Alberto Bosi

R-CHOP standard chemotherapy is successful in about 60% of diffuse large B-cell lymphoma (DLBCL) patients. Unresponsive patients have a poor prognosis, and predictive biomarkers of response to R-CHOP are lacking. We conducted the first prospective GWAS study aimed at exploring constitutional biomarkers predictive of R-CHOP efficacy and toxicity. Overall, 216 any-stage chemonaïve DLBCL patients candidate to R-CHOP were enrolled. The median age of the 185 eligible patients was 59.2 years, 49.7% were women and 45.4% were stage I–II patients. According to the Revised International Prognostic Index (R-IPI), 14.1%, 56.8% and 29.2% were in the very good, good and poor prognosis groups, respectively. Of the patients, 85.9% produced a complete response. Highly significant associations (i.e., p < 5 × 10⁻⁸) were found between progression-free survival (PFS) and six SNPs (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241). Additionally, five SNPs (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569) were highly associated with overall survival (OS). Wild-type patients showed a prolonged PFS or OS compared with patients carrying deleterious alleles (p < 0.001). No association with the adequate significant threshold was observed between SNPs and the objective response or toxicity. In the future, these SNPs, alone or in combination, after a proper validation in an independent cohort, could contribute to improving the prediction of R-CHOP response.

The aim of the current study was to explore under-considered psychosocial needs for lymphoma cancer group. A model of the role of psychosocial factors and Stressful Life Events was operationalized. We used Discriminant Analysis to test predictive power of the model. 103 oncological patients (gender: 42.7 % vs 49.3 % of females 55.2 ±15.6 vs 53.7±14.9) were matched with 140healthy control groups in the study. The following instruments were utilized to conduct the study: the Florence Psychiatric Interview, Hospital Anxiety Depression Scale, Multidimensional Scale of Perceived Social Support, Beck Depression Inventory I, and Sense of Mastery. The model satisfied the assumption criteria and were significant (Ʌ= .665, χ2= 105.83, p< .001). Stressful events, depression and anxiety were adequate markers of the psychological status of lymphoma patients. Our results point out the relevance of taking into account psychosocial factors in hematology.

Background. New drugs with or without autologous stem cell transplantation (ASCT) can induce deep CR responses. MRD can be now considered in the response evaluation by the IMWG and many studies propose it as surrogate for survivals. Multiparametric flow cytometric assays have now been replaced by advanced assays that permit to assess simultaneously more than 8 markers in a single tube. In particular, Euro-flow consortium has developed NGF, a novel high sensitive and standardized approach for MM MRD evaluation that is based on the use of 2 single 8-color tubes, containing all the markers needed to distinguish normal vs MM PCs. However, it is necessary to work on fresh samples and to acquire 10⁷ cell/sample, so to have the possibility to evaluate the Limit Of Quantification (LOQ) and the Limit Of Detection (LOD). The LOQ is calculated as 50 clonal plasmacells among 10⁷ nucleated cells; the LOD as 20 clonal plasmacells among 10⁷ nucleated cells. Aim. DART4MM is a single arm, multicenter, prospective study that evaluate Daratumumab effect on MM patients who already achieved VGPR/CR but MRD positive by NGF after a first line therapy (ASCT, VMP) (Gozzetti et al. IMW 2019). The purpose was to analyze 10.000.000 cells for MRD evaluation and reach at least 10^-6 level. Patients and Methods. Next generation flow (NGF) is centralized and measured at Siena University Hospital with two 8 colors tubes panel developed by the EuroFlow Consortium (BD OneFLOW Tm PCSTe BD OneFLOW Tm PCD. BD BioSciences) with detection of MRD with a sensitivity (≥ 1 in 105 /10-6). Daratumumab 16 mg/kg administered at weekly intervals for 8 weeks, then every 2 weeks for an additional 8 weeks, will be given to 50 MM patients who achieved a VGPR or more defined as per IMWG criteria and MRD-positivity (by NGF). Daratumumab starts at least 12 weeks from ASCT and at least 4 weeks after VMP. Free light chain (FLC) and CT/PET are evaluated at time 0 and every 6 months. NGF is done on marrow aspirate at time 0, at 2 months and every 6 months for 2 years. Primary endpoint is achievement of MRD negativity at 6 months: if patients are MRD negative after 6 months of therapy, treatment is stopped. Otherwise treatment will continue every 4 weeks up to 2 years. Rapid infusion was allowed from the third dose (cycle 1, day 15) if no serious IRR was seen in the previous infusion (second). The infusion rate was calculated to deliver 20% of the dose over 30 min (200 mL/hr), and then the rate was increased to deliver the remaining 80% over 60 min (450 mL/hr). This resulted in a 90 min estimated infusion time (total volume 550 mL). Results. Recruitment started at the end of December 2018. 70 patients were screened until July 2020 at 5 centers in Italy. At least 10 million cells were analyzed for sensitivity at flow for each sample. 31/70 (44%) resulted MRD positive and eligible. M/F =15/16, median age was 61 (range 48-68).Three patients were excluded from the protocol because of consent withdraw. Previous therapy were single ASCT (21 patients), double ASCT 3 patient, VMP (3 patients), KRD (1 patient). ISS stage was I in 8 patients, II in 9 patients, and III in the other 6 patients. Cytogenetics/FISH analysis at diagnosis was done in 25/28 patients : it was negative for 17p deletion, t(14q) and 1q amplification in 16 patients, 2 had t(4;14) , 5 had t(11;14), 2 had del 17p, 1 del 13q, +11 in 2. Grade 2 reaction (moderate infusion-related reactions) during first daratumumab infusion was seen in 10/28 (35%) patients and promptly resolved with corticosteroids administration and temporary infusion interrumption. More than 200 rapid infusions were given to 16 patients. No serious adverse event was registered. 22/28 (79%) patients completed 8 weeks of treatment (2 months) and evaluated MRD. 17/28 (60%) completed 6 months of therapy. MRD negativity was reached at 6 months in 9/17patients (53%). Interestingly 9/13 (62%) patients treated previously with ASCT were MRD negative (10^-6) after 6 months of Dara and stopped treatment. 12 patients reached 12 months of follow up: 2/12 patients are still MRD negative at 10^-7 (6 lost MRD negativity). Conclusions. Follow up will continue with marrow evaluation for MRD every 6 months until 2 years. Having at disposition high quality BM samples for MRD evaluation can ameliorate our assays, even to 10^-6 or 10^-7 and it is crucial to have a good coordination between clinicians and laboratories so to improve the accuracy, sensitivity, and specificity of MM MRD detection in MM patients.

