Treatment-free remission in chronic myeloid leukemia patients treated front-line with nilotinib: 10-year followup of the GIMEMA CML 0307 study.

We report the final analysis, with a 10-year follow-up, of the phase II study GIMEMA CML 0307 (NCT00481052), which enrolled 73 adult patients (median age 51 years; range, 18-83) with newly diagnosed chronic-phase chronic myeloid leukemia to investigate the efficacy and the toxicity of front-line treatment with nilotinib. The initial dose was 400 mg twice daily; the dose was reduced to 300 mg twice daily as soon as this dose was approved and registered. The 10-year overall survival and progression- free survival were 94.5%. At the last contact, 36 (49.3%) patients were continuing nilotinib (22 patients at 300 mg twice daily, 14 at lower doses), 18 (24.7%) patients were in treatment-free remission, 14 (19.2%) were receiving other tyrosinekinase inhibitors and four (5.5%) patients have died. The rates of major and deep molecular responses by 10 years were 96% and 83%, respectively. The median times to major and deep molecular response were 6 and 18 months, respectively. After a median duration of nilotinib treatment of 88 months, 24 (32.9%) patients discontinued nilotinib while in stable deep molecular response. In these patients, the 2-year estimated treatment-free survival was 72.6%. The overall treatment-free remission rate, calculated on all enrolled patients, was 24.7% (18/73 patients). Seventeen patients (23.3%), at a median age of 69 years, had at least one arterial obstructive event. In conclusion, the use of nilotinib front-line in chronic phase chronic myeloid leukemia can induce a stable treatment-free remission in a relevant number of patients, although cardiovascular toxicity remains of concern.

Questions concerning tyrosine kinase-inhibitor therapy and transplants in chronic phase chronic myeloid leukaemia.

In this provocative commentary, we consider several questions posed by the late chronic myeloid leukaemia (CML) expert Prof. Michele Baccarani, which he challenged us to address after his death. He noted only a small proportion of people with chronic phase CML receiving tyrosine kinase-inhibitor (TKI)-therapy are likely to achieve sustained therapy-free remission (TFR) and even fewer are likely to be cured. Persons most likely to fail TKItherapy can be identified at diagnosis or soon after starting TKI-therapy. These persons are likely to need lifetime TKI-therapy with attendant risks of adverse events, cost and psychological consequences. Allogeneic transplants achieve much higher rates of leukaemia-free survival compared with TKI-therapy but are associated with transplant-related adverse events including an almost 20 percent risk of transplant-related deaths within 1 year post-transplant and a compromised quality-of-life because of complications such as chronic graft-versus-host disease. Subject-, disease- and transplant-related co-variates associated with transplant outcomes are known with reasonable accuracy. Not everyone likely to fail TKI-therapy is a transplant candidate. However, in those who candidates are physicians and patients need to weigh benefits and risks of TKI-therapy versus a transplant. We suggest transplants should be more often considered in the metric when counseling people with chronic phase CML unlikely to achieve TFR with TKI-therapy. We question whether we are discounting a possible important therapy intervention; we think so.

INCB84344-201: Ponatinib and steroids in frontline therapy for unfit patients with Ph+ acute lymphoblastic leukemia.

