Differences among young adults, adults and elderly chronic myeloid leukemia patients

Castagnetti, Fausto; Gugliotta, Gabriele; Baccarani, Michele; Breccia, Massimo; Specchia, Giorgina; Levato, Luciano; Abruzzese, Elisabetta; Rossi, Giuseppe; Iurlo, Alessandra; Martino, Bruno; Pregno, Patrizia; Stagno, Fabio; Cuneo, Antonio; Bonifacio, Massimiliano; Gobbi, Marco; Russo, Domenico; Gozzini, Antonella; Tiribelli, Mario; Vivo, Antonio De; Alimena, Giuliana; Cavo, Michèle; Martinelli, Giovanni; Pane, Fabrizio; Saglio, Giuseppe; Rosti, Gianantonio; Salvi, Flavia; Pini, Massimo; Leoni, Pietro; Rupoli, Serena; Galieni, Piero; Bigazzi, Catia; Coppola, Nicola; Palmieri, Fausto; Albano, Francesco; Rossi, Antonella Russo; Rambaldi, Alessandro; Intermesoli, Tamara; Palandri, Francesca; Testoni, Nicoletta; Luatti, Simona; Soverini, Simona; Iacobucci, Ilaria; Bochicchio, Maria Teresa; Apolinari, M.; Fogli, Miriam; Cervello, I.; Capucci, Adele; Malagola, Michele; Malpignano, A.; Girasoli, Mariella; Angelucci, Emanuele; Usala, Emilio; Storti, Sergio; Biasi, E. De; Tagariello, Giuseppe; Sartori, Roberto; Raimondo, Francesco Di; Vigneri, Paolo; Impera, Stefana; Molica, S.; Lanza, Francesco; Viganò, C; Grasso, Maria Grazia; Rapezzi, Davide; Cavazzini, Francesco; Bosi, Alberto; Santini, Valeria; Capalbo, Silvana; Spinosa, Giuseppina; Pierri, Ivana; Bergamaschi, Micaela; Carella, A. M.; Bacigalupo, Andrea; Blasio, Anna De; Ciccone, Fabrizio; Renzo, Nicola Di; Musolino, Caterina; Russo, Salvatore; Cortelezzi, Agostino; Morra, Enrica; Pungolino, Ester; Luppi, Mario; Marasca, Roberto; Pogliani, Enrico Maria; Gambacorti‐Passerini, Carlo; Luciano, Luigia; Ferrara, F.; Annunziata, Mario; Latte, Giancarlo; Noli, Daniel; Rege‐Cambrin, Giovanna; Fava, Carmen; Semenzato, Gianpietro; Binotto, Gianni; Fanfani, Francesco; Turri, Diamante; Siragusa, Sergio; Caracciolo, Clementina; Musso, Maurizio; Porretto, Ferdinando; Aversa, Franco; Crugnola, Monica; Cazzola, M.; Orlandi, Ester; Falini, Brunangelo; Falzetti, Franca; Visani, Giuseppe; Isidori, Alessandro; Fioritoni, Giuseppe; Lorenzo, Roberto Di; Vallisa, Daniele; Trabacchi, Elena; Petrini, Mario; Galimberti, Sara; Pizzuti, Michele; Zaccaria, Alfonso; Salvucci, Marzia; Ronco, Francesca; Ielo, Domenica; Merli, Francesco; Avanzini, Paolo; Tosi, Patrizia; Merli, A; Musto, Pellegrino; Stefano, Valerio De; Sica, Simona; Latagliata, Roberto; Fabritiis, Paolo de; Trawiska, Margherita; Majolino, Ignazio; Pacilli, L; Ronci, Benedetto; Cedrone, Michele; Petti, M C; Pisani, Francesco; Tafuri, Agostino; Madon, E; Iuliano, Francesco; Dore, Franca; Pardini, Simonetta; Bocchia, Monica; Defina, Marzia; Liberati, A.M.; Luzzi, D.; Boccadoro, Mario; Ferrero, Dario; Vitolo, Umberto; Gherlinzoni, Filíppo; Calistri, Elisabetta; Fanin, Renato; Pizzolo, G.; Meneghini, Vittorio; F, Rodighiero; D'Emilio, Anna

doi:10.1093/annonc/mdu490

Cited by 81 publications

(72 citation statements)

References 22 publications

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“…Recent data suggest that CML patients aged 5-29 years have less frequent cytogenetic and molecular responses to TKI therapy compared with older individuals and an increased risk of transformation to blast phase. 13,14 These data are consistent with our findings of an unfavorable impact of age on the probability of TFR. Others report a similar association.…”

