Adherence and future discontinuation of tyrosine kinase inhibitors in chronic phase chronic myeloid leukemia. A patient-based survey on 1133 patients

Therapeutic approach for chronic myeloid leukemia (CML) patients has undergone a revolutionary change with the introduction of tyrosine kinase inhibitors, which improved overall survival and quality of life. Optimal therapy adherence has become of paramount importance to maximize the benefits in the long-term outcome. Several evidences have been reported that personal factors, such as social support, psychological and subjective perceptions about the drug used and the future, could influence adherence. We here report the results of a questionnaire specifically designed to evaluate factors influencing adherence and perceptions about the future, distributed to patients during regional Italian meetings. Overall, 1133 patients compiled the questionnaire: median age was 57 years. High rate of adherence was reported, but 42% of interviewed patients admitted that they had occasionally postponed a dose and 58% had discontinued therapy mainly for forgetfulness. The majority of patients discussed with personal physician about the importance of adherence and received sufficient information about illness and treatment, but would like to have discussed more about discomfort, anxiety and fear of the future. Summarizing personal drug compliance and estimating how many days a month, on average, the patients did not take the drug, the majority answered that it was less than 3 days (55%) and only a minority (4%) admitted that it was more than 7 days. Interviewed about discontinuation, 49% of patients answered that wouldn't interrupt because of fear of losing all the results achieved so far. This study suggests a higher level of satisfaction with more information received but the need of improving communication about possible future treatment free remission

Managing chronic myeloid leukemia for treatment-free remission: a proposal from the GIMEMA CML WP

Several papers authored by international experts have proposed recommendations on the management of BCR-ABL1+ chronic myeloid leukemia (CML). Following these recommendations, survival of CML patients has become very close to normal. The next, ambitious, step is to bring as many patients as possible into a condition of treatment-free remission (TFR). The Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA; Italian Group for Hematologic Diseases of the Adult) CML Working Party (WP) has developed a project aimed at selecting the treatment policies that may increase the probability of TFR, taking into account 4 variables: the need for TFR, the tyrosine kinase inhibitors (TKIs), the characteristics of leukemia, and the patient. A Delphi-like method was used to reach a consensus among the representatives of 50 centers of the CML WP. A consensus was reached on the assessment of disease risk (EUTOS Long Term Survival [ELTS] score), on the definition of the most appropriate age boundaries for the choice of first-line treatment, on the choice of the TKI for first-line treatment, and on the definition of the responses that do not require a change of the TKI (BCR-ABL1 6410% at 3 months, 641% at 6 months, 640.1% at 12 months, 640.01% at 24 months), and of the responses that require a change of the TKI, when the goal is TFR (BCR-ABL1 >10% at 3 and 6 months, >1% at 12 months, and >0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR

L'importanza delle differenze di genere nella valutazione dello stress lavoro correlato percepito

novità assolute che ha proposto la normativa relativa alla prevenzione nei luoghi di lavoro. Il testo unico introduce l’obbligo della valutazione del rischio da stress lavoro correlato nonché quelli connessi alle differenze di genere. Le differenze di genere devono essere tenute in considerazione nella valutazione dello stress lavoro-correlato infatti le evidenze scientifiche hanno dimostrato come sia aspetti di carattere biologico che differenze socio-ambientali siano in grado di modulare la diversa percezione e la conseguente risposta allo stress. Sotto il profilo biologico è noto come i livelli di estrogeni siano capaci di modulare negativamente la presenza di recettori ipotalamici e ipofisari dei glucocorticoidi, rendendo, quindi, il feed-back meno efficace. Per spiegare in modo esauriente l’importanza delle differenze di genere rispetto al fenomeno dello stress lavoro-correlato è opportuno, dopo aver considerato fattori di carattere biologico e comportamentale, mettere in risalto fattori dell’ambiente e del contesto che possono amplificare e predisporre al rischio stress. La valutazione del rischio da stress lavoro-correlato deve tenere conto delle differenze di genere e per il raggiungimento di tale scopo sono richieste delle competenze di carattere specialistico ed una specifica formazione da parte delle figure professionali che ruotano attorno alla gestione dello stress. Inoltre è richiesto che tali figure siano capaci di cooperare apportando ognuno il proprio contributo all’assolvimento di questo obiettivo.absolute novelty that has proposed legislation on prevention at workplaces. The law introduces the obligation to assess the risk of stress related work as well as those related to gender differences. Gender differences need to be taken into account in the work-related stress assessment. In fact, scientific evidence has shown that both biological aspects and socio-environmental differences are capable to modulate the different perception and consequent response to stress. Regarding the biological profile is known as estrogen levels are able to modulate negatively the presence of hypothalamic and hypophysaric glucocorticoid receptors, thus making the feed-back less effective. In order to fully explain the importance of gender differences about the work-related stress, it is appropriate, after considering biological and behavioral factors, to emphasize environmental and context factors that can amplify and predispose to the risk stress. The work-related work stress risk assessment must take into account gender differences and, to achieve this goal, specialist skills are required and a specific training by professional figures around the management of stress is required. It is also required that these figures are able to cooperate by bringing each contribution to the attainment of this goal

