Second primary malignancy in myelofibrosis patients treated with ruxolitinib.

Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non-melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real-world context. Median follow-up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22-4·60, P = 0·01] and thrombocytosis> 400 × 109 /l at RUX start (HR:1·98, 95%CI: 1·10-4·60, P = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24-7·92, P = 0·02) and duration of hydroxycarbamide and RUX therapy > 5 years (HR: 3·20, 95%CI: 1·17-8·75, P = 0·02 and HR: 2·93, 95%CI: 1·39-6·17, P = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11-5·25, P = 0·03), platelet > 400 × 109 /l (HR: 3·30, 95%CI: 1·67-6·50, P = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48-8·14, P = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.

In vitro assessment of skin irritation potential of surfactant-based formulations by using a 3-D skin reconstructed tissue model and cytokine response.

The personal care industry is focused on developing safe, more efficacious, and increasingly milder products, that are routinely undergoing preclinical and clinical testing before becoming available for consumer use on skin. In vitro systems based on skin reconstructed equivalents are now established for the preclinical assessment of product irritation potential and as alternative testing methods to the classic Draize rabbit skin irritation test. We have used the 3-D EpiDerm™ model system to evaluate tissue viability and primary cytokine interleukin-1α release as a way to evaluate the potential dermal irritation of 224 non-ionic, amphoteric and/or anionic surfactant-containing formulations, or individual raw materials. As part of our testing programme, two representative benchmark materials with known clinical skin irritation potential were qualified through repeated testing, for use as references for the skin irritation evaluation of formulations containing new surfactant ingredients. We have established a correlation between the in vitro screening approach and clinical testing, and are continually expanding our database to enhance this correlation. This testing programme integrates the efforts of global manufacturers of personal care products that focus on the development of increasingly milder formulations to be applied to the skin, without the use of animal testing.

A study of the distribution of polymer/surfactant coacervate between solution and foam in archetypal shampoo systems.

The research reported here attempted to answer the question, "is the foam important in delivering coacervates from shampoos." In order to answer this question, we have measured the amount of polymer in the foam and in the liquid phases of several cationic polymer/anionic surfactant systems by gravimetry and by FTIR techniques. In all cases studied, we discovered that the concentration of solids and, especially the polymer, in the liquid phase and in the foam phase were essentially the same. We conclude that the foam is unlikely to be an important factor in the topical delivery of polymer/surfactant coacervates.

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

BACKGROUND: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong. METHODS: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR3.0 ) and to improve Health Related Quality of Life (HRQoL). RESULTS: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR3.0 /MR4.0 completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR3.0 was 81% and 23.5% of the patients who lost the molecular response regained the MR3.0 after resuming TKI continuously. Patients' HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001). CONCLUSIONS: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR3.0 /MR4.0 in 81% of the patients during the first 12-24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR3.0 regained the MR3.0 and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.

Case Report: Late Onset of Myelodysplastic Syndrome From Donor Progenitor Cells After Allogeneic Stem Cell Transplantation. Which Lessons Can We Draw From the Reported Case?

BACKGROUND: Myelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an in vivo model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes. CASE PRESENTATION: We report a case of DC-MDS diagnosed 5 years after an allo-SCT from a matched related donor (patient's sister) in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). The sex-mismatch allowed us to identify the donor cell origin. At the onset, the DC-MDS was characterized by chromosome seven monosomy and NRAS, RUNX1, and BCOR mutations. Because of a familiar history of colorectal neoplasia and the variant allele frequency (VAF) of NRAS mutation at the onset, this mutation was searched on germline DNA in both the donor and the recipient, but the result was negative. Moreover, after transplant (+4 months), the patient developed severe and long-lasting chronic graft-versus-host disease (cGVHD), requiring multiple lines of treatments. Because of the severe immunosuppression, recurrent infections occurred and, lately, the patient died due to septic shock. CONCLUSION: This case report highlights the need, whenever possible, to evaluate the donor origin of the posttransplant myelodysplasia and acute leukemias. The potential key role of the impaired immune surveillance and of long-lasting immunosuppression appears to be emerging in the development of this case of DC-MDS. Finally, this case reminds the importance to investigate the familiar genetic predisposition in donors with a familiar history of neoplasia.

