Nilotinib-induced bone marrow CD34+/lin-Ph+ cells early clearance in newly diagnosed CP-Chronic Myeloid Leukemia: Final report of the PhilosoPhi34 study.

Chronic Myeloid Leukemia is a clonal disorder characterized by the presence of the Ph-chromosome and the BCR-ABL tyrosine-kinase (TK). Target-therapy with Imatinib has greatly improved its outcome. Deeper and faster responses are reported with the second-generation TKI Nilotinib. Sustained responses may enable TKI discontinuation. However, even in a complete molecular response, some patients experience disease recurrence possibly due to persistence of quiescent leukemic CD34+/lin-Ph+ stem cells (LSCs). Degree and mechanisms of LSCs clearance during TKI treatment are not clearly established. The PhilosoPhi34 study was designed to verify the in-vivo activity and timecourse of first-line Nilotinib therapy on BM CD34+/lin-Ph+ cells clearance. Eighty-seven CP-CML patients were enrolled. BM cells were collected and tested for Ph+ residual cells, at diagnosis, 3, 6 and 12 months of treatment. FISH analysis of unstimulated CD34+/lin- cells in CCyR patients were positive in 8/65 (12.3%), 5/71 (7%), 0/69 (0%) evaluable tests, respectively. Per-Protocol analysis response rates were as follows: CCyR 95% at 12 months, MR4.5 31% and 46% at 12 and 36 months, respectively. An exploratory Gene Expression Profiling (GEP) study of CD34+/lin- cells was performed on 30 patients at diagnosis and after, on 79 patients at diagnosis vs 12 months of nilotinib treatment vs 10 healthy subjects. Data demonstrated some genes significantly different expressed: NFKBIA, many cell cycle genes, ABC transporters, JAK-STAT signaling pathway (JAK2). In addition, a correlation between different expression of some genes (JAK2, OLFM4, ICAM1, NFKBIA) among patients at diagnosis and their achievement of an early and deeper MR was observed.

Immunotherapy in Underrepresented Populations of Patients with Cancer: Do We Have Enough Evidence at Present? A Focus on Patients with Major Viral Infections and Autoimmune Disorders.

The safety and activity of immune checkpoint inhibitors have been characterized in interventional and observational studies. However, only small studies have specifically investigated these agents in patients who are excluded or underrepresented in clinical trials, frequently referred to as "special populations" or "underrepresented populations." These include older adults, those with dysregulated immune activation, patients with a compromised immune function, and those carrying major viral infections, lymphoproliferative diseases, and major organ dysfunctions. Therefore, there remains substantial uncertainty regarding the use of immune checkpoint inhibitors in these specific settings. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project, with the contribution of oncologists and other specialists, to retrieve the existing evidence on the use of immunotherapy in patients with solid and hematological cancers with the final aim to provide an expert guidance. The results of this effort are presented in this article, which is focused on patients with major viral infections or those with immune dysregulation/autoimmune diseases, and could be useful to guide decisions in clinical practice and to design prospective clinical trials focusing on the use of immunotherapy in these populations. IMPLICATIONS FOR PRACTICE: Substantial uncertainty remains regarding the use of immune checkpoint inhibitors in "underrepresented" patients, such as older adults, those with dysregulated immune activation, and patients with a compromised immune function, major viral infections, lymphoproliferative diseases or major organ dysfunctions. The Network of Italian Supportive Care in Oncology has carried out a multidisciplinary project to retrieve the existing evidence on the use of immunotherapy in underrepresented patients with cancer in order provide an expert guidance. The results of this effort, with a focus on patients with major viral infections or those with immune dysregulation/autoimmune diseases, are presented in this article and could be useful to guide decisions both in clinical practice and to design clinical trials.

Long-Term Follow-Up of a Donor versus No-Donor Comparison in Patients with Multiple Myeloma in First Relapse after Failing Autologous Transplantation.

