A real-world retrospective-prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience.

INTRODUCTION: Ixazomib, lenalidomide, and dexamethasone (IRd) have been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) based on the results of the TOURMALINE-MM1. OBJECTIVES AND METHODS: We conducted a retrospective-prospective analysis of 106 RRMM patients (pts) treated with IRd in 21 centers in Northern Italy, with the aim to evaluate the efficacy and safety of IRd in real life. RESULTS: At IRd initiation, 34% of pts were aged ≥75 (median 72.5), 8.5% had an ECOG performance status ≥2, 54.7% of evaluable pts carried high-risk cytogenetic abnormalities [del17p and/or t(4;14) and/or t(14;16) and/or 1 g gain/amp], 60.2% had received ≥2 prior lines of therapy (pLoT), 57.5% were lenalidomide (Len)-exposed (including both Len-sensitive and Len-refractory pts), and 22% were Len-refractory. Main G ≥3 adverse events (AEs) were thrombocytopenia (16%) and neutropenia (12.3%). G ≥3 non-hematologic AEs included infections (9.4%) and GI toxicity (diarrhea 5.7%, hepatotoxicity 2.8%), VTE, skin rash, and peripheral neuropathy were mainly G1-2. The overall response rate was 56.4% (≥VGPR 30%). With a median follow-up of 38 m, median PFS (mPFS) was 16 m and the 1-year OS rate was 73%. By subgroup analysis, an extended PFS was observed for pts achieving ≥VGPR (mPFS 21.2 m), time from diagnosis to IRd ≥5 years (26.2 m), 1 pLoT (34.4 m), Len-naïve (NR), age ≥70 (20 m). In pts exposed to Len, non-refractory in any prior line and immediately prior to IRd, mPFS was 16 and 18 m, respectively. An inferior PFS was seen in Len-refractory pts (4.6 m). By multivariate analysis, independent predictors of PFS were age ≥70 (HR 0.6), time from diagnosis ≥5 years (HR 0.32), refractoriness to Len in any prior line (HR 3.33), and immediately prior (HR 4.31). CONCLUSION: IRd might be effective and safe in RRMM pts with an indolent disease, in early lines of treatment, and who proved Len-sensitive, independent of age, and cytogenetic risk.

Co-administration of proton pump inhibitors and/or of steroids may be a risk factor for low trough concentrations of posaconazole delayed-released tablets in adult patients with haematological malignancies.

AIMS: The aim of this study was to determine clinical variables associated with posaconazole exposure among adult patients with haematological malignancies who received posaconazole tablets for prophylaxis of invasive fungal infections (IFIs). METHODS: The study population included adult patients with haematological malignancies who received posaconazole delayed-release tablets for prophylaxis of IFIs after induction chemotherapy for acute leukaemia or graft-versus-host-disease (GVHD) complicating hematopoietic stem cell transplantation (HSCT) in the period January 2016-December 2017. RESULTS: Sixty-six consecutive patients with 176 posaconazole Cmin were included for evaluation in the study. Subtherapeutic posaconazole concentrations (< 0.7 mg l-1 ) were observed at least once in 33.3% of patients (22/66), and overall in 17.0% of therapeutic drug monitoring (TDM) episodes (30/176). At multilevel linear regression, use of PPIs (P = 0.008), use of intermediate or high dose steroids (>0.7 mg kg-1 daily) (P = 0.022) and male gender (P = 0.025) were significantly associated with decreased Cmin , whereas time from starting therapy (P = 0.032) was associated with increased Cmin in our patient population. CONCLUSION: Posaconazole exposure during treatment with delayed-released tablet formulation may be affected by the use of PPIs and/or of intermediate or high dose steroids.

High prognostic value of pre-allogeneic stem cell transplantation minimal residual disease detection by WT1 gene expression in AML transplanted in cytologic complete remission.

We analyzed the outcome of allogeneic stem cell transplantation (allo-SCT) in acute myeloid leukemia (AML) patients according to molecular Minimal Residual Disease (MRD) status prior to allo-SCT. MRD was assessed by the quantitative expression of the pan-leukemic marker Wilms' tumor (WT1) gene, according to the validated LeukemiaNet method. Between 2005 and 2016, 122 consecutive AML patients, WT1 positive at diagnosis, received allo-SCT in cytologic complete remission (cCR). The median age at SCT was 53 years (range 18-70). Quantitative analysis of WT1 gene expression (bone marrow samples) was available in all cases both at diagnosis (100% of samples overexpressed WT1 with a mean of 8607±8187 copies/104 Abelson) and immediately before allo-SCT. Eighty one cases (66%) were MRD-WT1 negative (WT1 <250 copies) and 41/122 (44%) cases were MRD-WT1 positive (WT1 >250 copies) prior to allo-SCT. We evaluated post-SCT overall survival (OS), disease free survival (DFS) and relapse rate (RR), according to MRD-WT1 status pre-SCT. Both post-allo-SCT OS and DFS were significantly improved in patients who were MRD-WT1 negative at the time of SCT compared with those who were MRD-WT1 positive, with a median OS and DFS not reached in the MRD-WT1 negative group and 9 and 8 months, respectively, in the WT1 positive group (OS log-rank p<0.0001; hazard ratio [HR] 3.9, 95% confidence interval [95% CI] 2.0-7.38; DFS log-rank p<0.0001; HR 3.73, 95% CI 2.0-6.72). The RR after SCT was 15% (12/81) in pre-SCT MRD-WT1 negative cases and 44% (18/41) in MRD-WT1 positive cases (p=0.00073). Univariate analysis showed that MRD-WT1 negativity pre-SCT and grade <2 acute GVHD were significant prognostic factors for improved OS and DFS. However multivariate analysis showed MRD-WT1 negativity pre-SCT was the only independent prognostic factor for improved OS and DFS. These data show that pre allo-SCT molecular MRD evaluation using WT1 expression is a powerful predictor of post allo-SCT outcomes in AML undergoing SCT in cCR. Patients with both cCR and MRD-WT1 negativity before SCT have a very good outcome with lower RR and improved OS. The pre allo-SCT MRD-WT1 stratification in AML is a valuable tool to identify patients at high risk of post-SCT relapse, and can influence conditioning regimen intensification and/or post-SCT preemptive strategies.

Graves' Disease Thyrotoxicosis and Propylthiouracil Related Agranulocytosis Successfully Treated with Therapeutic Plasma Exchange and G-CSF Followed by Total Thyroidectomy.

Antithyroid drugs can be a rare cause of agranulocytosis (0.5% of treated patients). Suspension of these drugs is mandatory in these patients and may result in worsening hyperthyroidism. We report the case of a 27-year-old woman who is 3 months post-partum, breastfeeding, and suffering with Graves' disease hyperthyroidism treated first with methimazole and then with propylthiouracil due to a methimazole allergy. She was admitted for urosepsis and agranulocytosis. The patient was diagnosed with propylthiouracil related agranulocytosis, diffuse toxic goiter and thyro-gastric syndrome. Antithyroid drug therapy was stopped resulting in a worsening of thyrotoxicosis. Agranulocytosis was treated with 8 doses of G-CSF with full recovery. To rapidly restore euthyroidism and to perform a thyroidectomy, the patient received 6 therapeutic plasma exchange (TPE) procedures, to clear thyroid hormones and anti-TSH receptor antibodies from blood, resulting in a pre-surgical euthyroid state without antithyroid drug therapy. Two years after thyroidectomy, the patient is well under thyroid hormone replacement therapy with a normal granulocyte count.