Search Results (33)

Background/Objectives: The advent of tyrosine kinase inhibitors (TKIs) revolutionized the management of chronic myeloid leukemia (CML), achieving survival rates near those of the general population. Despite this success, prolonged therapy presents challenges, including physical, emotional, and financial burdens. Treatment-free remission (TFR), defined as sustained deep molecular response (DMR) after discontinuing TKIs, has emerged as a viable clinical goal. This study evaluates real-world data from the Canary Islands Registry of CML (RCLMC) to explore outcomes, predictors, and the feasibility of TFR. Methods: This retrospective observational study included 393 patients diagnosed with CML-CP between 2007 and 2023. Molecular response was monitored according to international guidelines. Survival probabilities were estimated using the Kaplan–Meier method. Logistic regression analysis was performed to identify predictors of molecular relapses after TKI discontinuation. Results: Of the 383 patients who received TKI treatment, 58.3% achieved molecular response grade 2 (MR2) (BCR-ABL1 ≤ 1%), 95.05% achieved MR2, and 50.5% reached MR4 within the first year. Of the 107 patients attempting TFR, 73.2% maintained remission at 36 months. Relapses occurred in 24 patients, all regaining molecular response upon reintroduction of TKIs. No cases of disease progression were observed. Conclusions: Our findings support the feasibility and safety of TFR in a real-world clinical setting for well-selected patients, with outcomes consistent with international studies. The study underscores the importance of molecular monitoring and patient-specific strategies to optimize outcomes. Full article

Over the past two decades, the treatment landscape of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) has undergone a profound transformation. Once considered the subtype with the worst prognosis, Ph+ ALL is now associated with the possibility of long-term survival in a significant proportion of patients. This dramatic improvement has been driven by the advent of tyrosine kinase inhibitors (TKIs) and, more recently, by the incorporation of blinatumomab, a bispecific T-cell engager antibody, into frontline therapeutic strategies. In this evolving context, two major areas have become the focus of clinical investigation: on the one hand, the identification of high-risk patients who truly benefit from allogeneic hematopoietic stem cell transplantation (allo-HSCT); on the other, the characterization of patients who can achieve durable responses without transplantation and who may be candidates for treatment discontinuation of TKIs. This review aims to summarize the current evidence supporting the concept of treatment-free remission (TFR) in Ph+ ALL. Full article

Background: Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs), patients with chronic myeloid leukemia (CML) often face adverse effects, prompting investigations into treatment-free remission (TFR) for patients with sustained deep responses. Methods: Our objective was to assess real-world outcomes of TFR in a single-center cohort of patients in the southeastern U.S., as well as to compare different TKI management strategies (abrupt cessation of a TKI at a standard dose, TKI dose tapering prior to cessation, or upfront TKI dose reduction followed by abrupt cessation before TFR). Results: We queried our CML database of 233 patients and identified 39 patients that aimed for TFR. The median TFR duration was 14.6 months, with 63% actively remaining in TFR with a median follow-up of 21 m. TFR was lost by 54%, 16%, 8%, and 21% of patients in 0–6 m, 6–12 m, 1–2 y, and >2 y, respectively. Among the three TKI management strategies, the safety outcomes were comparable, with no instances of disease progression or CML-related mortality. All patients who lost TFR successfully regained a major molecular response (MMR) upon the resumption of TKIs. In terms of efficacy, 61%, 59%, and 59% of patients who underwent abrupt cessation of standard-dose TKIs, standard-dose tapering, or upfront dose reduction maintained TFR, respectively. Conclusions: Our study highlights the relative safety of pursuing TFR via different TKI treatment strategies in a real-world setting. Full article