We report the long-term clinical outcomes of a retrospective multicenter study that enrolled 169 patients with multiple myeloma (MM) in first relapse after failing autologous stem cell transplantation (SCT). After HLA typing at relapse, 79 patients with a suitable donor, 72 (91%) of whom eventually underwent salvage allogeneic SCT (allo-SCT), were compared with 90 patients without a donor who were treated with multiple lines of salvage treatment with bortezomib and/or immunomodulatory agents. At a median follow-up of 30 months (range, 2-180 months) for all patients and 110 months (range, 38-180 months) for surviving patients, 7-year progression-free survival (PFS) was 18% in the donor group and 0% in the no-donor group (hazard ratio [HR], 2.495; 95% confidence interval [CI], 1.770-3.517; P < .0001). Seven-year overall survival (OS) was 31% in the donor group and 9% in the no-donor group (HR, 1.835; 95% CI, 1.306-2.577; P < .0001). By multivariate analysis, chemosensitivity to salvage treatments and presence of a suitable donor were significantly associated with better PFS and OS. The long-term follow-up of this study confirms the significant PFS benefit and provides new evidence of an OS advantage for patients with MM who have a suitable donor and undergo allo-SCT. Allo-SCT should be considered as a treatment option in young relapsed patients with high-risk disease features after first-line treatment.

Serum thymus and activation-regulated chemokine level monitoring may predict disease relapse detected by PET scan after reduced-intensity allogeneic stem cell transplantation in patients with Hodgkin lymphoma.

Patients with relapsed and refractory Hodgkin lymphoma (HL) may experience long-term survival after allogeneic stem cell transplantation (alloSCT), but disease recurrence represents the main cause of treatment failure. Positron-emission tomography (PET)-positive patients after alloSCT have a dismal outcome. Serum thymus and activation-regulated chemokine (TARC) is produced by Reed-Sternberg cells and may be a marker of disease. Our study aimed at assessing whether TARC levels after alloSCT correlated with disease status and whether TARC monitoring could increase the ability to predict relapse. Twenty-four patients were evaluated in a prospective observational study. TARC serum level and PET were assessed before and after alloSCT during the follow-up (median, 30 months; range, 2 to 54). Before alloSCT, the median TARC level was 721 pg/mL (range, 209 to 1332) in PET-negative patients and 2542 pg/mL (range, 94 to 13,870) in PET-positive patients. After alloSCT, TARC was 620 pg/mL (range, 12 to 4333) in persistently PET-negative patients compared with 22,397 pg/mL (range, 602 to 106,578) in PET-positive patients (P < .0001). In 7 patients who relapsed after alloSCT, TARC level increased progressively even before PET became positive, with a median fold increase of 3.19 (range, 1.66 to 7.11) at relapse. The cut-off value of 1726 pg/mL had a sensitivity of 100% and a specificity of 71% for PET positivity. Patients with at least 1 TARC value above 1726 pg/mL during the first year after alloSCT had a worse progression-free survival (P = .031). In conclusion, TARC was correlated with disease status and its monitoring may be able to predict PET positivity after alloSCT, thus potentially allowing an early immune manipulation.

Impact of cytomegalovirus replication and cytomegalovirus serostatus on the outcome of patients with B cell lymphoma after allogeneic stem cell transplantation.

Cytomegalovirus (CMV) replication after allogeneic hematopoietic stem cell transplantation (HSCT) was historically associated with increased nonrelapse mortality (NRM). More recently, different groups have reported an association between CMV replication and reduced risk of acute myeloid leukemia (AML) relapse. Given the conflicting results, we evaluated the impact of CMV replication and other covariates on the outcome of a retrospective cohort of 265 adults with B cell lymphoma receiving allogeneic HSCT from HLA-identical siblings or alternative donors. In time-dependent multivariate analysis, CMV replication, evaluated by pp65 antigenemia, had no independent effect on the risk of relapse (hazard ratio [HR], 1.0; 95% confidence interval [CI], .6 to 1.6; P = .9), although it was associated with a reduced overall survival (HR, 2.0; 95% CI, 1.3 to 3.2; P = .001) and an increased NRM (HR, 2.5; 95% CI, 1.1 to 5.3; P = .01). Consistently, donor and/or recipient CMV seropositivity were not associated with a different outcome relative to CMV double-negative serostatus. In multivariate models, a diagnosis of follicular lymphoma (P < .0001) and pretransplantation complete remission status (P < .0001) were the main independent predictors for improved relapse-free survival. In summary, contrary to what is observed in patients with AML, this report identifies no independent role for CMV replication or serostatus on the relapse of patients with B cell lymphomas undergoing allogeneic HSCT.

