BackgroundIntermittent treatment with TKIs is an option for elderly CML patients who are often candidate to life-long treatment.Matherials and MethodsThe Italian phase III multicentric randomized OPTkIMA study aimed to evaluate if a progressive de-escalation of TKIs is able to maintain the MR3.0 and to improve Health Related Quality of Life (HRQoL) in CML elderly patients.Results215 patients in stable MR3.0/MR4.0 were randomized to receive an intermittent TKI schedule 1 month ON-1 month OFF for 3 years (FIXED arm; n=111) vs a progressive de-escalation TKI dose up to one third of the starting dose at the 3rd year (PROGRESSIVE arm; n=104). 203 patients completed the 3rd year of OPTkIMA study. At last follow up, MR3.0 loss was 27% vs 46% (p=0.005) in the FIXED vs PROGRESSIVE arm, respectively. None of these patients experienced disease progression. The 3 years probability of maintaining the MR3.0 was 59% vs 53%, respectively (p=0.13). HRQoL globally improved from baseline to the 3rd year, without any significant difference between the two arms. After the 3rd year, the proportion of patients who was address to TKI discontinuation in the two arms was 36% (FIXED) vs 58% (PROGRESSIVE) (p=0.03).ConclusionsThe intensification of intermittent TKI therapy is associated with a higher incidence of MR3.0 loss, but those patients who maintain the MR3.0 molecular response at the end of the study have been frequently considered eligible for TFR. The HRQoL generally improved during the de-escalation therapy in both randomization arms.MICROABSTRACT- Both FIXED and PROGRESSIVE intermittent TKI therapy are feasible and safe schedules in elderly patients with sustained major or deep molecular response.- The PROGRESSIVE intermittent schedule is associated with a higher incidence of MR3.0 loss.- The HRQoL improved during both intermittent schedules.- The PROGRESSIVE schedule was considered by Clinicians as a valid tool to select patients eligible for TKI discontinuation.
ABSTRACT Objectives The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP‐CML patients. Methods A retrospective analysis was conducted on 332 CP‐CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the “Campus CML” project. Results Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second‐generation TKIs (2G‐TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G‐TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra‐hematologic toxicity (9.5%), with no significant difference between IM and 2G‐TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G‐TKIs. Conclusions IM was in our Centers the preferred frontline therapy for older CP‐CML patients, with increasing utilization after the introduction of generic formulations. However, 2G‐TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.
Background: Family planning is important in patients (pts) with chronic myeloid leukemia (CML) who can have a near normal lifespan in tyrosine kinase inhibitors (TKI) era. Management of CML on conceptions and pregnancies is not defined as cases are rare and data are scarce. To investigate this issue a multicenter retrospective and prospective observational study of conception/pregnancy in CML pts was initiated within the European LeukemiaNet (ELN) from February 2014 till present. All ELN centers and participants from other countries were invited and received the study's protocol which was adopted in agreement with specific national laws. Aims: The main goal was to describe CML pts in terms of pregnancy/conceptions management and outcome. Secondary goals included demographics, characteristics of CML, management during pregnancy, pregnancy outcomes and characteristics of children. Methods: Adult pts aged ≥18 years with Ph+ positive CML and pregnancy were included after signing a written informed consent. Data were collected either in the coordinating centers in Moscow (Russia) and Rome (Italy) followed by the analyses of the entire data set. A total 305 pregnancy cases in 234 CML female pts from 15 centers of 13 countries worldwide were analyzed (Table 1). Results: Chronic phase at diagnosis was in 217/221(98%) pts. In 50 (21%) pts CML was diagnosed during pregnancy, while 184 (67%) got pregnant after diagnosis. Median (Me) time from CML diagnosis to pregnancy was 59 months (range 1–203). The outcomes of 305 pregnancies were as follows: labor 234 (77%), induced abortion 42 (14%), spontaneous abortion 21 (7%) and ongoing pregnancy or unknown outcome 8 (2%). Labor at full term was in 141 (75%) of 187 cases fully reported (Table 2). Molecular response (MR) evaluations at the start of pregnancy were recorded in 249/305 cases. Deep MR (DMR or BCR-ABL≤0,01% IS), major MR (MMR or BCR-ABL≤0,1%> >0,01% IS), MR2 (BCR-ABL>0,1%> ≤1% IS) and no MR2 (BCR-ABL>1% IS) was observed in 80 (32%), 31 (12%), 32 (13%) and 106 (43%) cases respectively. In 182 (71%) of 257 pregnancies with known data pts conceived while on TKI: 77% under imatinib (IM) and 23% TKI 2nd/3rd generation. TKIs were usually stopped early in 1st trimester (4–5 week of gestation) when the pregnancy was discovered. In 82 pregnancies pts were treated during 2nd-3rd trimester, after placental formation, until labor with IM: 33 (40%) of cases), nilotinib (NIL): 8 (9%), interferon (IFN): 23 (28%, 1 PEG-IFN), hydroxyurea: 6 (7%). IM was used throughout pregnancy in 13 (16%). One case of leukaferesis was recorded. The number of born children in 226 fully reported labors was 233 (including twins). Congenital abnormalities were recorded in 4 (1,7%) cases as follows: polydactyly (1), hypospadias (1) and non-closed foramen ovale of interatrial septum (2). None of the abnormalities were severe or life threatening, relationship to TKI use was considered unlikely by physicians. Low birth weight was recorded in 13 children with IM or NIL exposure at late pregnancy. The follow-up of all children was uneventful, with Me age at follow-up of 5 years (range 2 months-17 years).Summary/Conclusion: Most pregnancies in CML female pts resulted in normal childbirth with no increased rate of birth abnormalities in spite of TKI use at conception even if treatments were mostly early stopped at implant (4–5 weeks). Different therapies were used during pregnancy when needed. The results in terms of conception/pregnancy may be valuable for the development of CML treatment schemes particularly considering the variety of disease status.
Allogeneic hematopoietic cell transplantation (HCT) is an effective therapeutic option for high-risk hematological malignancies; 80% of those who survive the first 2-years are expected to become long-term survivors.
Disease progression to accelerated/blast phase (AP/BP) in patients with chronic phase chronic myeloid leukemia (CP-CML) after treatment discontinuation (TD) has never been systematically reported in clinical trials. However, recent reports of several such cases has raised concern. To estimate the risk of AP/BP among TD-eligible patients, we conducted TFR-PRO, a cohort retro-prospective study: 870 CP-CML patients eligible for TD formed a discontinuation cohort (505 patients) and a reference one (365 patients). The primary objective was the time adjusted rate (TAR) of progression in relation to TD. Secondary endpoints included the TAR of molecular relapse, that is, loss of major molecular response (MMR). With a median follow up of 5.5 years and 5188.2 person-years available, no events occurred in the TD cohort. One event of progression was registered 55 months after the end of TD, when the patient was contributing to the reference cohort. The TAR of progression was 0.019/100 person-years (95% CI [0.003-0.138]) in the overall group; 0.0 (95% CI [0-0.163]) in the discontinuation cohort; and 0.030 (95% CI [0.004-0.215]) in the reference cohort. These differences are not statistically significant. Molecular relapses occurred in 172/505 (34.1%) patients after TD, and in 64/365 (17.5%) patients in the reference cohort, p < .0001. Similar rates were observed in TD patients in first, second or third line of treatment. CML progression in patients eligible for TD is rare and not related to TD. Fears about the risk of disease progression among patients attempting TD should be dissipated.
Abstract 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 ≤10% at 3 months, ≤1% at 6 months, ≤0.1% at 12 months, ≤0.01% 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.
