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Background: We retrospectively analysed relapsed/refractory MM (RRMM) patients treated with pomalidomide and dexamethasone (PomaD) either in real life, or previously enrolled in an interventional (STRATUS, MM-010) or currently enrolled in an observational study (MM-015) to provide further insights on safety and tolerability and clinical efficacy. Methods: Between July 2013 and July 2018, 76 RRMM patients (including 33 double refractory MM) received pomalidomide 4 mg daily given orally on days 1–21 of each 28-day cycle, and dexamethasone 40 mg weekly (≤75 years) or 20 mg weekly for patients aged > 75 years. In nine patients a third agent was added to increase the response: Cyclophosphamide (in two fit patients) or clarithromycin (in seven frail patients). Patients received subcutaneous filgrastim as part of the prophylaxis regimen for neutropenia. Results: A median number of six (range 2–21) PomaD cycles were given. The regimen was well tolerated with grade 3–4 haematological and non-haematological adverse events in 39 (51%) and 25 (33%) patients, respectively. In patients who developed serious AE, pomalidomide dose reduction (11%, 14%) or definitive discontinuation (18%, 23%) were applied. All patients have been evaluated for response within the first two cycles. The disease control rate (DCR), i.e., those patients that had a response equal or better than stable disease (≥ SD), was high (89%), with 44% overall response rate (ORR) after six cycles. The achieved best responses were complete remission (CR, 5%), very good partial remission (VGPR, 4%), partial remission (PR, 35%), minimal response (MR, 7%), and stable disease (SD, 38%). After a median follow up of 19.6 months, median progression free survival was 9.4 months, and overall survival (OS) was 19.02 months. Univariate analysis showed that double refractory patients, or who received more than three previous lines had shorter PFS. At 18 months, regardless of the depth of response, patients with a disease control of at least six months, defined as maintenance of a best clinical and/or biochemical response to treatment for almost six months, had prolonged PFS (35.3% versus 20.6%, p = 0.0003) and OS (81.2% versus 15.9%, p < 0.0001) Conclusions: Our findings indicate that PomaD is a safe and well-tolerated regimen in real-life, associated with prolonged PFS and OS with acceptable toxicity. Moreover, Pd induced disease control in most intensively pre-treated patients and some of them achieved longer PFS than that obtained with the previous treatment.

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Background: Isavuconazole is an effective treatment of invasive fungal infections (IFI). Since its broad spectrum of activity and favorable toxicity, it could also be used as a prophylaxis. Experience in use of isavuconazole as prophylaxis of IFI is, however, limited. In allogeneic transplant setting, its feasibility should also be assessed in regard of changes of Cyclosporine (CYA) metabolism. Aim: To evaluate feasibility of the administration of Isavuconazole as short term prophylaxis during early phase of allogeneic transplantation and to study its influence on CYA trough blood levels and CYA dosing. Methods: In a prospective study from July 2017 to April 2019, we treated 34 HSC transplantation using Isavuconazole (ISA) prophylaxis, ISA was administered at dosage of 200 mg /day i.v. (with a loading-dose of 200 mg x 3 /days for the first 48 hours) from day + 2 after HSCT infusion and until day + 30. The patients were selected using the criteria: any underlying diagnosis; age 18-70; any type of allogeneic donor; GVHD prophylaxis including CYA i.v.. Blood trough levels of CYA were measured bi-weekly by ELISA. Blood CYA level was maintained between 100 - 300 mcg/ml by dose adjustment. The need for CYA dose modification, IFI rate and patient outcome (TRM, OS) was studied and compared to an historical control group who received prophylaxis using Fluconazole during day +2 to day +30 (n 29). Results: Groups receiving Isavuconazole or Fluconazole were not significanly different in diagnosis, age, sex, disease status at transplant, donor type, stem cell-source, GVHD-prophylaxis and conditioning regimen. No patients in the Fluco-group had a previous invasive fungal infection (IFI), while 2 patients had a previously IFI in the Isa-group. All patients reached engraftment, neutrophils engraftment was reached in a mean of 19 days and 18 days in the Isa and Fluco-group, respectively. No IFI occurred in the fluco-group, while 1 proven IFI (Blastoschyzomyces Capitatus blood-stream infection) occurred in the Isa-group. Mucositis occurred in 56 patients (88%). Mucositis grade III-IV grade of was registered in 62% and 61%, in the Isa- and Fluco-Group respectively. Isavuconazole was well tolerated, without significant toxicity, no patient needed dose-reduction or suspension. Mean values of trough CyA blood-levels were compared at for 1st, 2nd, 3rd and 4th week and no difference was found between the two groups (Mann Whitney U test p value: 0.2, 0.5, 0.8, 0.9 respectively for 1st, 2nd, 3rd and 4th week), Fig 1. Mean number of CYA-dose adjustments was 1.3 /patient in Isa-group and 1.2/patient in Fluco-group. Difference was not significant (p = 0.6, Mann-Whitney U-test). Overall survival (OS) at 1 year was 64 % in Fluco-group (95% CI: 44-79%) and 66% in Isa-group (95% CI: 44-81%) (log-rank, p value: 0.9). Non-relapse mortality (NRM) at 1 year was 16.3% (95% CI: 5.7-31%) in Isa-group and 14.2% (95% CI:4.3-29%) in Fluco-group (Gray test, p: 0.61). Conclusions: In this prospective study, short term prophylaxis using Isavuconazole, after allogeneic HSC transplant, was found to be feasible. No significant difference with standard fluconazole prophylaxis was found in trough CYA blood levels and in the need of cyclosporin dose modification. Further studies are needed extending the lenght of Isavuconazole prophylaxis. Figure 1 Disclosures No relevant conflicts of interest to declare.