A phase II study evaluating the efficacy of enzalutamide and the role of liquid biopsy for evaluation of ARv7 in mCRPC patients with measurable metastases including visceral disease (Excalibur study).

Background: Up to 30% of patients with metastatic castration-resistant prostate cancer (mCRPC) develop visceral metastases, which are associated with a poor prognosis. Objectives: Efficacy of enzalutamide in mCRPC patients with measurable metastases, including visceral and/or extra-regional lymph nodes. Methods: In this phase II multicenter study, patients with mCRPC and measurable metastases received enzalutamide as the first line. Primary endpoint: 3-month (mo) disease control rate (DCR) defined as the proportion of patients with complete (CR) or partial response (PR) or stable disease (SD) as per Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoint: safety. Exploratory endpoint: the association between ARv7 splicing variants in basal circulating tumor cell (CTC)-enriched blood samples and treatment response/resistance using the AdnaTest ProstateCancerSelect kit and the AdnaTest ProstateCancer Panel AR-V7. Results: From March 2017 to January 2021, 68 patients were enrolled. One patient never started treatment. Median age: 72 years. A total of 52 patients (78%) received enzalutamide as a first line for mCRPC. The median follow-up was 32 months. At the 3-month assessment, 24 patients presented an SD, 1 patient achieved a CR, and 23 patients had a PR (3-mo-DCR of 72%). Discontinuations due to adverse events (AEs), disease-related death, or disease progression occurred in 9%, 6%, and 48% of patients. All patients reported at least one grade (G) 1-2 AE: the most common were fatigue (49%) and hypertension (33%). Six G3 AEs were reported: two hypertension, one seizure, one fatigue, one diarrhea, and one headache. Basal detection of ARv7 was significantly associated with poor treatment response (p = 0.034) and a nonsignificant association (p = 0.15) was observed between ARv7 detection and response assessments. At month 3, ARv7 was detected in 57%, 25%, and 15% of patients undergoing progressive disease, SD, and PR, respectively. Conclusion: The study met its primary endpoint, showing the efficacy of enzalutamide in men with mCRPC and measurable metastatic lesions in visceral and/or lymph node sites. Trial registration: ClinicalTrials.gov Identifier: NCT03103724. First Posted: 6 April 2017. First patient enrollment: 19 April 2017.

Bortezomib plus dexamethasone followed by escalating donor lymphocyte infusions for patients with multiple myeloma relapsing or progressing after allogeneic stem cell transplantation.

Multiple myeloma relapsing after allogeneic stem cell transplantation (alloSCT) has a poor outcome. To assess the safety and efficacy of bortezomib and dexamethasone (VD) combination followed by donor lymphocyte infusions (DLIs) in myeloma patients relapsing or progressing after alloSCT, a prospective phase II study was designed. The treatment plan consisted of three VD courses followed by escalated doses of DLIs in case of response or at least stable disease. Nineteen patients were enrolled with a median age of 57 years (range, 33 to 67); 14 patients were allografted from human leukocyte antigen-identical siblings and 5 from alternative donors. Sixteen of 19 patients received the planned treatment, but 3 patients did not: 2 patients because of disease progression and 1 refused. After the VD phase the response rate was 62%, with 1 complete remission, 6 very good partial remissions, 5 partial remissions, 2 patients with stable disease, and 5 with progressive disease. After the DLI phase, the response rate was 68%, but a significant upgrade of response was observed: 3 stringent complete remissions, 2 complete remissions, 5 very good partial remissions, 1 partial remission, 4 with stable disease, and 1 with progressive disease. With a median follow-up of 40 months (range, 29 to 68), the 3-year progression-free survival and overall survival rates were 31% and 73%, respectively. Neither unexpected organ toxicities, in particular severe neuropathy, nor severe acute graft-versus-host disease flares were observed. VD-DLIs is a safe treatment for multiple myeloma patients relapsing or progressing after alloSCT and may be effective.

