicity was only responsible for study discontinuation in 13 % of cases. Conclusion: Our data demonstrate efficacy and safety of phase I clinical trials in lymphoma, thus offering an interesting alternative therapeutic option for fit young and elderly relapsed/refractory lymphoma patients. The GR simple score, can both help in selecting patients most likely to benefit from a phase I trial (better OS) and to determine the phase II recommended dose (reduced early trial discontinuation). Disclosures No relevant conflicts of interest to declare.

Description: Background: Phase I clinical trials are conducted to determine the recommended phase II dose through safety and pharmacokinetic assessments. Potential clinical benefit is also a key aim. To improve patient's selection and identify patients most likely to benefit from these studies in hematological malignancies (HM), we designed and then validated in an independent cohort, a prognostic score based on simple variables. Patients and Methods: We retrospectively collected data from 82 consecutive patients enrolled in 14 phase I trials at Gustave Roussy (GR) between January 2008 and February 2012 (cohort 1). A simple scoring system was established through multivariate analysis (MVA) of multiple potential prognostic factors (age, gender, BMI, smoking status, comorbidities, histological subtype, WHO performance status (PS), prior autologous stem cell transplant, prior radiotherapy, LDH, serum albumin and protein levels). We then prospectively collected data from 88 consecutive patients treated in 17 phase I trials in the GR phase I department from February 2012 to May 2014, to validate this prognostic score on an independent cohort (cohort 2). Stratification was done according to histology given the heterogeneity of diseases. Results: All patients had progressive HM after a median of 2 prior systemic standard therapeutic lines in cohort 1. The distribution of HM was: acute myeloid leukemia (AML) 23%, indolent non Hodgkin lymphoma (iNHL) 22%, myelofibrosis (MF) 21%, aggressive non-Hodgkin lymphoma (aNHL) 16%, chronic lymphoid leukemia (CLL) 10%, Hodgkin lymphoma (HL) 6% and multiple myeloma (MM) 2%. Median age was 73 years (range: 27-93) and 56 patients (67%) had more than one comorbidity. Best overall response rate (ORR) and disease control rate (DCR: objective response and stable disease rates) were 20% and 64 % respectively. Within a median follow up of 26 months, median progression-free survival (PFS) and overall survival (OS) were respectively 5 (CI95%: 4; 8) and 17 months (CI95%: 12; 26). One toxicity-related death (2%) occurred. Thirty-seven patients (45%) experienced grade 3 or 4 adverse events (AE) and 9 patients (11%) a dose-limiting toxicity (DLT). MVA identified PS 〉 0 at inclusion, baseline albumin ≤ 35 g/l and histological subtype as prognostic factors for OS. We defined the GR score using this MVA data: +1 if PS 〉 0, +1 if albumin ≤ 35 g/l. Patients with a GR score = 0 experienced significantly better OS compared to patients with a score = 1 and a score = 2 (37 months versus 17 months versus 8 months; p = 0.003). Cohort 2 patients were characterized by a median age of 64 years (range: 23-84) and a similar comorbidity rate (61%). Distribution among hematological entities was: 22% iNHL, 21% AML, 19% aNHL, 14% MM, 13% HL, 7% MF and 5% CLL. Patients received a median of 3 systemic therapeutic lines prior to phase 1 inclusion. Best ORR and DCR were respectively 28% and 57%. Within a median follow up of 11 months, median PFS and OS were 3 (CI95%: 1.5; 5) and 20 months (CI95%: 12; NA) respectively. No toxicity-related death occurred. Forty-seven patients (53%) experienced grade 3 or 4 toxicity and 1 patient (1%) a dose-limiting toxicity. Pre-established GR score was predictive of OS in this validation cohort (p=0.033). Main study discontinuation reason was progressive disease (75% and 80% in cohorts 1 and 2, respectively). Drug related toxicity was responsible for study discontinuation in 9% and 14% of cases in cohorts 1 and 2 respectively. The GR score distinguishes patients most likely to remain on study for more than 6 weeks, considered as the minimum required period for response and toxicity evaluation (classical DLT and targeted therapies associated long term toxicities). Among patients who discontinued prematurely clinical trials, GR score was ≥ 1 in 88% and 89% of cases respectively in cohort 1 (Cochran-Armitage: p= 0.02 and p=0.06) and cohort 2 (p=0.036). Conclusion: Our data demonstrate safety and efficacy of phase I trials in a significant number of relapsed/refractory HM patients with a clinical benefit achieved in more than half of patients. Response rates are higher than previously reported in solid tumors (Arkenau HT et al. 2008), thus encouraging HM patients inclusions in phase I trials. The simple GR score based on PS and albumin offers a valuable selection tool enabling OS and early trial discontinuation prediction. Disclosures No relevant conflicts of interest to declare.