Treatment-free remission (TFR) is a key therapeutic goal for chronic myeloid leukemia (CML) patients in deep molecular response (DMR). While predicting patient outcome remains challenging, different NK cell populations seem crucial. We conducted an immunological sub-study from the Argentina Stop Trial (AST), including 46 patients in 2019 (AST I) and 35 new patients between 2022 and 2023 (AST II). To characterize NK cell subsets in patients attempting TFR, peripheral blood mononuclear cell samples were collected before stopping treatment and phenotype and functional characteristics were assessed by flow cytometry. Non-relapsing patients from AST I exhibited NK cell subpopulations with cytomegalovirus-related memory features, high expression of cytotoxicity markers, and robust functionality. Remarkably, though clinical variables were very similar between cohorts, significant immune differences were observed. NK cell percentage and CD16 and CD57 receptor expression levels were significantly reduced in AST II (p = 0.0051; p = 0.0222; p = 0.0033, respectively), whereas NKp46, NKp44 and PD-1 expression levels were significantly increased (p = 0.0081; p < 0.0001; p < 0.0001, respectively). NK cells from AST II patients demonstrated higher overall functionality and more memory-like subpopulations, characterized mainly by the expression of CD57, NKG2C, NKp30 and NKp46 receptors among CD56^dim NK cells, also with enhanced functional performance. However, in AST II, we were unable to report an association with clinical outcome. Given the enrollment time of both cohorts and that they appear to be clinically homogeneous, we consider that COVID could be impacting the immune landscape; accordingly, serum samples from AST II, but not AST I, confirmed the presence of anti-SARS-CoV-2 IgG. The influence of the COVID pandemic and the different vaccine platforms on NK cells cannot be underestimated when evaluating the role of the immune system in cancer. Full article

Background: We previously showed that peptides encompassing the unique b3a2 or b2a2 breakpoint amino-acid sequence of oncogenic p210 induced peptide-specific T-cell responses in chronic myeloid leukemia (CML) patients. Methods: From 2007 to 2011, two multicenter peptide vaccine phase II studies, GIMEMA CML0206 and SI0207, enrolling overall 109 CML patients (68 b3a2 and 41 b2a2) with persistence of molecular disease during imatinib treatment, were carried out. Peptide vaccination schedule included the following: “immunization phase” (six vaccinations every 2 weeks); “reinforcement” phase (three monthly boosts) and “maintenance” phase (two boosts at 3-month intervals). GM-CSF (granulocyte-macrophage-colony-stimulating factor, sarmograstim) served as the immunological adjuvant. Results: The short-term results (at completion of vaccine protocol—12 months) and long-term follow-up are reported. All patients completed the vaccination schedule with no toxicity. After vaccinations, the BCR::ABL1 peptide-specific CD4+ T-cell response was documented in 80% of patients. In the short term, 30% of patients achieved a reduction in BCR::ABL1, while the majority showed stable molecular disease with fluctuations. The median follow-up since diagnosis and last vaccination are 18 and 10 years, respectively, with an overall survival (OS) rate at 18 years of 89%. In addition, 97/109 (89%) patients are alive, while 12/109 (11%) died of CML-unrelated reasons. Overall, 18/109 (16.5%) patients are in treatment-free remission (TFR) for a median time of 48 months. Conclusions: The long-term results of p210 peptide vaccinations in CML patients with persisting disease during imatinib treatment showed its feasibility, safety, absence of off-targets events, high OS and not negligible rate of successful TFR. Active immunotherapeutic approaches in CML patients with low disease burden, eventually employing newer vaccine strategies such as mRNA vaccines, may be reconsidered. Full article

Background/Objectives: Chronic myeloid leukemia (CML) is characterized by the presence of the BCR::ABL1 fusion gene, most commonly in the e14a2 or e13a2 variants. Studies show that the transcript type in CML may be important for achieving treatment-free remission (TFR). This study aimed to immunologically characterize CML patients with e13a2 and e14a2 transcripts to search for differences that may contribute to achieving remission in patients after therapy withdrawal. Methods: Using multicolor flow cytometry, we analyzed the differences in the immune system at the time of imatinib discontinuation and the early stage of TFR in fifty-one CML patients with different transcripts. RQ-PCR and ddPCR were used to monitor the dynamics of BCR::ABL1 transcript changes. The patients were grouped using principal component analysis (PCA) based on the percentage of detected immune cells that were classified as populations consistently selected by the MCFS-ID algorithm from randomly selected data. Results: PCA separated CML patients into two groups defined by k-means clustering, indicating significant heterogeneity within the studied population. We found a significant association between Cluster metrics (Cluster 1 and 2) and BCR::ABL1 transcript types (e13a2 or e14a2) (p = 0.003, 95% CI: 0.026–0.595, OR = 0.14, Fisher test). The e13a2 transcript was less frequent in Cluster 2 than in Cluster 1, while e14a2 was more common in Cluster 2. Additionally, patients grouped into Cluster 1 had significantly higher percentages of the PD1 expressing populations cDC PD1⁺, CD56^dimCD16⁺PD1⁺, CD8⁺PD1⁺, CD4⁺PD1⁺, and CD19⁺PD1⁺, as identified by the MCFS-ID algorithm, compared to patients in Cluster 2. Conclusions: Our results suggest that immunological differences may be related to the BCR::ABL1 transcript type, which could affect the number of active CML cells represented by the BCR::ABL1 transcript amount and thus may determine molecular recurrence. Full article