Long-term molecular remission with lenalidomide treatment of relapsed chronic lymphocytic leukemia.

Lenalidomide is effective against relapsed chronic lymphocytic leukemia (CLL). We report the first case of long-term molecular remission with continuous lenalidomide treatment in a young patient with CLL relapsed to multiple treatments. Minimal residual disease was assessed by nested polymerase chain reaction on bone marrow samples with patient-specific primers. A 20-yr-old patient with standard-risk CLL was treated with lenalidomide after multiple relapses and achieved a 4 yr long complete molecular response with minimal toxicities. Published biologic data support that lenalidomide induces an immune-mediated control of CLL, and our case suggests that long-term treatment with lenalidomide is effective at a molecular level in patients with relapsed CLL.

Allogeneic stem cell transplantation in multiple myeloma relapsed after autograft: a multicenter retrospective study based on donor availability.

Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians. We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including 24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42% in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS, but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS. In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT in patients with relapsed MM who have a suitable donor.

Long-term patterns of humoral and cellular response after vaccination against influenza A (H1N1) in patients with hematologic malignancies.

OBJECTIVES: The efficacy of a novel vaccine against influenza virus A (H1N1) in patients with hematologic malignancies is largely unknown. METHODS: We prospectively evaluated the humoral and cellular immune responses after one injection of monovalent adjuvanted 2009 H1N1 vaccine in 47 adults with hematologic malignancies and 77 controls by hemagglutination-inhibition assay and flow-cytometry analysis on day 0, 28, 50, and 90. RESULTS: On day 28 postvaccination, patients had lower seroprotection (95.2% vs. 75.2%, P < 0.01) and seroconversion (88.7% vs. 51.1%, P < 0.01) rates, as well as geometric mean titer (GMT; 256 vs. 134, P < 0.05), relative to controls. Response to vaccination varied according to the evaluated time point and the patient status: Patients not receiving chemotherapy had seroprotection and GMTs similar to controls in all time points, while patients receiving chemotherapy or allogeneic hematopoietic stem cell transplant (HSCT) had lower seroprotection and seroconversion levels than controls on day 28 and 50. EMEA cutoffs for efficacy were reached from day 28 by patients in follow-up or under treatment and only from day 90 by those with HSCT, especially if still under immunosuppressants. Patients treated with immunomodulatory drugs had higher antibody responses in terms of seroprotection and GMTs. T- and NK cell-mediated responses mounted from day 50 and did not differ between patients and controls. CONCLUSIONS: According to EMEA recommendation, H1N1 vaccination strategy was effective at protecting most of the hematologic patients, but needed to be improved in those more immunocompromised.

The evolving panorama of HER2-targeted treatments in metastatic urothelial cancer: A systematic review and future perspectives.