Matched-pair analysis of transplant from haploidentical, Unmanipulated bone marrow donor versus HLA identical sibling for patients with hematologic malignancies

A matched-pair analysis of transplant-related outcomes was carried out in 116 of 255 consecutive patients who received transplants from an HLA identical sibling (n = 58) or haploidentical related donor (n = 58). The 2 patient series were matched with 9 variables: period of transplant, patient and donor age, sex, diagnosis, disease phase, conditioning regimen, donor-recipient sex, and cytomegalovirus (CMV) status combinations. As graft-versus-host disease (GVHD) prophylaxis, all patients received the standard cyclosporine and methotrexate association with the addition of anti-thymocyte globulins, mycophenolate mofetil, and basiliximab in haploidentical, unmanipulated bone marrow recipients. Anti-infectious management, transfusion policy, and supportive care were identical for all patients. By comparing the 2 patient series, no statistically significant difference was observed for the cumulative incidence of advanced acute and extensive chronic GVHD, transplant-related mortality, and relapse. With a median follow-up of 3.5 years, the 5-year disease-free survival was 37% ± 6% and 36% ± 6% for HLA identical sibling and haploidentical recipients, respectively. The results of transplant from HLA identical siblings and haploidentical donors are comparable. Regardless of the HLA matching, other factors known to affect the transplant outcomes, such as donor-recipient age, sex, and CMV status combinations, might drive the search for the best donor

Five-Year Results of Nilotinib 400 Mg BID in Early Chronic Phase Chronic Myeloid Leukemia (CML): High Rate of Deep Molecular Response - Update of the Gimema CML WP Trial CML0307

