Abstract Treatment of Chronic Myeloid Leukaemia (CML) has evolved rapidly in the last 10 years. The objectives of this national consensus meeting were to describe the optimal procedures to perform at ...diagnosis, the most appropriate choice of tyrosine kinase inhibitor (TKI) in the first line setting, the correct monitoring procedures, the appropriate timing for resistance identification allowing a rapid TKI switch, and the future possibility of treatment discontinuation. A panel of experts in CML management were invited for a 2-day workshop. Prior to the conference, the organizing committee selected several topics and assigned them to different physicians divided in four groups. Issues discussed were (1) role of cytogenetic and molecular response monitoring in 2013; (2) frontline treatment of CML in 2013 and therapeutic objectives; (3) how to monitor response and when to change therapy after resistance or non-optimal responses; (4) possible therapy discontinuation after achievement of deep and stable molecular responses. Different national experts reviewed the literature, analyzed levels of evidence for each topic and, after extensive discussions within smaller working groups, presented their conclusions during the meeting. Each consensus aim was then evaluated by a general vote in the plenary sessions.
The management of patients with chronic myeloid leukemia (CML) during pregnancy is a matter of continuous debate. The introduction of the tyrosin kinase inhibitors (TKIs) in clinical practice has ...dramatically changed the prognosis of CML patients. Patients diagnosed in chronic phase can expect an excellent disease control and a normal lifespan. Issues relating to fertility and pregnancy must be introduced at diagnosis. Different reports were published in patients conceving/getting pregnant during Imatinib treatment, while there are only sporadic data about other TKIs. The GIMEMA CML working party has started a retrospective and prospective study to describe all female pregnancies/male conception outcome in the CML population from January 2013 until 2015.
Inclusion criteria were age>18, CML in any phase of the disease, conception/pregnancy while diagnosed with CML, treatment with TKIs (before, during or after pregnancy), and signed written informed consent IRB approved.
Sixty-three patients have been enrolled so far in the study. Male to female ratio was 43/20, mother age at pregnancy (female patients or female partners of male patients) varies from 22 to 37 years. CML was diagnosed when patients were aged between 17 and 55 years old, all patients were in chronic phase at time of conception, but one. This patient was a male patient with accelerated phase aged 31 treated with Nilotinib whose conception outcome was unremarkable. Data on 71 pregnancies have been harvested. The majority of pregnancies were spontaneous, with 3 PMA (pregnancy medically assisted). All pregnancies were carried on, 2 are ongoing, and 6 ended up in an abortion within the 3rdmonth, 2 of which non induced (miscarriages). At pregnancy/conception 8 patients were treated with Nilotinib, 4 with Dasatinib, 3 with Bosutinib, the remaining patients were treated with Imatinib or were at onset with no treatment. All carried pregnancies were unremarkable, except two placental detachment, one at 5 months and one at 12 weeks pregnancy, 1 abortion threat requiring rest, 1 gestational diabetes with intra-uterine growth retard, 1 oligohydramnios, 1 congenital hip dysplasia, and 1 speech retard in a 36 months old baby girl.
Data on female patients population, regarding the status of CML at pregnancy, the CML therapy since conception and throughout pregnancy, particularly regarding the organogenesis period (between 5-12 weeks), the status of the illness during pregnancy (any MR4.5, MR4 and major molecular response, complete cytogenetic response, hematologic response losses, and progressions), the outcome of pregnancy, breast feeding, baby growth and development (walk, speech, behaviour), will be detailed. The same will be for female partners of male patients treated with TKIs other than Imatinib.
Acquiring detailed information about how a pregnancy/conception is managed will increase our knowledge in order to establish a consensus on patients with CML receiving TKIs who wants to father a child or become/are pregnant.
Abruzzese:novartis, bristol myers squibb, ariad, pfizer, takeda: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Gugliotta:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau.
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Introduction. Chronic myeloid leukemia (CML) patients (pts) treated with imatinib first line achieve complete cytogenetic response (CCyR) in > 70% of cases and major molecular response (MMR) in ...18-58%. These pts have a life expectancy similar to the general population. However even undetectable BCR-ABL may not equate to eradication of the disease because of the sensitivity of Q-RT-PCR. A new diagnostic method, the digital-PCR (dPCR), able to detect 1 BCR-ABL+ cell out of 107 cells, has been recently developed (Goh HG et al., 2011). dPCR corresponds to a 100 fold increase in sensitivity as compared to Q-RT-PCR. Therefore, dPCR by assessing the presence of minimal residual disease with higher sensitivity, could potentially identify pts in whom CML has been eradicated.
Aims. The Imatinib Suspension And Validation (ISAV) study is aimed at validating the capability of dPCR to predict relapses after imatinib discontinuation in CML pts with negative Q-RT-PCR results.