PURPOSE: HER2 alterations are potential candidates for targeted treatments in metastatic urothelial/bladder cancer (mUC). ERBB2 gene amplification and mutations are found in around 6% and 4% of mUC, respectively. METHODS: This is a systematic review of clinical trials evaluating HER2-targeting (amplification and mutations) in mUC. We assigned each study to one of the following strategies: HER2-targeting with single agents, anti-HER2 agents in combination with cytotoxic chemotherapy, dual HER2 blockade, HER2-targeted antibody-drug conjugates (ADCs), and other novel therapeutic approaches. RESULTS: 36 clinical trials (17 with results and 19 ongoing) were included. As for ERBB2 amplification, anti-HER2 single agents (5 studies) and combinations with chemotherapy (4 studies) failed to provide any benefit, whereas dual HER2 blockade through monoclonal antibodies proved active in one trial in pretreated patients. Two studies assessed single-agent targeting for ERBB2 mutations with negative results. Most promising data come from 2 studies with ADCs in ERBB2 amplified tumors (disitamab-vedotin and trastuzumab-duocarmazine), while 2 other studies with TDM-1 and ADCT-502 was discontinued due to toxicity. In this category, trastuzumab-deruxtecan and other ADCs are still under investigation for either ERBB2-amplified or mutated mUC. Novel approaches include ADCs with immunotherapy (1 study with results), CAR-T cells, and HER2-sensitising vaccines. CONCLUSIONS: ERBB2 amplification could become a novel target in mUC, although the magnitude of clinical benefit remains to be clarified. To this regard, novel ADCs are the most promising strategy. ERBB2 mutations are still at very early stage of clinical study.

Haploidentical stem cell transplantation after a reduced-intensity conditioning regimen for the treatment of advanced hematologic malignancies: posttransplantation CD8-depleted donor lymphocyte infusions contribute to improve T-cell recovery.

Haploidentical hematopoietic stem cell transplantation provides an option for patients with advanced hematologic malignancies lacking a compatible donor. In this prospective phase 1/2 trial, we evaluated the role of reduced-intensity conditioning (RIC) followed by early add-backs of CD8-depleted donor lymphocyte infusions (DLIs). The RIC regimen consisted of thiotepa, fludarabine, cyclophosphamide, and 2 Gy total body irradiation. Twenty-eight patients with advanced lymphoproliferative diseases (n = 24) or acute myeloid leukemia (n = 4) were enrolled. Ex vivo and in vivo T-cell depletion was carried out by CD34(+) cell selection and alemtuzumab treatment. The 2-year cumulative incidence of nonrelapse mortality was 26% and the 2-year overall survival (OS) was 44%, with a better outcome for patients with chemosensitive disease (OS, 75%). Overall, 54 CD8-depleted DLIs were administered to 23 patients (82%) at 3 different dose levels without loss of engraftment or acute toxicities. Overall, 6 of 23 patients (26%) developed grade II-IV graft-versus-host disease, mainly at dose level 2. In conclusion, our RIC regimen allowed a stable engraftment with a rather low nonrelapse mortality in poor-risk patients; OS is encouraging with some long-term remissions in lymphoid malignancies. CD8-depleted DLIs are feasible and promote the immune reconstitution.

The Evolutionary Landscape of Treatment for BRAFV600E Mutant Metastatic Colorectal Cancer.

The BRAFV600E mutation is found in 8-10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients.

The Quest for Improving Treatment of Cancer of Unknown Primary (CUP) Through Molecularly-Driven Treatments: A Systematic Review.

Background: Carcinomas of unknown primary (CUP) account for 3-5% of all malignancy and, despite a reduction in incidence, the overall survival has not improved over the last decade. Chemotherapy regimens have not provided encouraging results. New diagnostic technologies, such as next generation sequencing (NGS), could represent a chance to identify potentially targetable genomic alterations in order to personalize treatment of CUP and provide insights into tumor biology. Methods: A systematic review of studies of patients with CUP, whose tumor specimen was evaluated through a NGS panel, has been performed on June 10th, 2019 according to PRISMA criteria from PubMed, ASCO meeting library and Clinicaltrial.gov. We have identified potentially targetable alterations for which approved/off-label/in clinical trials drugs are available. Moreover, we have included case reports about CUP patients treated with targeted therapies driven by NGS results in order to explore the clinical role of NGS in this setting. Results: We have evaluated 15 publications of which eleven studies (9 full-text articles and 2 abstracts) have analyzed the genomic profiling of CUPs through NGS technology, with different platforms and with different patients cohorts, ranging from 16 to 1,806 patients. Among all these studies, 85% of patients demonstrated at least one molecular alteration, the most frequent involving TP53 (41.88%), KRAS (18.81%), CDKN2A (8.8%), and PIK3CA (9.3%). A mean of 47.3% of patients harbored a potentially targetable alteration for which approved/off-label/in clinical trials drugs were available. Furthermore, we have identified 4 case reports in order to evaluate the clinical relevance of a specific targeted therapy identified through NGS. Conclusions: NGS may represent a tool to improve diagnosis and treatment of CUP by identifying therapeutically actionable alterations and providing insights into tumor biology.

