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The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6-8; 15 mg/m2, days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).
Rationale: Steroid refractory graft-vs-host disease (sr-GvHD) represents a challenging complication after allogeneic hematopoietic cell transplantation (allo-HCT). Intestinal microbiota (IM) diversity and dysbiosis were identified as influencing factors for the development of acute GvHD. Fecal microbiota transfer (FMT) is hypothesized to restore IM dysbiosis, but there is limited knowledge about the significance of FMT in the treatment of sr-GvHD.
Objectives: We studied the effects of FMT on sr-GvHD in allo-HCT patients from two German tertiary clinical centers (n = 11 patients; period: March 2017 until July 2019). To assess safety and clinical efficacy, we analyzed clinical data pre- and post-FMT (day -14 to +30 relative to FMT). Moreover, IM were analyzed in donor samples and in a subset of patients pre- and post-FMT by 16S rRNA sequencing.
Results: Post-FMT, we observed no intervention-associated, systemic inflammatory responses and only minor side effects (5/11 patients: abdominal pain and transformation of peristalsis—each 3/11 and vomiting—1/11). Stool frequencies and volumes were significantly reduced [pre- vs post-FMT (d14): P < .05, respectively] as well as clear attenuation regarding both grading and staging of sr-GvHD was present upon FMT. Moreover, IM analyses revealed an increase of alpha diversity as well as a compositional shifts toward the donor post-FMT.
Conclusions: In our study, we observed positive effects on sr-GVHD after FMT without the occurrence of major adverse events. Although these findings are in line with published data on beneficial effects of FMT in sr-GvHD, further randomized clinical studies are urgently needed to better define the clinical validity including mode of action.
Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with <nCR after first ASCT were assigned tandem ASCT in both trials. In patients with <nCR and tandem ASCT (LEN: n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.