Section: -12supporting

confidence: 92%

E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy

et al. 2017

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E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy Treatment-free remission (TFR) is a new therapy goal for patients with chronic phase chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitors (TKIs), with approximately 40% sustaining deep molecular responses after stopping treatment.1-3 However, it is difficult to predict precisely who will achieve TFR and the subject remains controversial.3 We present data from 64 patients who stopped TKI therapy. Data show a significant association between the type of BCR-ABL1 transcript and age on the probability of TFR.Subjects were in 1 st chronic phase and had a deep molecular response (≥MR4 on the International Scale) for one year or more before stopping TKI therapy, equivalent to the eligibility criteria of the Euro-Ski trial. 4Molecular response level was calculated by standard criteria 5 and molecular relapse defined as loss of MR3. Time to molecular relapse was measured from the date of TKI discontinuation to the first of 2 or more consecutive quantitative real-time polymerase chain reaction (qRT-PCR) assessments confirming less than MR3.Treatment-free remission was defined as the interval between the date of stopping TKI therapy and the date of molecular relapse or, if this did not happen, the date of last contact. Continuous variables were dichotomized to assess prognostic values for TFR using the median value. Sensitivity analysis was performed for these variables excluding outlier values. To explore the impact of age, we interrogated cut-off points at the median age (51 years) and at ages 40 and 60 years. P<0.05 (two-tailed) was considered significant. Potential predictive variables for TFR were analyzed in univariate analysis using the KaplanMeier method. Only statistically significant variables were included in multivariate analysis using a Cox proportional hazard regression model. Subject-, disease-and therapy-related variables before stopping TKI therapy are shown in Table 1. Median follow up from stopping TKI therapy was 26 months (range 6-121 months). Forty-one subjects [64%; 95% confidence interval (CI): 53, 75%)] stopped TKI because of intolerance, 7 (11%; 95%CI: 5, 19%) in order to conceive, and 16 (25%; 95%CI: 14, 36%) were elected to stop treatment on achieving a sustained deep response. At the time of discontinuing TKI, 32 subjects (50%; 95%CI: 38, 63%) were receiving imatinib and 32 (50%; 95%CI: 38, 63%), dasatinib or nilotinib. The frequency of patients with e13a2 (42%) or e14a2 transcripts (58%) is similar to that reported within the European LeukemiaNet (ELN) registry, at 45% and 55%, respectively. 6Thirty-seven subjects (58%; 95%CI: 45, 70%) remain in molecular remission at a median of 26 months (range 7-64 months) after stopping TKI therapy. The 3-year actuarial probability of TFR is 53% (95%CI: 38, 66%). Twenty-seven subjects (42%; 95%CI: 30, 55%) had a molecular relapse at a median of four months (range 1...

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Section: -12supporting

confidence: 92%

E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy

et al. 2017

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“…Recent studies reported a poorer prognostic profile in young adults (less than 30 years of age) as compared with other age groups. 37 38 This observation corresponds to our modelling of age in the ELTS score:…”

Section: Discussionsupporting

confidence: 78%

Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia

et al. 2015

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In patients with chronic myeloid leukemia (CML), first-line imatinib treatment leads to 8-year overall survival (OS) probabilities above 80%. Many patients die of reasons unrelated to CML. This work tackled the reassessment of prognosis under particular consideration of the probabilities of dying of CML. Analyses were based on 2290 patients with chronic phase CML treated with imatinib in six clinical trials. 'Death due to CML' was defined by death after disease progression. At 8 years, OS was 89%. Of 208 deceased patients, 44% died of CML. Higher age, more peripheral blasts, bigger spleen and low platelet counts were significantly associated with increased probabilities of dying of CML and determined a new long-term survival score with three prognostic groups. Compared with the low-risk group, the patients of the intermediate- and the high-risk group had significantly higher probabilities of dying of CML. The score was successfully validated in an independent sample of 1120 patients. In both samples, the new score differentiated probabilities of dying of CML better than the Sokal, Euro and the European Treatment and Outcome Study (EUTOS) score. The new score identified 61% low-risk patients with excellent long-term outcome and 12% high-risk patients. The new score supports the prospective assessment of long-term antileukemic efficacy and risk-adapted treatment.

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“…Its interpretation is not unequivocal and raises the question of the importance of age related phenomena such as the number, ability and speed of quiescent stem cells to enter cell cycle at different ages [25].…”

Section: Discussionmentioning

confidence: 99%

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

et al. 2015

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Imatinib is effective for the treatment of chronic myeloid leukemia (CML). However even undetectable BCR-ABL1 by Q-RT-PCR does not equate to eradication of the disease. Digital-PCR (dPCR), able to detect 1 BCR-ABL1 positive cell out of 10 7 , has been recently developed. The ISAV study is a multicentre trial aimed at validating dPCR to predict relapses after imatinib discontinuation in CML patients with undetectable Q-RT-PCR. CML patients under imatinib therapy since more than 2 years and with undetectable PCR for at least 18 months were eligible. Patients were monitored by standard Q-RT-PCR for 36 months. Patients losing molecular remission (two consecutive positive Q-RT-PCR with at least 1 BCR-ABL1/ABL1 value above 0.1%) resumed imatinib. The study enrolled 112 patients, with a median follow-up of 21.6 months. Fifty-two of the 108 evaluable patients (48.1%), relapsed; 73.1% relapsed in the first 9 months but 14 late relapses were observed between 10 and 22 months. Among the 56 not-relapsed patients, 40 (37.0% of total) regained Q-RT-PCR positivity but never lost MMR. dPCR results showed a significant negative predictive value ratio of 1.115 [95% CI: 1.013-1.227]. An inverse relationship between patients age and risk of relapse was evident: 95% of patients <45 years relapsed versus 42% in the class 45 to <65 years and 33% of patients 65 years [P(v 2 ) < 0.0001]. Relapse rates ranged between 100% (<45 years, dPCR1) and 36% (>45 years, dPCR-). Imatinib can be safely discontinued in the setting of continued PCR negativity; age and dPCR results can predict relapse.

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Differences among young adults, adults and elderly chronic myeloid leukemia patients

Abstract: NCT00510926, NCT00514488, NCT00769327, NCT00481052.

Cited by 81 publications

References 22 publications

E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy

E14a2 BCR-ABL1 transcript is associated with a higher rate of treatment-free remission in individuals with chronic myeloid leukemia after stopping tyrosine kinase inhibitor therapy

Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia

Age and dPCR can predict relapse in CML patients who discontinued imatinib: The ISAV study

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