Description: Background: Busulfan (Bu) is the corner stone of hematopoietic stem-cell transplantation (HSCT) regimens with a narrow therapeutic window (TW). Graft rejection or toxicities are reported according to plasmatic exposure. In very young children, Bu exhibits large pharmacokinetic (PK) variability. Bu clearance was demonstrated to be non-linearly related to body weight (BW) and thus BW is used to optimally define the Bu dosage in children [Vassal et al., CCP 2006]. Search for additional data to confirm the TW and to describe clinical outcomes is still a topical question to better understand Pk/Pd relationship and to safely use Bu in young children and infants. Objective: To study the Pk/Pd relationship of Bu in pediatric recipients of bone marrow transplantation (BMT) receiving Bu-based conditioning regimens (CR). To correlate early toxicities (mainly hepatic veno-occlusive disease (VOD), non infectious pulmonary disease (niPD) and outcome i.e. overall survival (OS) at last follow up with type of CR, the underlying diseases, age at transplantation and Pk of busulfan Patients and Method: This multicenter prospective observational study included 307 pts transplanted between 2006 and 2013 from 14 French Pediatric BMT units; median age at transplantation was 18.4 months [1.3-289], with a median BW of 11.3 kg [3.4-82]. 100 pts were younger than 1 year, 71 pts 〈 9 kg and 171 pts 〈 16 kg. Patients were mostly affected by non-malignant diseases (primary immune deficiency (n=143), inherited metabolic disorders (n=50), hemoglobinopathies (n=20) while 78 patients suffered from malignant disease. 257 patients received allogenic HSCT (genoidentical donor n=79, matched unrelated donor n=33, mismatch unrelated donor n=18, haploidentical intra-familial donor n=59, other mismatched intra familial donor n=8 or unrelated cord blood n=51) and 41 autologous BMT. All patients received Bu-based conditioning regimen in combination with cyclophosphamide (BuCy n=119), fludarabine (BuFlu n=88), melphalan (BuMel n=36) or thiotepa (BuTTP n=3). 40 patients received BuFlu associated with a second alkylating agent (Mel, TTP or Cy), 12 patients received BuCy associated with a third agent (Mel or VP16). Serotherapy was given in 70% of the patients. Starting doses of Bu were given according to the European SmPC or EBMT-ESID recommendations. The median posology was 1 mg/kg 4x/day for 4 days [0.6-1.3 mg/kg]. PK was assessed on plasma samples with area under the curve (AUC) evaluation from the 1st(D1), 9th (D9) and 13th (D13) dose in 150 patients, D1 and D9 in 40 patients, D1 and D13 in 46 patients while 62 patients were monitored on D1 only (684 PK datasets). PK analysis was performed using Non linear Mixed Effect Modelling. A one-compartment PK model suitably fitted the concentrations vs time data. Median follow up is 27 months (0.33 to 96 months post BMT). Results: At D1, 67% of patients were within the therapeutic window (TW) [900-1500 µM.min] and 66% of patients reached the cumulative TW [14400-24000 µM.min]. Incidence of VOD and niPD were respectively 35% and 14%. Both toxicities correlated with type of CR and age