Methods. This study involves 15 sites, 10 in Italy and 1 in each of the following countries: Germany, Spain, The Netherlands, Canada and Israel. CML pts (Chronic or Accelerated Phase) under imatinib therapy since more than 2 years and in complete molecular remission (CMR) were eligible for this study. Patients had to be in CMR for at least 18 months (mts), with a minimum of 3 Q-RT-PCR performed at their own sites. After signing the informed consent, blood samples are obtained for dPCR and the pts discontinue imatinib therapy. Standard Q-RT-PCR is performed monthly (mts 1-6) and then bimonthly for 36 mts to assess the maintenance of the molecular remission. The loss of molecular remission is defined as two consecutive positive Q-RT-PCR tests with at least one BCR-ABL/ABL value above 0.1%. Patients losing molecular remission resume imatinib treatment at the same dosage used before interruption. Patients’ quality of life during imatinib discontinuation/resumption is evaluated through the EORTC – C30 Quality of Life questionnaire.
Results. The enrolment in ISAV began in November 2011 and ended in July 2013. The study enrolled 112 pts: Italy 69.6%, Germany 21.4%, Canada 5.3%, Spain 2.6% and Israel 0.9%. Among the 112 pts, 59.3% were male and 37.0% were aged 65 or older; median duration of imatinib treatment was 103.1 mts with median duration of CMR of 25.8 mts before imatinib discontinuation. To date, the median follow-up (FUP) time is 16.6 mts 95% CI: 14.9-18.2. Forty-seven pts (43.5%, 95% CI: 34.0-53.4) of the 108 eligible pts relapsed and resumed imatinib; 38/47 (80.9%) of them relapsed in the first 9 mts and the last relapse occurred 19.6 mts after imatinib discontinuation. A loss of CCyR occurred in 11 pts (23.4%): 10/11 CCyR losses were recovered; 1 patient withdrew the consent shortly after obtaining a partial cytogenetic response. No case of CML progression was observed. After the resumption of imatinib the median time to either MMR or CMR was 1.9 95% CI: 1.2-2.4 mts. Of the 61 not-relapsed pts, 43 (39.8% of the total) regained Q-RT-PCR positivity but never lost MMR. The median time to Q-RT-PCR positivity was 3.6 mts 95% CI: 3.0-4.8 and the range of duration of Q-RT-PCR positivity (below 0.1%) was between 5.7 and 29.2 mts. No significant correlation between relapse and previous duration of imatinib treatment, use of interferon, time to CCyR or duration of CMR was identified. An inverse relationship between pts age and risk of relapse is evident: 90% of pts < 45 years relapsed vs 37.5% in the class ≥ 45 - < 65 years and 27.5% of pts ≥ 65 years, p(χ2)<0.0001. dPCR results showed that 23.4% of pts were positive and 76.6% negative, with a dPCR Negative Predictive Value (NPV) of 63.4% (Tab.1) and a significant NPV ratio (dPCR/Q-RT-PCR) of 1.131 95% CI: 1.032-1.239. Age and dPCR results predicted the risk of relapse: pts with less than 45 years and with a positive dPCR had the highest risk of relapse (100%) as opposed to pts ≥ 45 years and with negative dPCR (30.6%; Fig.1).
Conclusions. After 32 mts from the beginning of the study, with a median FUP of 16.6 mts, 43.5% of pts relapsed; the majority of relapses developed in the first 9 months after imatinib discontinuation. Age < 45 years and dPCR positivity are significantly associated with relapses. Funded by Regione Lombardia.
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No relevant conflicts of interest to declare.
The BCR-ABL oncoprotein of chronic myelogenous leukemia (CML) localizes to the cell cytoplasm, where it activates proliferative and antiapoptotic signaling pathways. We previously reported that the ...combination of the ABL kinase inhibitor imatinib mesylate (IM) and the nuclear export inhibitor leptomycin B (LMB) traps BCR-ABL inside the nucleus, triggering the death of the leukemic cells. To evaluate the efficacy of the combination of IM and LMB on human cells we collected CD34-positive cells from 6 healthy donors and myeloid progenitors from 35 patients with CML. The sequential addition of IM and LMB generated the strongest reduction in the proliferative potential of the leukemic cells, with limited toxicity to normal myeloid precursors. Furthermore, nested reverse transcriptase-polymerase chain reaction (RT-PCR) analysis on colonies representative of each experimental condition demonstrated that the combination of IM and LMB was the most effective regimen in reducing the number of BCR-ABL-positive colonies. The efficacy of the 2-drug association was independent of the clinical characteristics of the patients. Our results indicate that strategies aimed at the nuclear entrapment of BCR-ABL efficiently kill human leukemic cells, suggesting that the clinical development of this approach could be of significant therapeutic value for newly diagnosed and IM-resistant CML patients.
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