Acute myeloid leukemia (AML) “with myelodysplasia-related changes (MRC)” is considered a separate entity by the World Health Organization (WHO) classification of myeloid neoplasms. While anamnestic and cytogenetic criteria provide objective attribution to this subset, with clear unfavorable prognostic significance, the actual role of multi-lineage dysplasia (MLD) as assessed by morphology is debated. The aim of our work was to study MLD by a technique alternative to morphology, which is multiparameter flow cytometry (MFC), in a large series of 302 AML patients intensively treated at our Center. The correlation with morphology we observed in the unselected analysis reiterated the capability of the MFC-based approach at highlighting dysplasia. MLD data, estimated through an immune-phenotypic score (IPS), provided no insight into prognosis when considered overall nor within well-defined genetic categories. Of interest, IPS-related dysplasia conveyed significant prognostic information when we focused on genetically undefined patients, triple-negative for NPM1, FLT3 and CEBPA (TN-AML). In this context, the lack of dysplastic features (IPS_0) correlated with a significantly higher CR rate and longer survival compared to patients showing dysplasia in one or both (neutrophil and erythroid) cell lineages. The impact of IPS category maintained its validity after censoring at allogeneic HSCT and in a multivariate analysis including baseline and treatment-related covariates. In a subgroup featured by the lack of genetic determinants, our data could help address the relative unmet needs in terms of risk assessment and treatment strategy, and provide insight into prediction of response in the rapidly evolving therapeutic scenario of AML.

Lenograstim and filgrastim in the febrile neutropenia prophylaxis of hospitalized patients: efficacy and cost of the prophylaxis in a retrospective survey [Corrigendum]

Purpose: We conducted a retrospective study to evaluate the efficacy and related costs of using two different molecules of granulocyte-colony stimulating factor (G-CSF) (lenograstim – LENO or filgrastim – FIL) as primary prophylaxis of chemotherapy-induced neutropenia in a hematological inpatient setting. Methods: The primary endpoints of the analysis were the efficacy of the two G-CSFs in terms of the level of white blood cells, hemoglobin and platelets at the end of the treatment and the per capita direct medical costs related to G-CSF prophylaxis. Results: Two hundred twelve patients (96 LENO, 116 FIL) have been evaluated. The following statistically significant differences have been observed between FIL and LENO: the use of a higher number of vials (11 vs 7; PP=0.031) and an increased number of days of hospitalization (8 vs 5; P Conclusion: The use of LENO has been associated with a lower number of days of hospitalization, number of vials and less incidence of grade 3–4 neutropenia at the time of G-CSF discontinuation. LENO seems to be cost-saving when compared with FIL (–15.2%).

Background: The efficacy of umbilical cord blood transplantation (UCBT) as treatment for acute myeloid leukaemia (AML) relies on immune‐mediated graft‐versus‐leukaemia effects. Previous studies have suggested a strong association between graft‐versus‐host disease (GVHD) occurrence and graft‐versus‐leukaemia effects after allogeneic hematopoietic cell transplantation.Methods: Here, we evaluated the kinetics of relapse rate in correlation with GVHD occurrence after UCBT. The kinetics of relapse rate over time in correlation to GVHD occurrence were assessed by calculating the relapse rate per patient‐year within sequential 90‐day intervals. The impact of GVHD on relapse and mortality was further studied in multivariate Cox models handling GVHD as a time‐dependent covariate.Results: The study included data from 1068 patients given single (n = 567) or double (n = 501) UCBT. The proportion of patients with grade II, III and IV acute GVHD was 20%, 7% and 4%, respectively. At 2 years, the cumulative incidence of chronic GVHD was 42%, the cumulative incidence of relapse was 32%, and overall survival was 32% as well. Relapse rates declined gradually over time during the first 30 months after transplantation. There was a possible suggestion that grade II–IV acute (HR = 0.8, P = 0.1) and chronic (HR = 0.65, P = 0.1) GVHD decreased relapse risk. However, grade II–IV acute GVHD significantly increased early (the first 18 months after UCBT) mortality (HR = 1.3, P = 0.02), whilst chronic GVHD increased each early (HR = 2.7, P < 0.001) and late (HR = 4.9, P < 0.001) mortality after UCBT.Conclusions: The occurrence of grade II–IV acute or chronic GVHD each increases overall mortality after UCBT for AML mitigating the possible graft‐versus‐leukemia effect of GVHD.