Italian Physicians' Perceptions about the Role of Asciminib in Later Lines Chronic Myeloid Leukemia in Clinical Practice: A GIMEMA Survey

Unmet needs remain in later lines chronic myeloid leukemia (CML): the response rate and the overall survival of resistant patients in the chronic phase who changed a second-generation TKI in the second line with another TKI with similar action are usually poor, while the off-target toxicities and the potential development of mutations increase. The recent approval of asciminib, a STAMP inhibitor, in the third line, has the potential to soon change the therapeutic algorithm for this subset of patients. Here, we report the results of a GIMEMA survey assessing the number of patients currently treated in the third line in Italy, the current approach in later lines by Italian physicians, and the future role of this drug according to the reason to switch to asciminib (resistance and/or intolerance), as well as the perceptions about the future position of this agent

Digital PCR improves the quantitation of DMR and the selection of CML candidates to TKIs discontinuation

Treatment-free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real-time quantitative PCR (RT-qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT-qPCR for BCR-ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24\ua0months. Digital PCR detected BCR-ABL1 transcripts in the RT-qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR4.0 and MR4.5 (P\ua0=\ua00.0104) or MR5.0 (P\ua0=\ua00.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR4.0 vs MR4.5-5.0 ) were superimposable. Conversely, patients with dPCR values <0.468 BCR-ABL1 copies/\ub5L (as we previously described) showed a longer DMR duration (P\ua0=\ua00.0220) and mainly belonged to MR4.5-5.0 (P\ua0=\ua00.0442) classes compared to patients with higher dPCR values. Among the 142 patients, 111 (78%) discontinued the TKI treatment; among the 111 patients, 24 (22%) lost the MR3.0 or MR4.0 . RT-qPCR was not able to discriminate patients with higher risk of MR loss after discontinuation (P\ua0=\ua00.8100). On the contrary, according to dPCR, 12/25 (48%) patients with BCR-ABL1 values 650.468 and 12/86 (14%) patients with BCR-ABL1 values <0.468 lost DMR in this cohort, respectively (P\ua0=\ua00.0003). Treatment-free remission of patients who discontinued TKI with a dPCR <0.468 was significantly higher compared to patients with dPCR\ua0 65\ua00.468 (TFR at 2\ua0years 83% vs 52% P\ua0=\ua00.0017, respectively). In conclusion, dPCR resulted in an improved recognition of stable DMR and of candidates to TKI discontinuation

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 &gt;10% at 3 and 6 months, &gt;1% at 12 months, and &gt;0.1% at 24 months). These suggestions may help optimize the treatment strategy for TFR

Genetics of a combined lung small cell carcinoma and large cell neuroendocrine carcinoma with adenocarcinoma

Combined nonneuroendocrine-neuroendocrine lung tumors are relatively infrequent and little is known as for their genetic basis. Here, we report the case of a 69-year-old male with a solitary neoplasm in the upper lobe of the right lung. At histological examination, the tumor showed two components. The main part was an adenocarcinoma of the acinar type. The second part showed morphological and immunohistochemical phenotype of a neuroendocrine carcinoma composed of a small cell lung carcinoma and a large cell neuroendocrine carcinoma. The aim of our study was to investigate the genetic relationship between neuroendocrine and nonneuroendocrine tumor components. To this purpose, we performed a loss of heterozygosity (LOH) analysis with 40 chromosomal microsatellite markers. Microallelotyping revealed a common genetic profile in the different tumor areas. In 9 of 30 informative regions analyzed, LOH involved the same allele in all components, regardless of their histological type and grade. These findings support the true combined nature of this exocrine-neuroendocrine carcinoma of the lung and suggest a common monoclonal origin from a pluripotent epithelial (alveolar or bronchial) precursor cell for the two different tumor components

Famiglie e bambini/e con disabilit\ue0 complessa. Comunicazione della diagnosi, forme di sostegno, sistema integrato dei servizi

Il problema della disabilit\ue0 in et\ue0 evolutiva, dopo un faticoso percorso culturale, sviluppato negli ultimi 30 anni, ci consegna oggi un quadro che ha avuto evoluzioni positive, anche se ancora insufficienti, sui versanti dell\u2019integrazione scolastica, lavorativa e sociale, problematico in altri settori e spazi di vita. Tra questi, uno particolarmente critico per le famiglie \ue8 costituito dai primi anni di vita dei/delle figli/e con disabilit\ue0 complessa e/o pluridisabilit\ue0. La mancanza di informazione, la comunicazione della diagnosi, la gestione dei bisogni sono vissuti dalla famiglia in condizioni di profonda solitudine e sofferenza. In questo scenario risulta indispensabile immaginare percorsi di accompagnamento che coniughino supporti psicologici, sostegni educativi e socio-assisitenziali in un\u2019ottica fortemente integrata. Per meglio approfondire questi problemi, la Fondazione \uabEmanuela Zancan\ubb e la Fondazione \uabPaideia\ubb hanno promosso un percorso di riflessione, con momenti di studio e confronto i cui risultati sono raccolti in questo volume. In particolare, i vari contributi affrontano: i criteri di definizione di disabilit\ue0 complessa e/o pluridisabilit\ue0; i problemi riguardanti il processo di comunicazione della diagnosi di deficit e di disabilit\ue0 e la gestione di azioni nelle quali la riabilitazione, quando presente, sia componente di un progetto olistico di sostegno, al/lla bambino/a e alla sua famiglia, che comprenda gli aspetti psico-pedagogici, relazionali e socio assistenziali; le modalit\ue0 di attuazione di adeguati percorsi di accompagnamento all\u2019accoglienza del/della bambino/a nel nucleo famigliare; l\u2019importanza delle reti di prossimit\ue0 a supporto della famiglia: associazionismo e volontariato, progetti di domiciliarit\ue0, gruppi di sostegno e auto-aiuto tra famiglie. Ci auguriamo che il volume possa offrire indicazioni a quanti, impegnati nel lavoro con genitori di bambini/e con disabilit\ue0, intendano contribuire con competenza e progettualit\ue0 alla qualit\ue0 dei percorsi esistenziali di coloro che vivono una situazione complessa