Tyrosine kinase inhibitors have improved survival for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, prognosis for old or unfit patients remains poor. In the INCB84344-201 (formerly GIMEMA LAL 1811) prospective, multicenter, phase 2 trial, we tested the efficacy and safety of ponatinib plus prednisone in newly diagnosed patients with Ph+ ALL ≥60 years, or unfit for intensive chemotherapy and stem cell transplantation. Forty-four patients received oral ponatinib 45 mg/d for 48 weeks (core phase), with prednisone tapered to 60 mg/m2/d from days-14-29. Prophylactic intrathecal chemotherapy was administered monthly. Median age was 66.5 years (range, 26-85). The primary endpoint (complete hematologic response [CHR] at 24 weeks) was reached in 38/44 patients (86.4%); complete molecular response (CMR) in 18/44 patients (40.9%) at 24 weeks. 61.4% of patients completed the core phase. As of 24 April 2020, median event-free survival was 14.31 months (95% CI 9.30-22.31). Median overall survival and duration of CHR were not reached; median duration of CMR was 11.6 months. Most common treatment-emergent adverse events (TEAEs) were rash (36.4%), asthenia (22.7%), alanine transaminase increase (15.9%), erythema (15.9%), and γ-glutamyltransferase increase (15.9%). Cardiac and vascular TEAEs occurred in 29.5% (grade ≥3, 18.2%) and 27.3% (grade ≥3, 15.9%), respectively. Dose reductions, interruptions, and discontinuations due to TEAEs occurred in 43.2%, 43.2%, and 27.3% of patients, respectively; 5 patients had fatal TEAEs. Ponatinib and prednisone showed efficacy in unfit patients with Ph+ ALL; however, a lower ponatinib dose may be more appropriate in this population. This trial was registered at www.clinicaltrials.gov as #NCT01641107.

Prognostic Factors for Overall Survival In Chronic Myeloid Leukemia Patients: A Multicentric Cohort Study by the Italian CML GIMEMA Network.

An observational prospective study was conducted by the CML Italian network to analyze the role of baseline patient characteristics and first line treatments on overall survival and CML-related mortality in 1206 newly diagnosed CML patients, 608 treated with imatinib (IMA) and 598 with 2nd generation tyrosine kinase inhibitors (2GTKI). IMA-treated patients were much older (median age 69 years, IQR 58-77) than the 2GTKI group (52, IQR 41-63) and had more comorbidities. Estimated 4-year overall survival of the entire cohort was 89% (95%CI 85.9-91.4). Overall, 73 patients (6.1%) died: 17 (2.8%) in the 2GTKI vs 56 (9.2%) in the IMA cohort (adjusted HR=0.50; 95% CI=0.26-0.94), but no differences were detected for CML-related mortality (10 (1.7%) vs 11 (1.8%) in the 2GTKIs vs IMA cohort (sHR=1.61; 0.52-4.96). The ELTS score was associated to CML mortality (high risk vs low, HR=9.67; 95%CI 2.94-31.74; p<0.001), while age (per year, HR=1.03; 95%CI 1.00-1.06; p=0.064), CCI (4-5 vs 2, HR=5.22; 95%CI 2.56-10.65; p<0.001), ELTS score (high risk vs low, HR=3.11; 95%CI 1.52-6.35, p=0.002) and 2GTKI vs IMA (HR=0.26; 95%CI 0.10-0.65, p=0.004) were associated to an increased risk of non-related CML mortality. The ELTS score showed a better discriminant ability than the Sokal score in all comparisons.

Perspectives and Emotional Experiences of Patients With Chronic Myeloid Leukemia During ENESTPath Clinical Trial and Treatment-Free Remission: Rationale and Protocol of the Italian Substudy.

Achievement of deep molecular response following treatment with a tyrosine kinase inhibitor (TKI) allows for treatment-free remission (TFR) in many patients with chronic myeloid leukemia (CML). Successful TFR is defined as the achievement of a sustained molecular response after cessation of ongoing TKI therapy. The phase 3 ENESTPath study was designed to determine the required optimal duration of consolidation treatment with the second-generation TKI, nilotinib 300 mg twice-daily, to remain in successful TFR without relapse after entering TFR for 12 months. The purpose of this Italian 'patient's voice CML' substudy was to evaluate patients' psycho-emotional characteristics and quality of life through their experiences of stopping treatment with nilotinib and entering TFR. The purpose of the present contribution is to early present the study protocol of an ongoing study to the scientific community, in order to describe the study rationale and to extensively present the study methodology. Patients aged ≥18 years with a confirmed diagnosis of Philadelphia chromosome positive BCR-ABL1+ CML in chronic phase and treated with front-line imatinib for a minimum of 24 months from the enrollment were eligible. Patients consenting to participate the substudy will have quality of life questionnaires and in-depth qualitative interviews conducted. The substudy will include both qualitative and quantitative design aspects to evaluate the psychological outcomes as assessed via patients' emotional experience during and after stopping nilotinib therapy. Randomization is hypothesized to be a timepoint of higher psychological alert or distress when compared to consolidation and additionally any improvement in health-related quality of life (HRQoL) due to nilotinib treatment is expected across the timepoints (from consolidation, to randomization, and TFR). An association is also expected between dysfunctional coping strategies, such as detachments and certain personality traits, and psychological distress and HRQoL impairments. Better HRQoL outcomes are expected in TFR compared to the end of consolidation. This substudy is designed for in-depth assessment of all potential psycho-emotional variables and aims to determine the need for personalized patient care and counselling, and also guide clinicians to consider the psychological well-being of patients who are considering treatment termination. NCT number: NCT01743989, EudraCT number: 2012-005124-15.