Background: ABL1 tyrosine kinase inhibitor discontinuation securely became among the therapeutic goal for chronic myeloid leukemia chronic phase patients (CML-CP). To establish successful prognostic factors for treatment-free remission (TFR), it is necessary to diagnose the patients with high-risk molecular relapse, however, a biomarker for the achievement of TFR has not been completely elucidated. Recent investigations have determined that neutrophils function crucially in cancer immunology. Patients and Methods: The research was a multicenter retrospective observational study to examine the correlation between TFR and neutrophil counts before TKI discontinuation. The investigation included patients having Philadelphia chromosome-positive CML-CP who attempted the discontinuation of TKIs after a durable deep molecular response between January 2012 and July 2021 at four institutions in Japan. Results: 118 CML-CP patients in total discontinued TKIs and an estimated 36-month TFR rate was 65.1%. 52 patients received second-generation TKIs as frontline. Higher neutrophil count (>3210/μL) at TKIs discontinuation was determined as an independent prognostic variable for TFR in patients who received second-generation TKIs as frontline [(HR, 0.235 (95%, confidence interval (CI) 0.078–0.711); p = 0.010]. Conclusions: The neutrophil-mediated immunomodulation can be a significant component for the effective achievement of TFR in CML supported by our clinical observation. Full article

Tyrosine kinase inhibitor (TKI) drugs have significantly improved chronic myeloid leukemia (CML) outcomes. Neopeptides from CML cells may induce specific immune responses, which are crucial for deep molecular (DMR) and treatment-free remission (TFR). In this study of Ethiopian patients with CML (n = 162), the HLA alleles and single-nucleotide polymorphisms of five cytokines revealed significant associations with clinical outcomes. Clinically unfavorable outcomes correlated with HLA alleles A*03:01/02, A*23:17:01, B*57:01/02/03, and HLA-DRB4*01:01 (p-value = 0.0347, p-value = 0.0285, p-value = 0.037, and p-value = 0.0127, respectively), while HLA-DRB4*01:03:01 was associated with favorable outcomes (p-value = 0.0058). After assigning values for the ‘low’, ‘intermediate’, and ‘high’ gene expression of the SNPs’ respective cytokine genes, Kaplan–Meier estimates for relapse-free survival, adjusted for age, treatment duration, and relapse risk among patients after the administration of TKIs, indicated that a gene expression ratio above the overall median of TNF-α, IL-6, and the combination of TGF-β1/IL-10, IFNγ, and IL-6/IL-10 TGF-β1 was correlated with a higher likelihood of treatment failure ((RR: 3.01; 95% CI: 1.1–8.3; p-value = 0.0261) and (RR: 2.4; 95% CI: 1.1–5.2; p-value = 0.022), respectively). Multi-SNPs, surpassing single-SNPs, and HLA allele polymorphisms showed promise in predicting outcomes of patients with CML during TKI treatment, prompting further exploration into their potential utility. Full article

With the discovery of tyrosine kinase inhibitors (TKIs), overall survival in patients with chronic myeloid leukemia (CML) now approaches that of the general population. While these TKIs have proven to be lifesaving, remaining on them lifelong creates both physical and financial burdens for patients. Recently, multiple trials have begun looking into the efficacy of trialing patients off these TKIs to see if they can sustain treatment-free remission (TFR). TFR eligibility is currently limited to a small population of patients with both robust and sustained responses to TKIs. Currently, for those who attempt a trial of TFR, the average success rates are promising, with anywhere from 38 to 54% of patients experiencing sustained TFR. For those who fail to maintain sustained TFR, safety results to date are reassuring, with almost all patients successfully responding to the re-initiation of TKIs, with death and disease progression being very rare complications. Moving forward, research is being conducted to more accurately risk stratify patients at diagnosis and pair them with optimized upfront treatment regimens aimed at increasing candidacy for the trial of TFR. Full article