RT-qPCR versus Digital PCR: How Do They Impact Differently on Clinical Management of Chronic Myeloid Leukemia Patients?

Real-time quantitative PCR (RT-qPCR) is the gold standard to quantify the BCR-ABL1 transcript for molecular response monitoring in chronic myeloid leukemia (CML) patients, and it plays a pivotal role in clinical decision-making process, even if it presents technical limits. Increasing data suggest that digital PCR (dPCR) is more accurate and reliable than RT-qPCR in CML minimal residual disease monitoring and in patients' selection for treatment discontinuation. But what about the identification of treatment discontinuation failures? We present the case of a CML patient enrolled both in a study aiming to comparatively assess molecular response by RT-qPCR and dPCR and in the progressive arm of the OPTkIMA trial. This is a phase III trial including CML patients randomized to receive a fixed versus a progressive intermittent tyrosine kinase inhibitor regimen. At 24 months, because of two consecutive detections of MR2.0 by RT-qPCR, the patient resumed daily treatment. Conversely, dPCR revealed a stability of molecular response and even a slight decreasing of transcript over time. An additional specimen was sampled one month after the first MR2.0 detection because of clinical decision: RT-qPCR resulted MR3.0 and dPCR confirmed the transcript's stability. Nowadays, the resumption of therapy is RT-qPCR-driven despite its limits in detection and robustness. In this case, according to dPCR, the patient could have continued intermittent treatment and the stability of response was then confirmed by RT-qPCR. So, dPCR could be able to better identify peculiar clinical response to therapy.

Multidimensional geriatric assessment for elderly hematological patients (≥60 years) submitted to allogeneic stem cell transplantation. A French-Italian 10-year experience on 228 patients.

Nowadays, the evaluation of elderly patients' eligibility for allogeneic stem cell transplantation (allo-SCT) is crucial. We evaluated the feasibility and efficacy of a multidimensional geriatric assessment, the Fondazione Italiana Linfomi (FIL) score, on a cohort of 228 patients older than 60 years submitted to allo-SCT in Italy and France from 2008 to 2018. Based on FIL score, available in 215 patients, 125 (58%) patients were classified as "fit" and 90 as "unfit/frail." The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was measured in 222 patients (97%); 71 (32%) patients had HCT-CI 0, 75 (34%) patients scored 1-2, and 76 (34%) ≥3. A total of 121 (53%) patients died after a median follow-up of 36 months. FIL score was found to highly predict survival, due to an excess of NRM in unfit/frail group, and confirmed its independent prognostic role on OS (HR: 0.37; 95% CI: 0.25-0.55; p < 0.0001). On the contrary, the HCI-CI failed in allo-SCT outcome prediction (HR: 1.06; 95% CI: 0.96-1.16; p = 0.27). In summary, a comprehensive geriatric assessment with FIL score seems to add significant prognostic information in elderly patients submitted to allo-SCT. The pretransplant adoption of this easy-to-use tool could help the patients' selection and management.

Advances in CMV Management: A Single Center Real-Life Experience.

CMV infection is a major challenge in allogeneic stem cell transplantation (allo-SCT). The changing landscape in CMV management includes the introduction of letermovir in prophylaxis of high-risk patients and the source of CMV DNA monitoring (plasma-PL vs. whole blood-WB), for pre-emptive therapy (PET) initiation. We report here how our real-life experience in CMV management evolved, following letermovir registration. We focus on: (i) the effects of systematic use of letermovir for CMV prophylaxis in high-risk patients, (ii) the results of a longitudinal comparison of CMV DNAemia monitoring in PL and WB. From December 2018 to April 2020, 60 allo-SCTs have been performed in our center (LET ERA), of whom 45 received letermovir in prophylaxis from day 0 to day + 100, because of recipient positivity of anti CMV IgG. These patients were compared with a cohort of 41 allo-SCTs performed between November 2017 and November 2018 (NO LET ERA). Firstly, the incidence of CMV clinically significant infections, CMV disease, bacterial infections, proven/probable fungal infections, hospital re-admissions after allo-SCT by day + 100 in the two ERA were 8 vs. 44% (p = 0.0006), 2 vs. 12% (p = 0.02), 37 vs. 56% (p = 0.05), 8 vs. 19% (p = 0.09), and 23 vs. 39% (p = 0.09), respectively. By day + 180 these differences were 17 vs. 68% (p < 0.00001), 2 vs. 12% (p = 0.02), 45 vs. 78% (p = 0.09), 8 vs. 22% (p = 0.05), and 40 vs. 66% (p = 0.01), respectively. Secondly, from February to May 2019, we comparatively measured CMV DNA from WB and PL and we confirmed that there is a linear correlation between CMV DNA level in WB and PL (Spearman's test r = 0.86). Moreover, CMV DNAemia at the time of PET in the 12 patients with a clinically significant CMV infection was higher in WB vs. PL (5.202 vs. 4.981 copies/ml, p = 0.1). Our real-life experience confirms that: (i) letermovir is highly effective, leading to a significant drop in CMV clinically significant infections and CMV-related complications by day + 100 and + 180 after allo-SCT; (ii) WB may be an effective alternative to PL as a source for CMV DNA monitoring, as a linear correlation of DNAemia was confirmed between WB and PL, even if the CMV DNAemia at PET initiation was comparable in the two sources.