Molecular response and quality of life in chronic myeloid leukemia patients treated with intermittent TKIs: First interim analysis of OPTkIMA study.

BACKGROUND: Intermittent treatment with TKIs is an option for the great majority (70%-80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong. METHODS: The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de-escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR3.0 ) and to improve Health Related Quality of Life (HRQoL). RESULTS: Up to December 2018, 166/185 (90%) elderly CML patients in stable MR3.0 /MR4.0 completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR3.0 was 81% and 23.5% of the patients who lost the molecular response regained the MR3.0 after resuming TKI continuously. Patients' HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p < 0.001) but returned to the baseline value at 12 months and it was statistically significantly worse in women (p = 0.001). CONCLUSIONS: De-escalation of any TKI by 1 month ON/OFF schedule maintains the MR3.0 /MR4.0 in 81% of the patients during the first 12-24 months. No patients progressed to accelerated/blastic phase, all the patients (23.5%) losing MR3.0 regained the MR3.0 and none suffered from TKI withdrawn syndrome. The study firstly report on HRQoL in elderly CML patients moving from a continuous daily therapy to a de-escalated intermittent treatment.

Next-generation sequencing improves BCR-ABL1 mutation detection in Philadelphia chromosome-positive acute lymphoblastic leukaemia.

BCR-ABL1 kinase domain mutation testing in tyrosine kinase inhibitor (TKI)-resistant Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) patients is routinely performed by Sanger sequencing (SS). Recently, next-generation sequencing (NGS)-based approaches have been developed that afford greater sensitivity and straightforward discrimination between compound and polyclonal mutations. We performed a study to compare the results of SS and NGS in a consecutive cohort of 171 Ph+ ALL patients. At diagnosis, 0/44 and 3/44 patients were positive for mutations by SS and NGS respectively. Out of 47 patients with haematologic resistance, 45 had mutations according to both methods, but in 25 patients NGS revealed additional mutations undetectable by SS. Out of 80 patients in complete haematologic response but with BCR-ABL1 ≥0·1%, 28 (35%) and 52 (65%) were positive by SS and NGS respectively. Moreover, in 12 patients positive by SS, NGS detected additional mutations. NGS resolved clonal complexity in 34 patients with multiple mutations at the same or different codons and identified 35 compound mutations. Our study demonstrates that, in Ph+ ALL on TKI therapy, NGS enables more accurate assessment of mutation status both in patients who fail therapy and in patients with minimal residual disease above 0·1%.

Validation and reference values of the EORTC QLQ-CML24 questionnaire to assess health-related quality of life in patients with chronic myeloid leukemia.

Health-related quality of life (HRQOL) assessment is important to facilitate decisions in the current treatment landscape of chronic myeloid leukemia (CML). Therefore, the availability of a validated HRQOL questionnaire, specifically developed for CML patients treated with tyrosine kinase inhibitors (TKIs), may enhance quality of research in this area. We performed an international study including 782 CML patients to assess the validity of the EORTC QLQ-CML 24 questionnaire, and to generate HRQOL reference values to facilitate interpretation of results in future studies. Internal consistency, assessed with Cronbach's alpha coefficients, ranged from 0.66 to 0.83. In the confirmatory factor analysis, all standardized factor loadings exceeded the threshold of 0.40 (range 0.49-0.97), confirming the hypothesized scale structure. Reference values stratified by age and sex were also generated. Our findings support the use of the EORTC QLQ-CML 24, in conjunction with the EORTC QLQ-C30, as a valuable measure to assess HRQOL in CML patients.