Treatment-free remission (TFR) is achieved in approximately half of chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors. The mechanisms responsible for TFR maintenance remain elusive. This study aimed to identify immune markers responsible for the control of residual CML cells early in the TFR (at 3 months), which may be the key to achieving long-term TFR and relapse-free survival (RFS) after discontinuation of imatinib. Our study included 63 CML patients after imatinib discontinuation, in whom comprehensive analysis of changes in the immune system was performed by flow cytometry, and changes in the BCR::ABL1 transcript levels were assessed by RQ-PCR and ddPCR. We demonstrated a significant increase in the percentage of CD8⁺PD-1⁺ cells in patients losing TFR. The level of CD8⁺PD-1⁺ cells is inversely related to the duration of treatment and incidence of deep molecular response (DMR) before discontinuation. Analysis of the ROC curve showed that the percentage of CD8⁺PD-1⁺ cells may be a significant factor in early molecular recurrence. Interestingly, at 3 months of TFR, patients with the e13a2 transcript had a significantly higher proportion of the PD-1-expressing immune cells compared to patients with the e14a2. Our results suggest the important involvement of CD8⁺PD-1⁺ cells in the success of TFR and may help in identifying a group of patients who could successfully discontinue imatinib. Full article

Hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML) patients has transitioned from the standard of care to a treatment option limited to those with unsatisfactory tyrosine kinase inhibitor (TKI) responses and advanced disease stages. In recent years, the threshold for undergoing HSCT has increased. Most CML patients now have life expectancies comparable to the general population, and therefore, the goal of therapy is shifting toward achieving treatment-free remission (TFR). While TKI discontinuation trials in CML show potential for achieving TFR, relapse risk is high, affirming allogeneic HSCT as the sole curative treatment. HSCT should be incorporated into treatment algorithms from the time of diagnosis and, in some patients, evaluated as soon as possible. In this review, we will look at some of the recent advances in HSCT, as well as its indication in the era of aiming for TFR in the presence of TKIs in CML. Full article

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript. Full article

Background: While the outcomes of chronic phase chronic myeloid leukemia (CP-CML) patients aged over 65 years have been extensively evaluated in real-life experiences, limited data exist for the very elderly population (i.e., aged ≥ 75 years), especially for next-generation tyrosine kinase inhibitors (TKIs). In this retrospective study, we sought to evaluate the safety and efficacy of TKIs in this particular setting of patients. Methods: We conducted a retrospective analysis of a multicenter cohort of 123 newly diagnosed CP-CML very elderly patients. Results: The median age at diagnosis was 80 years (range: 75–96). In the first line, 86.1% of patients received imatinib, 7.1% dasatinib, 5.6% nilotinib, and 0.81% received bosutinib. A total of 31 patients (25.2%) switched to second-line therapy, nine patients to a third line, and one patient to a fourth line of therapy. Resistance to treatment was the primary reason for switching therapy in both the first (64.5%) and second lines (77.7%). At diagnosis, reduced doses were administered in 36.5% of patients, in 61.2% in the second line, and in all patients in subsequent lines of therapy. In the first-line setting, 71.9% of patients achieved an early molecular response (EMR, i.e., 3-month BCR::ABL1^IS < 10%); at 6, 12, and 24 months, MR3 was reached by 35.7%, 55.7%, and 75.0% of patients, respectively, with 16.6%, 35.7%, and 51.7% achieving a deep molecular response (DMR) at the same time points. Treatment-free remission (TFR) was successfully attempted in 11 patients. During the follow-up period, adverse events (AEs) were observed in 78.8% of patients, including 22 cases of cardiovascular AEs. Toxicity grade ≥ 3 was more commonly observed in patients treated with standard doses of TKIs compared to reduced doses (p = 0.033). Overall, the median follow-up was 46.62 months (range: 1.8–206.2), and 43 patients died due to non-CML-related causes. Three patients died due to disease progression to advanced (n = 1) and blastic (n = 2) phases. The 5-year overall survival (OS) for the entire cohort was 71.9% (95% CI: 0.63–0.81), with no significant difference between the patients treated with standard doses of TKIs compared to those treated with reduced doses (p = 0.35). Conclusions: TKIs appear to be safe and effective even in very elderly CML patients, and dose optimization strategies yield satisfactory molecular responses for adequate disease control with an improved safety profile. Full article