Nilotinib is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of CML based on the results of the phase 3 ENESTnd trial that demonstrated superior efficacy of nilotinib vs. imatinib, with higher and faster molecular responses and lower rates of progressions to accelerated-blastic phase (AP/BP)(3 years of follow-up). In the IRIS trial, after 5 years of follow-up, 69% of patients were still on imatinib; the event-free survival (EFS) and progression-free survival (PFS) were 83% and 93%, respectively (Druker BJ et al, NEJM 2006). In an intention-to-treat analysis of patients treated frontline with imatinib at the Hammersmith Hospital, EFS at 5 years was 63% and PFS was 83% (de Lavallade H, J Clin Oncol 2008). The long-term evaluation of the patients treated with nilotinib frontline is extremely relevant. METHODS: The GIMEMA CML WP conducted a multicentre phase 2 trial with nilotinib 400mg BID as frontline therapy (ClinicalTrials.gov.NCT00481052). Median follow-up for the present analysis was 51 months (range: 48 – 58 months); five years median follow-up data will be presented. Definitions: MR3.0 (Major Molecular Response) as a BCR-ABL/ABL ratio <0.1% IS; MR4.0, BCR-ABL/ABL ratio <0.01% with ≥10,000 ABL transcripts; failures: according to the 2009 ELN recommendations; events: failures and treatment discontinuation for any reason. All the analysis has been made according to the intention-to-treat principle. RESULTS: 73 patients enrolled: median age 51 years; 45% low, 41% intermediate and 14% high Sokal risk. The cumulative incidence of CCyR at 12 months was 100%. Only 1 patient had a confirmed loss of CCyR and subsequently progressed to AP/BP (see below). Two out of 73 patients never achieved a MR3.0, 1 is the patient who progressed to AP/BP (see below), the other 1 is in stable and confirmed CCyR at 48 months. Only 3 patients had a confirmed loss of MMR due to low adherence (all 3 still on nilotinib). The overall estimated probability of MR4.0 was 82%. Twenty-five percent (18/73 patients) showed a stable MR4.0 (defined based on 3 consecutive MR4.0 samples 4 months apart). Only one patient progressed at 6 months to AP/BP and subsequently died (high Sokal risk, T315I mutation). Overall, eleven patients (15%) discontinued permanently nilotinib: 1 patient progressed to AP/BP; 3 patients had recurrent episodes of amylase and/or lipase increase (no pancreatitis); 3 patients had peripheral arterial obstructive disease (after 45, 46, and 52 months of therapy; age at nilotinib start: 65, 66, and 76 years; 2 out of 3 with at least 1 cardiovascular risk factor); 1 patient had atrial fibrillation (unrelated to study drug); 1 patient died after 32 months of mental deterioration and starvation (unrelated to study drug); 2 patients for refusal (1 patient in confirmed MR4, still off-treatment and in MR4 9 months after discontinuation); 1 patient for withdrawal of informed consent, on imatinib). The estimated probability of overall survival, progression-free survival and failure-free survival was 97% at 5 years; the estimated probability of event-free survival was 83% at 5 years. CONCLUSIONS: After a median follow-up of 5 years, the great majority of patients are still on nilotinib and, reasonably, they will continue in the next future. Even more importantly, only 1 progression so far: considering the kinetic of progression with any TKI in CML (most progressions reported during the first 2–3 years with imatinib and during the first 1–2 years with nilotinib and dasatinib), a relevant future progression incidence is very unlikely. Given the very high rate of deep molecular response, many are candidate to treatment discontinuation

Podocalyxin is expressed in normal and leukemic monocytes

We have investigated the expression of podocalyxin in primary cultures of leukemic blast cells from 73 patients with acute mycloid leukemia. Podocalyxin was expressed at moderate levels in 15 patients and at high levels in 13 patients. The analysis of membrane markers showed that Podocalyxin expression in leukemic blasts was associated with a monocytic immunophenotype. Cases of podocalyxin-positive acute myelogenous leukemia had high blastcell counts at diagnosis and elevated CD123, CD135, VLA-4 and CXCR4 expression, features associated with poor prognosis. Podocalyxin expression in leukemic blasts was coupled with the concomitant expression of VEGF-RI, -R2, -R3 and Tie-2, the capacity to release VEGF-A and angiopoictin1 and the ability to differentiate into endothelial cells under appropriate culture conditions. These findings show that podocalyxin is a marker of acute myeloid leukemia with a monocytic phenotype and suggest that podocalyxin-positive cases of acute myeloid leukemia originate from the malignant transformation of progenitors common to the mycloid and endothelial lineages. These observations suggest a possible relationship between the monocytic lineage and podocytes. (c) 2006 Elsevier Inc. All rights reserved

Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic- phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052)

High and Early Rates of Cytogenetic and Molecular Response with Nilotinib 800 Mg Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase 2 Trial of the GIMEMA CML Working Party

Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia in early chronic phase (ECP): the results of the IRIS trial have shown a 72 months overall survival of 95%; EFS and PFS were 83% and 93%, respectively; the cumulative rate of complete cytogenetic response (CCgR) for the IM 400 mg arm was 25% at 3 months (at 6, 12, 18 and 60 months it was 51%, 69%, 76% and 87%, respectively). Nilotinib, a second generation TKI, has a higher binding affinity and selectivity for Abl with respect to IM, being 20 to 50 times more active in IM-sensitive cell lines and is highly effective in IM resistant patients, across every disease phase. To investigate the therapeutic efficacy and the safety of nilotinib 400 mg BID in untreated, ECP, Ph-pos CML patients, the italian GIMEMA CML Working Party is conducting an open-label, single stage, multicentric, phase II study trial (ClinicalTrials.gov. NCT00481052); all patients provided written informed consent. The primary endpoint is the CCgR rate at 1 year; the kinetic of molecular response is studied by Q-PCR baseline and after 1, 2, 3, 6, 9 and 12 months from treatment start