Environmental life cycle assessment of the recycling processes of waste plastics recovered by landfill mining.

Enhanced Landfill Mining (ELFM) is a powerful tool for the sustainable management of landfill sites, aiming at both land reclamation and material recovery/reuse. To enhance the recovery and recycling rate of excavated plastic fractions, in most cases destined to energy recovery, new convenient, effective and sustainable strategies are needed. In this study, a recovery and valorization process of ELFM excavated plastics has been validated through an integrated experimental and Life Cycle Assessment (LCA) approach, demonstrating the environmental sustainability of the secondary raw material generated, in terms of use of resources and emissions generated. In particular, the secondary granulate from ELFM was compared with a virgin product and the last one resulted to have a higher impact (more than 4.46 times greater than the first one), in particular for the use of the resource crude oil as raw material in the production of primary LDPE. The valorization process of the excavated plastic made the mechanical properties of the secondary raw material comparable to that of a primary material.

Qualitative and quantitative polymerase chain reaction monitoring of minimal residual disease in relapsed chronic lymphocytic leukemia: early assessment can predict long-term outcome after reduced intensity allogeneic transplantation.

BACKGROUND: The graft-versus-leukemia effect is able to induce clinical responses in patients with chronic lymphocytic leukemia treated with a reduced intensity conditioning regimen, followed by allogeneic stem cell transplantation. We investigated whether molecular remissions could be attained after reduced intensity conditioning and allogeneic stem cell transplantation in patients with relapsed chronic lymphocytic leukemia and whether the assessment of minimal residual disease might be used to predict the clinical outcome. DESIGN AND METHODS: Minimal residual disease was monitored by polymerase chain reaction using the immunoglobulin heavy-chain gene rearrangement as a molecular marker in 29 relapsed patients who achieved complete remission following reduced intensity conditioning and allogeneic stem cell transplantation. A nested-polymerase chain reaction with patient-specific primers derived from complementarity determining regions (CDR2 and CDR3) was carried out in all the patients. Real-time polymerase chain reaction was performed in patients whose nested reaction gave positive or mixed results. RESULTS: Three patterns of minimal residual disease were observed: negative (31%), mixed (24%), and always positive (45%). The cumulative incidence of relapse according to the minimal residual disease status at 6 and 12 months after transplantation was significantly different between polymerase chain reaction-negative and -positive patients (p=0.031 and p=0.04, respectively). Two-year disease-free survival was 93% and 46% for polymerase chain reaction-negative and -positive patients at 6 months after transplantation, respectively (p=0.012). Similarly, 2-year disease-free survival was 100% and 57% for polymerase chain reaction-negative and -positive patients at 12 months, respectively (p=0.037). No clinical or biological factors were predictive of the achievement of polymerase chain reaction negativity after allogeneic stem cell transplantation. Graft-versus-host disease was more frequent in patients who did not relapse (p=0.04). Quantitative monitoring of minimal residual disease was able to identify polymerase chain reaction-positive patients with a higher risk of relapse. CONCLUSIONS: These findings demonstrate that relapsed patients can achieve molecular remission after reduced intensity conditioning and allogeneic stem cell transplantation and suggest a minimal residual disease-driven intervention that might be useful to prevent overt hematologic relapse.

Recycling Polyethylene-Rich Plastic Waste from Landfill Reclamation: Toward an Enhanced Landfill-Mining Approach.