Individuals with chronic myeloid leukemia (CML) constitute a unique group within individuals with oncohematological disease (OHD). They receive treatment with tyrosine kinase inhibitors (TKIs) that present immunomodulatory properties, and they may eventually be candidates for treatment discontinuation under certain conditions despite the chronic nature of the disease. In addition, these individuals present a lower risk of infection than other immunocompromised patients. For this study, we recruited a cohort of 29 individuals with CML in deep molecular response who were on treatment with TKIs (n = 23) or were on treatment-free remission (TFR) (n = 6), and compared both humoral and cellular immune responses with 20 healthy donors after receiving the complete vaccination schedule against SARS-CoV-2. All participants were followed up for 17 months to record the development of COVID-19 due to breakthrough infections. All CML individuals developed an increased humoral response, with similar seroconversion rates and neutralizing titers to healthy donors, despite the presence of high levels of immature B cells. On the whole, the cellular immune response was also comparable to that of healthy donors, although the antibody dependent cytotoxic activity (ADCC) was significantly reduced. Similar rates of mild breakthrough infections were observed between groups, although the proportion was higher in the CML individuals on TFR, most likely due to the immunomodulatory effect of these drugs. In conclusion, as with the healthy donors, the vaccination did not impede breakthrough infections completely in individuals with CML, although it prevented the development of severe or critical illness in this special population of individuals with OHD. Full article

A Deep Molecular Response (DMR), defined as a BCR::ABL1 transcript at levels ≤ 0.01% by RT-qPCR, is the prerequisite for the successful interruption of treatment among patients with Chronic Myeloid Leukemia (CML). However, approximately 50% of patients in Treatment-Free Remission (TFR) studies had to resume therapy after their BCR::ABL1 transcript levels rose above the 0.1% threshold. To improve transcript detection sensitivity and accuracy, transcript levels can be analyzed using digital PCR (dPCR). dPCR increases BCR::ABL1 transcript detection sensitivity 10–100 fold; however, its ability to better select successful TFR patients remains unclear. Beyond the role of the immune system, relapses may be due to the presence of residual leukemic stem cells (LSCs) that are transcriptionally silent. Flow cytometry can be used to identify and quantify circulating bone marrow Ph+ LSCs CD34+/CD38− co-expressing CD26 (dipeptidylpeptidase-IV). To date, the significance of circulating Ph+ LSCs in TFR is unclear. The aim of this work is to compare and examine the values obtained using the three different methods of detecting minimal residual disease (MRD) in CML at RNA (RT-qPCR and dPCR) and LSC (flowcytometry) levels among patients in TFR or exhibiting a DMR. The twenty-seven patients enrolled received treatment with either imatinib (12), dasatinib (6), nilotinib (7), bosutinib (1), or interferon (1). Twelve patients were in TFR, while the rest exhibited a DMR. The TFR patients had stopped therapy for less than 1 year (3), <3 years (2), 6 years (6), and 17 years (1). Blood samples were collected and tested using the three methods at the same time. Both d-PCR and LSCs showed higher sensitivity than RT-qPCR, exhibiting positive results in samples that were undetectable using RT-qPCR (17/27). None of the patients tested negative with d-PCR; however, 23/27 were under the threshold of 0.468 copies/μL, corresponding to a stable DMR. The results were divided into quartiles, and the lowest quartiles defined the lowest MRD. These data were strongly correlated in 15/27 patients, corresponding to almost half of the TFR patients. Indeed, the TFR patients, some lasting up to 17 years, corresponded to the lowest detectable DMR categories. To the best of our knowledge, this is the first attempt to analyze and compare DMRs in a CML population using standard (RT-qPCR) and highly sensitive (dPCR and LSCs) methods. Full article