Acute myeloid leukemia with biallelic mutation of CEBPA(CEBPAdm AML) is a distinct good prognosis entity recognized by WHO 2016 classification. However, testing for CEBPA mutation is challenging, due to the intrinsic characteristics of the mutation itself. Indeed, molecular analysis cannot be performed with NGS technique and requires Sanger sequencing. The association of recurrent mutations or translocations with specific immunophenotypic patterns has been already reported in other AML subtypes. The aim of this study was the development of a specific cytofluorimetric score (CEBPA-dm score), in order to distinguish patients who are unlikely to harbor the mutation. To this end, the correlation of CEBPA-dm score with the presence of the mutation was analyzed in 50 consecutive AML patients with normal karyotype and without NPM1 mutation (that is mutually exclusive with CEBPA mutation). One point each was assigned for expression of HLA DR, CD7, CD13, CD15, CD33, CD34 and one point for lack of expression of CD14. OS was not influenced by sex, age and CEBPA-dm score. Multivariate OS analysis showed that CEBPA-dm (p<0.02) and FLT3-ITD (p<0.01) were the strongest independent predictors of OS. With a high negative predictive value (100%), CEBPA-dm score < 6 was able to identify patients who are unlikely to have the mutation. Therefore, the application of this simple score might optimize the use of expensive and time-consuming diagnostic and prognostic assessment in the baseline work up of AML patients. Highlights AML with CEBPA-dm is a distinct entity with an overall favorable outcome. The evaluation of CEBPA-dm requires difficult and time consuming Sanger sequencing. CEBPA-dm AML has a peculiar immunophenotypic signature. The presence or the absence of CEBPA-dm can be predicted with our IF score.
Cisplatin-containing salvage regimens followed by autologous hematopoietic stem cell (HSC) transplantation are the current standard of care for relapsed or refractory (R/R) lymphomas. We retrospectively analyzed efficacy and stem cell mobilizing activity of oxaliplatin, cytarabine, dexamethasone and rituximab (R-DHAOX) in 53 R/R diffuse large B cell lymphomas (DLBCL) treated in our centre (median lines 2, range 2-5; median age 59, range 22-79). Hematological toxicity was manageable and no patients experienced renal impairment. After 2 courses the overall response rate was 60% (CR 49%, PR 11%). Median overall survival (OS) was 30.53 months (95% CI 11.5-49.55), 3year OS 40.5%. Twenty-two eligible patients collected HSC and transplantation was performed in 21/22 patients (95%), after a median of 52 days from last cycle. Our results suggest that in DLBCL R-DHAOX has an excellent stem cell mobilizing capability, response rate comparable to cisplatin-containing regimens and good toxicity profile.
BACKROUND Hodgkin lymphoma (HL) is a lymphoid malignancy of B-cell origin with a high long-term survival. Despite the efficacy of frontline therapy, about 30% of patient will show relapse or refractory disease (R/R). In this patient population, the treatment of choice consists of salvage chemotherapy followed by intensive conditioning regimen and autologous stem cell transplantation (ASCT). However 30-50% of patients receiving salvage chemotherapy fail to achieve at least PR and further therapy with Brentuximab-Vedotin (BV) may be administered to induce a clinical response. Nonetheless, therapeutic options for truly refractory patients are still limited. Recently, immune-check point inhibitors have shown promising results in HL patients relapsed after ASCT. Anti-PD1 Nivolumab is currently approved with this indication. Unfortunately,expected CR rate is only about 20%.Thus, we reasoned that earlier administration of Nivolumab, as post-ASCT consolidation, might improve its efficacy. However, several reports have highlighted the importance of patient immune-competence, which is severely impaired in heavily pre-treated lymphoma patients undergoing ASCT, to achieve durable response with anti-PD1 immunotherapy. AIMS OF THE STUDY Here we report the preliminary results of a prospective trial investigating the feasibility, and the efficacy, in terms of both immunological recovery andclinical response,ofthe reinfusion of autologous lymphocytes (ALI), early after ASCT, concomitant with anti-PD1 consolidation immunotherapy in very high-risk HD patients. METHODS Patients under the age of 60 with high risk HD identified by PET2 or PET6 positivity following ABVD were scheduled for a pre-emptive lymphocyte apheresis with a target of 5x107 CD3+/kg. Patients who failed to achieve at least PR with salvage chemotherapy proceeded to ASCT with FEAM conditioning followed by early Nivolumab and ALI.The first ALI was performed 7 days after engraftment; the second ALI was administered at day +14 after the first dose whereas the third and the fourth doses were given every 21 days. ALI dosing was incremental, one logarithm at each infusion, starting from 1x104CD3+ cells/kg in the first infusion to a maximum of 1x107/kg in the fourth and last infusion. Each ALI was followed within 48 hours by the administration of Nivolumab 240 mg flat dose. Toxicity was evaluated and graduated according to CTCAE-EORTC standards. Circulating lymphocyte subpopulationswere extensively studied before and after each ALI and each Nivolumab administration by 12-colours flow cytometry. Clinical response was evaluated 21 days after completion of the fourth ALI + Nivolumab. PRELIMINARY RESULTS Four R/R HD patients have completed the treatment and3are currently under treatment. All patientshad failed to achieve CR with first and second line chemotherapy. PET scan before ASCT showed progressing disease in all patients despite BV therapy, with multiple-extra nodal involvement in 3 of them. Study patients underwent ASCT with FEAM conditioning and achieved complete engraftment after a median of 10 days (8-12). ALI induced faster T-cell recovery (p <0.05) as compared to HD patients receiving FEAM conditioning and ASCT without immunotherapy at the same time points after ASCT (days +30, +60, +90, +120). Moreover, after ALI administration, cytotoxic NK cells (CD56+,CD16+,CD57+) showed the most significant consistent increase (Fig. 1, p<0.05). Nivolumab administration by itself determined only a modest and transient increase in T-effector cell population. No grade 3 or 4 adverse events were recorded so far. In one patient grade 2 fever was observed after 1st ALI. All treated patient achieved negative PET scan after the procedure and are alive and disease-free after a median follow-up of 9 months. PRELIMINARY CONCLUSIONS Post-ASCT ALI proved to be feasible and effective allowing a faster immune recovery in heavily-pre-treated HD patients. Moreover, the early administration of check point inhibitors combined with ALI as post-ASCT consolidation therapy, may improve the low rate of CR expected with anti-PD1 blockade alone, providing a more effective option for refractory patient, which are usually considered not candidate for ASCT. Figure 1. Figure 1. Disclosures Gobbi: Amgen: Consultancy; Ariad: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfister: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy.
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