Correction: High-risk additional chromosomal abnormalities at low blast counts herald death by CML.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The EUTOS long-term survival (ELTS) score is superior to the Sokal score for predicting survival in chronic myeloid leukemia.

Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.

Chronic Myeloid Leukemia Prognosis and Therapy: Criticisms and Perspectives.

Ph+ chronic myeloid leukemia (CML) is a clonal myeloproliferative disease whose clinical course is characterized by progression disease from the early chronic phase (CP) to the fatal blastic phase (BP). This programmed course is closely related to the translocation t(9;22)(q22;q11) and the resulting BCR-ABL1 fusion protein (p210) that drives the leukemic transformation of hematopoietic stem cells. Therefore, the cure of CML can only pass through the abrogation of the Ph+ clone. Allogeneic stem cell transplantation (allo-SCT) and interferon-alpha (IFNα) have been proven to reduce the Ph+ clone in a limited proportion of CML population and this translated in a lower rate of progression to BP and in a significant prolongation of survival. Tyrosine-kinase inhibitors (TKIs), lastly introduced in 2000, by preventing the disease blastic transformation and significantly prolonging the survival in up to 90% of the patient population, radically changed the fate of CML. The current therapy with TKIs induces a chronicization of the disease but several criticisms still persist, and the most relevant one is the sustainability of long-term therapy with TKIs in terms of compliance, toxicity and costs. The perspectives concern the optimization of therapy according to the age, the risk of disease, the potency and the safety profiles of the TKIs. The prolongation of survival is the most important end point which should be guaranteed to all patients. The treatment free remission (TFR) is the new goal that we would like to give to an increasing number of patients. The cure remains the main objective of CML therapy.

High-risk additional chromosomal abnormalities at low blast counts herald death by CML.

Blast crisis is one of the remaining challenges in chronic myeloid leukemia (CML). Whether additional chromosomal abnormalities (ACAs) enable an earlier recognition of imminent blastic proliferation and a timelier change of treatment is unknown. One thousand five hundred and ten imatinib-treated patients with Philadelphia-chromosome-positive (Ph+) CML randomized in CML-study IV were analyzed for ACA/Ph+ and blast increase. By impact on survival, ACAs were grouped into high risk (+8, +Ph, i(17q), +17, +19, +21, 3q26.2, 11q23, -7/7q abnormalities; complex) and low risk (all other). The presence of high- and low-risk ACAs was linked to six cohorts with different blast levels (1%, 5%, 10%, 15%, 20%, and 30%) in a Cox model. One hundred and twenty-three patients displayed ACA/Ph+ (8.1%), 91 were high risk. At low blast levels (1-15%), high-risk ACA showed an increased hazard to die compared to no ACA (ratios: 3.65 in blood; 6.12 in marrow) in contrast to low-risk ACA. No effect was observed at blast levels of 20-30%. Sixty-three patients with high-risk ACA (69%) died (n = 37) or were alive after progression or progression-related transplantation (n = 26). High-risk ACA at low blast counts identify end-phase CML earlier than current diagnostic systems. Mortality was lower with earlier treatment. Cytogenetic monitoring is indicated when signs of progression surface or response to therapy is unsatisfactory.

MEC (mitoxantrone, etoposide, and cytarabine) induces complete remission and is an effective bridge to transplant in acute myeloid leukemia.