Feasibility of tumor­derived exosome enrichment in the onco­hematology leukemic model of chronic myeloid leukemia.

Due to the discovery of their role in intra­cellular communications, exosomes, which carry information specific to the cell of origin, have garnered considerable attention in cancer research. Moreover, there is evidence to suggest the possibility of isolating different exosome sub­populations based on target antigens at the cell surface. Philadelphia chromosome­positive (Ph+) chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the breakpoint cluster region­proto­oncogene 1 tyrosine­protein kinase (BCR­ABL1) fusion­gene, derived from the t (9;22) translocation. Tyrosine kinase inhibitors (TKIs) target BCR­ABL1 protein and induce major or deep molecular responses in the majority of patients. Despite the fact that several studies have demonstrated the persistence of leukemic cells in the bone marrow niche, even following treatment, TKIs prolong patient survival time and facilitate treatment­free remission. These characteristics render CML a plausible model for investigating the feasibility of tumor­derived exosome fraction enrichment. In the present study, patients in the chronic phase (CP) of CML were treated with TKIs, and the quantification of the BCR­ABL1 exosomal transcript was performed using digital PCR (dPCR). The possibility of tumor­derived exosomes enrichment was confirmed, and for the first time, to the best of our knowledge, the detection of the BCR­ABL1 transcript highlighted the presence of active leukemic cells in patients with CP­CML. According to these findings, tumor­derived exosomes may be considered a novel tool for the identification of active leukemic cells, and for the assessment of innovative monitoring focused on the biological functions of exosomes in CML.

CMV Management with Specific Immunoglobulins: A Multicentric Retrospective Analysis on 92 Allotransplanted Patients.

CMV represents one of the most severe life-threatening complications of allogeneic stem cell transplantation (allo-SCT). Pre-emptive treatment is highly effective, but toxicity and repetitive reactivation of CMV represent a significant challenge in the clinical practice. The use of anti-CMV specific immunoglobulins (Megalotect) is controversial. We retrospectively collected data on 92 patients submitted to allo-SCT for hematological malignancies, in whom Megalotect was used either for prophylaxis (n=14) or with pre-emptive therapy, together with an anti-CMV specific drug (n=78). All the patients were considered at high-risk, due to the presence of at least one risk factor for CMV reactivation. The treatment was well tolerated, with no reported infusion reactions, nor other adverse events, none of the 14 cases treated with Megalotect as prophylaxis developed CMV reactivation. 51/78 (65%) patients who received Megalotect during pre-emptive treatment achieved complete clearance of CMV viremia, and 14/51 patients (29%) developed a breakthrough CMV infection. 7/78 patients (9%) developed CMV disease. The projected 1-year OS, 1-year TRM, and 1-year RR is 74%, 15%, and 19%, respectively. No differences were observed in terms of OS, TRM, and RR by comparing patients who achieved a complete response after treatment versus those who did not. These retrospective data suggest that Megalotect is safe and well-tolerated. When used as prophylaxis, no CMV reactivation was recorded. Further prospective trials are warranted to identify the best set of patients who can benefit from Megalotect alone or in addition to anti-CMV specific drugs.