Over half of chronic myeloid leukemia (CML) patients in deep molecular response do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in clinical trials, but its applicability in the real-life setting remains unsettled. We describe the outcomes after TKI discontinuation in a nationwide series of 236 CML patients. Median follow-up from treatment discontinuation was 21.5 months and 5 patients died from CML-unrelated causes. TKI therapy was reinitiated due to MMR loss (n = 52), increase ≥ 1 log in BCR-ABL transcript level without losing MMR (n = 12), patient preference (n = 2), and withdrawal syndrome (n = 1). Treatment-free remission rate at 4 years was 64% (95% confidence interval, CI: 55%–72%). Cumulative incidence of molecular recurrence at 3 years was 33% (95% CI: 26%–38%). TKI treatment for < 5 years and MR4.5 duration shorter than 4 years were both associated with higher incidence of molecular recurrence. No patient had disease progression. Response status at last control was: MR4.5 (n = 196), MR4 (n = 15), MMR (n = 14), complete cytogenetic response (n = 10), and other (n = 1). A significant increase in Hb and cholesterol levels was observed after imatinib withdrawal. Our results demonstrate that TKI treatment discontinuation is feasible in real-life clinical practice.

Multiple myeloma is a heterogeneous disease with variable survival; this variability cannot be fully explained by the current systems of risk stratification. Early mortality remains a serious obstacle to further improve the trend toward increased survival demonstrated in recent years. However, the definition of early mortality is not standardized yet. Importantly, no study has focused on the impact of comorbidity on early mortality in multiple myeloma to date. Therefore, we analyzed the role of baseline comorbidity in a large populationbased cohort of 621 real-life myeloma patients over a 31-year period. To evaluate early mortality, a sequential multivariate regression model at 2, 6, and 12 months from diagnosis was performed. It was demonstrated that comorbidity had an independent impact on early mortality, which is differential and time-dependent. Besides renal failure, respiratory disease at 2 months, liver disease at 6 months, and hepatitis virus C infection at 12 months, were, respectively, associated with early mortality, adjusting for other well-established prognostic factors. On the other hand, the long-term monitoring in our study points out a modest downward trend in early mortality over time. This is the first single institution population-based study aiming to assess the impact of comorbidity on early mortality in multiple myeloma. It is suggested that early mortality should be analyzed at three key time points (2, 6, and 12 months), in order to allow comparisons between studies. Comorbidity plays a critical role in the outcome of myeloma patients in terms of early mortality.Am. J. Hematol. 91:700-704,

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We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p=0.042) with an increase in BMD (p<0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long-term therapy in mild to moderate naïve and ERT stabilized patients. No unexpected safety signals were identified during 12-years follow-up.

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In the latest recommendations for the management of chronic-phase chronic myeloid leukemia suboptimal responses have been reclassified as "warning responses." In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first-line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty-six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression-free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P 5 0.002); as well as the probability of achieving a deep molecular responses (MR 4.5 ): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P 5 <0.001) .The treatment change to 2GTKI remained safe; however, we have observed a 19% of treatment discontinuation due to side effects. We have observed an improvement of molecular responses after changing treatment to 2GTKI in patients with late suboptimal response treated with imatinib first line. However, these benefits were not correlated with an improvement of progression free survival or overall survival.Am. J. Hematol. 89:E206-E211,

In chronic myeloid leukemia (CML) patients, 3-month BCR-ABL1 levels have consistently been correlated with further outcomes. Monitoring molecular responses in CML using the GeneXpert (Cepheid) platform has shown an optimal correlation with standardized RQ-PCR (IS) when measuring BCR-ABL1 levels lower than 10%, as it is not accurate for values over 10%. The aim of the present study was to determine the predictive molecular value at three months on different outcome variables using the Xpert BCR-ABL1 MonitorTM assay (Xpert BCR-ABL1). We monitored 125 newly diagnosed consecutive CML patients in the chronic phase (CML-CP) using an automated method: Xpert BCR-ABL1. Only 5% of patients did not achieve an optimal response at 3 months, and the 10% BCR-ABL1 cutoff defined by RQ-PCR (IS) methods was unable to identify significant differences in the probabilities of achieving a complete cytogenetic response (CCyR) (50% vs. 87%, p = 0.1) or a major molecular response (MMR) (60% vs. 80%, p = 0.29) by 12 months. In contrast, a cutoff of 1.5% more accurately identified differences in the probabilities of achieving CCyR (98% vs. 54%, p<0.001) and MMR (88% vs. 56%, p<0.001) by 12 months, as well as probabilities of treatment changes (p = 0.005). Therefore, when using the Xpert BCR-ABL1 assay, a cutoff of 1.5% at 3 months could with high probability identify patients able to achieve an optimal response at 12 months.

performance status score, the presence of high-risk cytogenetic abnormalities by FISH including IgH translocations such as t(4;14) or t(14;16), del17p or abnormalities of chromosome 1, and ISS. Renal function was assessed by serum creatinine (sCr, mg/dL) and the estimated glomerular filtration rate (eGFR) according to the MDRD (modification of diet in renal disease) formula. Other variables of increasing interest were also included, such as the body mass index (BMI), the occurrence of weight loss before diagnosis, the delay in diagnosis (time from the first MM-related event to the bone marrow examination) as well as the therapeutic delay (time from bone marrow examination to date of initial treatment), the serum free light chain involved/uninvolved ratio (FLCr i/u), lactate dehydrogenase (LDH), C reactive protein, and the percentage of bone marrow plasma cell (BMPC) as measured by morphology. Patients were treated with conventional chemotherapy until 2006, when we started to use a bortezomib-based induction approach. ASCT has been used since 1995. Median overall survival (OS) was calculated in months (m) from the date of diagnosis (first bone marrow aspirate or biopsy) until