INTRODUCTION: Clinical response and chemosensitivity of relapse or refractory AML patients were evaluated after rescue and bridge-to-transplant MEC (mitoxantrone, etoposide, and cytarabine) regimen. METHODS AND PATIENTS: Fifty-five consecutive AML patients were treated with MEC from 2009 to 2018. Chemosensitivity was evaluated by WT1 quantification. RESULTS: 27/55 patients (49.1%) had AML resistant to induction and 28/55 patients (50.9%) had AML relapse. 25/55 patients (45.5%) achieved a CR after one course of MEC, and 12 patients (21.8%) achieved WT1 negativity. In 12 patients, a second MEC was administered. Four out of 12 patients improved significantly their response with the 2nd MEC. MEC was an effective bridge to transplant, 32/55 patients (58.2%) received an allogenic stem cell transplant. Median overall survival (OS) from MEC was 455 days (95% CI 307-602 days.); patient with WT1 negative CR had the best OS (P<.000). CONCLUSION: WT1 is a useful marker of chemosensitivity after MEC as rescue and bridge-to-transplant therapy.

Prospective assessment of NGS-detectable mutations in CML patients with nonoptimal response: the NEXT-in-CML study.

In chronic myeloid leukemia (CML) patients, tyrosine kinase inhibitors (TKIs) may select for drug-resistant BCR-ABL1 kinase domain (KD) mutants. Although Sanger sequencing (SS) is considered the gold standard for BCR-ABL1 KD mutation screening, next-generation sequencing (NGS) has recently been assessed in retrospective studies. We conducted a prospective, multicenter study (NEXT-in-CML) to assess the frequency and clinical relevance of low-level mutations and the feasibility, cost, and turnaround times of NGS-based BCR-ABL1 mutation screening in a routine setting. A series of 236 consecutive CML patients with failure (n = 124) or warning (n = 112) response to TKI therapy were analyzed in parallel by SS and NGS in 1 of 4 reference laboratories. Fifty-one patients (22 failure, 29 warning) who were negative for mutations by SS had low-level mutations detectable by NGS. Moreover, 29 (27 failure, 2 warning) of 60 patients who were positive for mutations by SS showed additional low-level mutations. Thus, mutations undetectable by SS were identified in 80 out of 236 patients (34%), of whom 42 (18% of the total) had low-level mutations somehow relevant for clinical decision making. Prospective monitoring of mutation kinetics demonstrated that TKI-resistant low-level mutations are invariably selected if the patients are not switched to another TKI or if they are switched to a inappropriate TKI or TKI dose. The NEXT-in-CML study provides for the first time robust demonstration of the clinical relevance of low-level mutations, supporting the incorporation of NGS-based BCR-ABL1 KD mutation screening results in the clinical decision algorithms.

Consistency matters: measurement invariance of the EORTC QLQ-C30 questionnaire in patients with hematologic malignancies.

PURPOSE: To ensure that observed differences in the scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) reflect actual differences in health-related quality of life (HRQoL) rather than measurement bias, measurement invariance needs to be established. We investigated the assumption of measurement invariance of the EORTC QLQ-C30 in patients with hematological malignancies across age, sex, comorbidity, disease type, and time. METHODS: We used a large database of patients with hematological malignancies, which included HRQoL data collected with the EORTC QLQ-C30. We used the structural equation modeling approach to test for measurement (metric and scalar) invariance across groups (age, sex, comorbidity, disease) and time (baseline, 1 month and 2 month follow-up). Longitudinal invariance was examined in a subgroup of patients diagnosed with myelodysplastic syndromes. RESULTS: Confirmatory factor analyses demonstrated full measurement invariance for age and comorbidity and over time, while support for partial scalar invariance was obtained for sex and disease. Violations of invariance for sex were observed for items of the physical functioning scale and the emotional functioning scale, while for disease type, violations of invariance were observed for items of the physical functioning scale, emotional functioning scale, and the cognitive functioning scale. CONCLUSIONS: Our findings support measurement invariance of the EORTC QLQ-C30 in a large sample of patients with hematological malignancies. The results showed that the number of non-invariant items was negligible, suggesting that this questionnaire is a valid and robust measurement tool in patients with hematological malignancies, also for comparisons across groups and time.

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 ≤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.