In the frame of a circular economy, the maximization of secondary raw-material recovery is necessary to increase the economic and environmental sustainability of landfill mining and reclamation activities. In this paper, the polyethylene-rich plastic fraction recovered from the reclamation of an abandoned industrial landfill (landfill-recovered plastic, LRP) has been characterized through spectroscopic, thermal, morphological, and mechanical analyses. Then, an economically viable valorization and recycling strategy was set up. The effectiveness of this strategy in the enhancement of LRP properties has been demonstrated through morphological and mechanical characterizations.

Allogeneic transplantation for relapsed and refractory Hodgkin lymphoma: long-term outcomes and graft-versus-host disease-free/relapse-free survival.

This monocentric retrospective study included 70 consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving reduced-intensity allogeneic stem cell transplantation (alloSCT). We evaluated overall and progression-free survival (OS, PFS), graft-versus host disease/relapse-free survival (GFRS), and chronic GVHD-free OS (cGVHD-free OS) defined as OS without moderate-to-severe cGVHD. Patients had a median age of 33 years (range, 18-60 years), 23% had refractory disease (SD/PD). Donors were HLA identical (39%), unrelated (30%), or haploidentical (31%). Median follow-up was 6.2 years. Five-year OS was 59% and PFS was 49%. NRM was 16% at 1 year. 44% of patients had cGVHD, and 14% moderate-to-severe cGVHD at last follow-up. GFRS and cGVHD-free OS were 26 and 48% at 5 years. In multivariate analysis, resistant disease at alloSCT impacted survival and GFRS. In conclusion, disease response before alloSCT impacts survival and GFRS. GVHD outcomes may help comparing the long-term effects of the new salvage treatments that bridge patients to alloSCT.

Nilotinib interferes with cell cycle, ABC transporters and JAK-STAT signaling pathway in CD34+/lin- cells of patients with chronic phase chronic myeloid leukemia after 12 months of treatment.

Chronic myeloid leukemia (CML) is characterized by the constitutive tyrosine kinase activity of the oncoprotein BCR-ABL1 in myeloid progenitor cells that activates multiple signal transduction pathways leading to the leukemic phenotype. The tyrosine-kinase inhibitor (TKI) nilotinib inhibits the tyrosine kinase activity of BCR-ABL1 in CML patients. Despite the success of nilotinib treatment in patients with chronic-phase (CP) CML, a population of Philadelphia-positive (Ph+) quiescent stem cells escapes the drug activity and can lead to drug resistance. The molecular mechanism by which these quiescent cells remain insensitive is poorly understood. The aim of this study was to compare the gene expression profiling (GEP) of bone marrow (BM) CD34+/lin- cells from CP-CML patients at diagnosis and after 12 months of nilotinib treatment by microarray, in order to identify gene expression changes and the dysregulation of pathways due to nilotinib action. We selected BM CD34+/lin- cells from 78 CP-CML patients at diagnosis and after 12 months of first-line nilotinib therapy and microarray analysis was performed. GEP bioinformatic analyses identified 2,959 differently expressed probes and functional clustering determined some significantly enriched pathways between diagnosis and 12 months of nilotinib treatment. Among these pathways, we observed the under expression of 26 genes encoding proteins belonging to the cell cycle after 12 months of nilotinib treatment which led to the up-regulation of chromosome replication, cell proliferation, DNA replication, and DNA damage checkpoint at diagnosis. We demonstrated the under expression of the ATP-binding cassette (ABC) transporters ABCC4, ABCC5, and ABCD3 encoding proteins which pumped drugs out of the cells after 12 months of nilotinib. Moreover, GEP data demonstrated the deregulation of genes involved in the JAK-STAT signaling pathway. The down-regulation of JAK2, IL7, STAM, PIK3CA, PTPN11, RAF1, and SOS1 key genes after 12 months of nilotinib could demonstrate the up-regulation of cell cycle, proliferation and differentiation via MAPK and PI3K-AKT signaling pathways at diagnosis.