Prognostic Value of BCR-ABL1 Transcript Type in Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib

Background. The fusion protein encoded by the BCR-ABL1 fusion gene may differ in size, but the great majority of chronic myeloid leukemia (CML) patients have a e13a2 (b2a2) or a e14a2 (b3a2) junction. In CML patients treated frontline with imatinib, the e14a2 transcript has been recently associated to faster and deeper molecular responses; in some studies a better outcome has been also reported. Very limited information on the prognostic impact of the BCR-ABL1 transcript type in CML patients treated frontline with second generation tyrosine kinase inhibitors (TKIs) is still available: a study from MDACC reported lower molecular response rates and a trend for inferior event-free survival in e13a2 patients. Aim. To evaluate if the BCR-ABL1 transcript type (e14a2 vs e13a2) affect the response and the clinical outcome in newly diagnosed adult CML patients treated frontline with nilotinib (NIL). Methods. An analysis of 345 CML patients in early chronic phase (ECP) enrolled within 3 multicentric prospective studies of the GIMEMA CML Working Party (ClinicalTrials.gov NCT00481052, NCT00769327, NCT01535391) was performed. The initial treatment was NIL 300 mg BID or NIL 400 mg BID. Definitions: major molecular response (MMR), BCR-ABL1IS ratio 10,000 ABL1 copies; progression, transformation to advanced phases; death, at any time and for any reason. Cumulative incidences of response were estimated under consideration of competing risks (progression, death) and compared by Gray test. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and compared by log-rank test. Results. Seven patients expressing rare transcripts (e1a2 or e19a2) and 10 patients with unknown transcript type were excluded: 328 out of 345 patients were evaluable, 124 (38%) with e13a2 transcript, 174 (53%) with e14a2 transcript and 30 (9%) expressing both transcripts. The baseline characteristics of patients with e13a2 or e14a2 transcripts were comparable: no significant differences in age, gender, Sokal or EUTOS long-term survival score distribution, presence of clonal chromosomal abnormalities in Ph+ cells, NIL dose were observed; the only difference was a higher platelet count in patients with e14a2 transcript (median 374 vs 313 x 103/µl, p=0.006). The median follow-up was 60 months in both groups (range 24-82 months). The response rates and the survival probabilities were uniformly lower in patients with e13a2 transcript (N=124) compared to patients with e14a2 transcript (N=174), but the differences were not significant: MMR by 12 months, 66% vs 72%, p=0.244; MR4.0 by 36 months, 56% vs 66%, p=0.067; estimated cumulative incidence of MMR, 82% vs 88%, p=0.135; estimated cumulative incidence of MR4.0, 60% vs 69%, p=0.101; estimated PFS, 88% vs 93%, p=0.547; estimated OS, 89% vs 94%, p=0.436 (Figure 1). The responses and the survival probabilities of patients co-expressing the e13a2 and the e14a2 transcripts (N=30) were similar to or even better than the ones of e14a2 patients. Grouping together the patients with e14a2 transcript alone and the patients with co-expression of both transcripts (N=174+30=204), and comparing them to patients with e13a2 transcript alone (N=124), the response differences became significant (cumulative incidence of MMR and MR4.0, p=0.050 and p=0.036, respectively), but no outcome differences emerged (PFS and OS, p=0.340 and p=0.276, respectively). Conclusions. Despite a trend for lower response rates and inferior outcome in patients with e13a2 transcript, the observed differences were small and mostly not significant. Further studies in larger patient cohorts are required to clarify whether nilotinib and other second generation TKIs are able to overcome the adverse prognostic impact of transcript type, potentially affecting the speed and the depth of molecular response, the probability of achieving a treatment-free remission and the patient outcome

Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia

The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use

Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia

The introduction of second-generation tyrosine-kinase inhibitors (TKIs) has generated a lively debate on the choice of first-line TKI in chronic phase, chronic myeloid leukemia (CML). Despite the TKIs have different efficacy and toxicity profiles, the planned use of two TKIs has never been investigated. We report on a phase 2 study that was designed to evaluate efficacy and safety of a treatment alternating nilotinib and imatinib, in newly diagnosed BCR-ABL1 positive, chronic phase, CML patients. One hundred twenty-three patients were enrolled. Median age was 56 years. The probabilities of achieving a complete cytogenetic response, a major molecular response, and a deep molecular response (MR 4.0) by 2 years were 93%, 87%, and 61%, respectively. The 5-year overall survival and progression-free survival were 89%. Response rates and survival are in the range of those reported with nilotinib alone. Moreover, we observed a relatively low rate of cardiovascular adverse events (5%). These data show that the different efficacy and toxicity profiles of TKIs could be favorably exploited by alternating their use