Chronic myeloid leukemia in blast crisis treated with imatinib 600 mg: outcome of the patients alive after a 6-year follow-up

Background Imatinib mesylate is the first line treatment for chronic myeloid leukemia. In patients with advanced phase of the disease, the advent of imatinib significantly increased survival. However, few long-term data, based on large, prospective and controlled trials are available on the outcome of these patients. Design and Methods We conducted a phase II trial of imatinib 600 mg daily in patients with chronic myeloid leukemia in blast crisis. The return to chronic phase was defined as <15% blasts and <30% blasts plus promyelocytes in blood or bone marrow and <20% peripheral basophils. A complete hematologic response required the normalization of platelet and white cell differential counts and absence of extramedullary involvement. Cytogenetic response was assessed by the standard banding technique and rated as usual. Results Ninety-two patients were enrolled (20 with lymphoid blast crisis and 72 with myeloid blast crisis). Forty-six patients (50%) returned to chronic phase, and 24 patients (26%) achieved also a complete hematologic response. Sixteen patients (17%) had a cytogenetic response (9 complete, 1 partial, and 6 minor or minimal). The complete cytogenetic response was subsequently lost by all but two patients between 2 and 12 months after first having achieved it: the median duration of complete cytogenetic response was 7 months. All responses were sustained for a minimum of 4 weeks. The median survival of all the patients was 7 months. After a median observation time of 66 months, seven (8%) patients are alive. Three of these patients are on imatinib treatment (1 in complete hematologic remission, 1 in partial cytogenetic response and 1 in complete cytogenetic remission). Three patients are in complete remission after allogeneic stem cell transplantation. One patient is alive in blast crisis, on therapy with a second-generation tyrosine kinase inhibitor. Conclusions Imatinib was effective and safe in the short-term treatment of chronic myeloid leukemia in blast crisis, but longer-term outcome was not significantly influenced (ClinicalTrials.gov identifier: [NCT00514969][1]). [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00514969&atom=%2Fhaematol%2F93%2F12%2F1792.ato

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 (NCT 00481052), 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 tyrosine-kinase 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

Treatment-Free Remission in Chronic Myeloid Leukemia Patients Treated With Low-Dose TKIs: A Feasible Option Also in the Real-Life. A Campus CML Study

Treatment-free remission (TFR) has become a primary therapeutic goal in CML and is also considered feasible by international guidelines. TKIs dose reduction is often used in real-life practice to reduce adverse events, although its impact on TFR is still a matter of debate. This study aimed to explore the attitude of Italian hematologists towards prescribing TKIs at reduced doses and its impact on TFR. In September 2020, a questionnaire was sent to 54 hematology centers in Italy participating to the Campus CML network. For each patient, data on the main disease characteristics were collected. Most of the hematologists involved (64.4%) believed that low-dose TKIs should not influence TFR. Indeed, this approach was offered to 194 patients. At the time of TFR, all but 3 patients had already achieved a DMR, with a median duration of 61.0 months. After a median follow-up of 29.2 months, 138 (71.1%) patients were still in TFR. Interestingly, TFR outcome was not impaired by any of the variables examined, including sex, risk scores, BCR-ABL1 transcript types, previous interferon, type and number of TKIs used before treatment cessation, degree of DMR or median duration of TKIs therapy. On the contrary, TFR was significantly better after dose reduction due to AEs; furthermore, patients with a longer DMR duration showed a trend towards prolonged TFR. This survey indicates that low-dose TKI treatment is an important reality. While one third of Italian hematologists still had some uncertainties on TFR feasibility after using reduced doses of TKIs outside of clinical trials, TFR has often been considered a safe option even in patients treated with low-dose TKIs in the real-life setting. It should be noted that only 28.9% of our cases had a molecular recurrence, less than reported during standard dose treatment. Consequently, TFR is not impaired using low-dose TKIs

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

he 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 us

Treatment discontinuation following low-dose TKIs in 248 chronic myeloid leukemia patients: Updated results from a campus CML real-life study

TKIs long-term treatment in CML may lead to persistent adverse events (AEs) that can promote relevant morbidity and mortality. Consequently, TKIs dose reduction is often used to prevent AEs. However, data on its impact on successful treatment-free remission (TFR) are quite scarce. We conducted a retrospective study on the outcome of CML subjects who discontinued low-dose TKIs from 54 Italian hematology centers participating in the Campus CML network. Overall, 1.785 of 5.108 (35.0%) regularly followed CML patients were treated with low-dose TKIs, more frequently due to relevant comorbidities or AEs (1.288, 72.2%). TFR was attempted in 248 (13.9%) subjects, all but three while in deep molecular response (DMR). After a median follow-up of 24.9 months, 172 (69.4%) patients were still in TFR. TFR outcome was not influenced by gender, Sokal/ELTS risk scores, prior interferon, number and last type of TKI used prior to treatment cessation, DMR degree, reason for dose reduction or median TKIs duration. Conversely, TFR probability was significantly better in the absence of resistance to any prior TKI. In addition, patients with a longer DMR duration before TKI discontinuation (i.e., >6.8 years) and those with an e14a2 BCR::ABL1 transcript type showed a trend towards prolonged TFR. It should also be emphasized that only 30.6% of our cases suffered from molecular relapse, less than reported during full-dose TKI treatment. The use of low-dose TKIs does not appear to affect the likelihood of achieving a DMR and thus trying a treatment withdrawal, but might even promote the TFR rate

Chronic Myeloid Leukemia Patient&apos;s Voice About the Experience of Treatment-Free Remission Failure: Results From the Italian Sub-Study of ENESTPath Exploring the Emotional Experience of Patients During Different Phases of a Clinical Trial

Background: The main objective of this study is to gain further insights on how chronic myeloid leukemia (CML) patients involved in an interventional clinical trial with the purpose of reaching treatment free remission (TFR) phase, perceived and experienced TFR failure. TFR failure was defined for the individual patient as either not being eligible for drug discontinuation or as having relapse in the TFR phase with reintroduction of nilotinib treatment. Methods: Using a qualitative approach, out of 25 patients with CML who experienced TFR failure 14 were interviewed. Patients' views and experiences were explored using in-depth interviews, analyzed using the Interpretative Phenomenological Analysis (IPA). Results: The analysis of the interviews revealed that the experience of the diagnosis seems to have been lived as a traumatic break that has created a dichotomy, like an ambivalence in the ways in which CML patients perceived and experienced the whole disease journey, with contradictory feelings of both positive and negative emotions (e.g., a diagnosis of cancer, that is something distressing and of being afraid of, but also with a treatment and a life expectancies of which being grateful). This ambivalence of feelings was found to give meaning to the way in which patients cognitively and emotionally experienced the different steps of their disease history. Thus, four main issues, corresponding to different steps of the patients' journey, were identified: (1) the moment of the diagnosis, (2) the experience of the illness journey: disease and treatment, (3) the moment of "TFR failure," and (4) the impact of disease, treatment and relapse on the patient's life. Conclusion: This qualitative analysis helps in understanding patients' perspective, both in terms of getting access to the inner subjective experience of having CML and its strict relationship with the involvement in a trial or its cessation. Clinicians should consider that the way in which CML patients feel engaged in a clinical trial, create expectancies about TFR or experience the TFR failure is linked to the process of coping with the diagnosis, which is characterized by ambivalence