Based on the results obtained in clinical trials, the use of the combination of lenalidomide and dexamethasone (Len/Dex) has become a potential therapeutic choice for newly diagnosed multiple myeloma (NDMM) ineligible for autologous stem cell transplantation. This study evaluated 89 frail NDMM patients treated with first-line oral association. At the last follow-up, 34 out of 89 patients (38.2%) were alive, and 22 were still in treatment with Len/Dex. Among 73 evaluable patients who received at least two cycles, the overall response rate was 71% (N = 52). The disease control rate, defined as any level of clinical response to therapy, occurred in 71 patients (97%). We reported one or more adverse events of grade 3 or 4 (G3/4) in 65.2% (N = 58) of patients, with a prevalence of hematological toxicity (24 patients), leading to an overall discontinuation of treatment in two cases. In univariate analysis, high ISS, high serum β2-microglobulin, and creatinine clearance <30 mL/min negatively impact OS, while the depth of response positively impacts OS. Moreover, G3-4 anemia, ISS, frailty score, and ECOG negatively impacts PFS. In conclusion, elderly and more frail patients benefit from the Len/Dex combination also in the era of monoclonal antibodies, ensuring an increased PFS and OS in patients where the therapeutic choice is often limited and usually not very effective.

The recent advances in cytogenetic and molecular diagnostic techniques has provided a better understanding of biology of CLL and a better prediction of disease progression and refractoriness but they are not easily accessible to all Institutions. CLL cells depend on microenvironmental interactions for proliferation and survival that are at least partially mediated through B cell receptor (BCR) signaling. An increased number of studies describe the emerging role of neutrophils and monocytes as mediators of the inflammation process and antitumor immunity modulation that support tumorigenesis and tumor progression. The neutrophil to lymphocyte ratio (NLR), has been recently published as new marker of systemic inflammation associated with outcome in different cancer types. In our study we retrospectively evaluated the prognostic significance of peripheral blood neutrophils, monocytes and non-neoplastic lymphocytes in a unicentric, unselected, CLL cohort of 400 CLL patients (160 were treated). The study was approved by the institutional board review;informed consent was obtained from patients. Using the blood count and the Flow cytometric analysis reports, peripheral blood absolute neutrophil count (ANC), absolute monocyte count (AMC) and absolute T-lymphocyte count (ALC-CD3+) were evaluated and the neutrophil to T-lymphocyte ratio (NLR), the monocyte to T-lymphocyte ratio (MLR) and the neutrophil to monocyte ratio (NMR) were calculated. Clinical and biological data from all patients were also retrieved. Serial count and ratio were evaluated at diagnosis, during follow up and at relapse to make a better comparison with the major clinical and prognostic markers commonly used. The median ratio for NLR 2.67 and patients with pre-treatment NLR > 3 had a shorter time from diagnosis to treatment initiation. CLL patients showed an increase in the absolute number of monocytes compared to normal controls (788±65 cells/μL vs 469±51 cells/μL, p=0.005) and MLR appeared higher in advanced stage (stage Binet C) and bulky disease (p=0.06). High level of both NLR and MLR (cut off >3) correlated with the presence of a complex karyotype detected by FISH (p=0.03, p=0.016). NLR ratio was associated with the absence of serum prognostic markers, such as the expression of CD38, ZAP-70 and CD49d. This result, apparently conflicting, could strengthen the NLR as an independent prognostic factor. NMR was higher in asymptomatic patients (absence vs. presence of B symptoms, p=0.02) and this data resulted independent from disease stage. NMR median value was significantly higher in untreated patients than in patients who received treatment (p=0.01), strengthening the hypothesis that this ratio is associated with a more indolent form of disease. In this contest, the subset of patients with CD49d positive disease showed the lowest NMR value. This data seems of relevance, being CD49d a recently discovered and validated prognostic marker. ANC/ALC and AMC/ALC ratio significantly increased at relapse compare to baseline (NLR average onset 2.3±0.4 vs 3.4±0.6 at relapse). The median NMR value showed conversely the opposite trend: NMR is reduced in first relapse (NMR average onset 7.2±0.4 vs. 5.4±0.5 at relapse). These combined ratios reflect both the inflammatory status, the immune response and the microenviromental network that contribute to aggressive tumor biology and disease progression. They are simple, cheap, easily measured and reproducible and can be integrated into daily clinical practice as new prognostic markers for CLL. Disclosures Chiarenza: Gilead: Consultancy; Janssen: Consultancy; Roche: Consultancy.

Patients who experience extramedullary relapses (EMR) of multiple myeloma (MM) have an adverse prognosis, also in this era of novel agents like proteasome inhibitors and immunomodulatory drugs. We describe the case of an MM patient with EMR at 2 different sites after allogeneic stem cell transplantation. EMR was refractory to bortezomib, anthracycline, and bendamustine, but the patient achieved long-term complete remission (4 years) with pomalidomide and dexamethasone. This supports the hypothesis that this could be due to the graft-versus-myeloma effect during therapy enhanced by pomalidomide.