Survival In Chronic Myeloid Leukemia Research Articles

The Use of 2 nd Generation TKIs As First Line Therapy Does Not Prevent CML Related Deaths: Results of an Italian CML Campus Prospective Study in 1277 Patients Treated First Line with Imatinib or 2 nd Generation TKIs

Background: In the last decades prognosis and survival of chronic myeloid leukemia (CML) patients have dramatically improved, thanks to a wider therapeutic armamentarium. Molecular responses are the milestones that guide clinical decisions; however, some information is still lacking and what we know derives mainly from investigational trials: it is still unclear if real-life management could lead to comparable results. For this reason, a prospective observational study was conducted by a CML Italian network to analyze molecular responses in a real-life setting. Methods: A web-based database (www.epiclin.it/lmc) was used to collect clinical and biological data on newly diagnosed CML prospective consecutive patients enrolled in 24 Italian Hematology Centers from January 2013 onwards. Patients were treated according to the policy of the center and the molecular data were obtained by performing tests in accordance with the IS% parameters. Results: A total of 1277 patients were enrolled (Tab. 1) with a median follow up of 4,1 years. There was a significant difference in the median age of patients who started with imatinib (IMA) or 2 nd gen TKIs (II-TKI): 70 vs 52, respectively. The Overall Survival (OS) of the whole cohort at 5 years was 80% for the IMA and 94% for II-TKI treated patients respectively. Out of the total 86 deaths observed in the IMA treated cohort only 11 (12.7%) were due to CML related causes, whereas out of the 32 deaths observed in the II-TKI treated cohort 12 (37.5%) were due to CML. Out of the 607 patients who were on first line IMA, 422/607 (69%) did not switch therapy and have an OS of 81% at 5 years. One hundred and eighty-five out of 607 (31%) changed therapy and showed an OS of 80% at 5 years. Out of 670 patients who started with II-TKI, 492 (73%) continued the same treatment and 178/670 (27%) changed therapy, showing a 5-year OS of 96% and 89%, respectively. In summary, patients who remain in the same type of therapy in which they were initially started show a 5-year OS of 81% and 96% for IMA and II-TKI respectively and only 9 of the total 73 deaths observed in this group of 914 patients were CML related (8 of 58 II-TKI treated patients). Patients who switched to another therapy showed 80% and 89% 5-year OS on IMA and II-TKI group, respectively. Of the 45 deaths observed in this group of 363 patients, 14 were CML related (3 on IMA and 11 on II-TKI) (Tab. 2). In IMA treated patients, 5-year OS according to 6- and 12-months molecular response was worse for patients with BCR::ABL1 >1% compared to those with values between 1 and 0.1% and <0.1% BCR::ABL1 patients (looking at 12 months response, OS was 65% vs 85% vs 90%, Fig. 1A). At 24 months there was a statistical difference in OS between patients with BCR::ABL1 between 1 and 0.1% versus those <0.1% (OS at 3 years was 82% vs 92%) (Fig. 1B). Among II-TKI treated patients, no significant differences in OS were observed, but there was only a generic trend for those with deeper molecular responses between patients with BCR::ABL1 >0.1 versus patients with BCR::ABL1 < 0.1% at all timepoints; to note, the deaths are few and were observed within the first year, independently from the molecular response achieved: at 6 months, 10 deaths on 113 patients of which 7 CML related; at 12 months, 5 deaths on 48 patients of which 4 CML related. Row comparisons of OS were confirmed with multivariable Cox models including main prognostic factors. Conclusions: The real-life data collected by this observational study support the good prognosis of CML patients obtained in our days independently by the TKI used in first line. Indeed, most of the deaths observed are due to CML unrelated causes and the use of II-TKIs does not seem to prevent the CML related deaths, whose number is similar in both cohorts. The fact that the OS is similar in those who remain in IMA therapy versus to those who switch could also simply reflect the presence of unfavorable prognostic factors at diagnosis not controlled by IMA nor by II-TKIs. In this scenario, the observation that the achievement of <1% at 12 months and of MMR at 24 months in patients treated with imatinib is endowed with a statistically significant better OS could simply represent an association rather than a determining factor. Early NGS study would probably provide helpful information at this regard and for identifying patients that, even if treated first line with II-TKIs, could benefit of an early switch, since 11 of the 12 progressions were observed in this group.

Chronic Myeloid Leukemia in Adolescents and Young Adults: A SEER-Based Analysis of Characteristics and Survival Outcomes of 1565 Patients

Introduction: Adolescents and Young Adults (AYA) are individuals between 15-39 years old. There are an estimated 1 million new cases of cancers in this age group yearly [1]. Although Chronic Myeloid Leukemia (CML) is typically a disease of middle-aged and elder patients, with a median age of 62 years [1], AYA accounts for about 22.1% of all CML cases [2]. There has been little focus directed towards this age group and most studies focus on the middle-aged and elderly. Despite the remarkable improvement in the survival of CML over the years, the largest study to date [3] suggested poor survival outcomes for patients in underserved populations and with low income. We aimed to determine whether sociodemographic differences exist in the AYA age group. Method: The Surveillance, Epidemiology, and End-Result (SEER) registry research plus database 17 (2000 -2020) was used to assess and compare the survival outcomes in the AYA group and older population diagnosed with CML. Both univariate and multivariate analyses were performed. Cox proportional hazards regression was used to determine prognostic factors for survival. A two-sided p-value ≤0.05 was considered significant. Results: A total of 6,319 patients with CML were identified, of which 75.2% (n= 4754) were adults ≥40 years, and 24.8% (n= 1565) were AYAs . Amongst the AYA, 51.4% (n=804) were Non-Hispanic White (NHW), 25 % (n=390) were Hispanics, 12.1% (n=189) were Non-Hispanic Black (NHB), 10.5% (n=164) were Non-Hispanic Asian or Pacific Islander (NHAPI) and 1.2% (n=18) were Non-Hispanic American Indian/Alaska Native (NHAIA) [Table 1]. The frequency of Hispanics in the AYA group was more compared to adults ≥40 years (25% vs 12.9%). NHWs had a lower frequency in the AYA group compared to adults ≥40 years (51.4% vs 67.5%) and NHBs had a similar distribution in both age groups (12.1% vs 11.6%). The proportion of mortality attributed to CML was lower in the AYA group compared to older adults ≥40 years (7.7% vs 11.9%). The results for individual Cox regression for each racial group show that AYA Hispanic males had a worse prognosis than females (HR= 2.930, 95% CI: 1.234-6.960), such observation was not seen in other AYA races [Table 2] but it was seen in Hispanic adult males ≥40 years (HR= 1.583, 95% CI: 1.074-2.334). Also, we identified that for patients aged ≥40 years, male sex was an independent poor prognostic factor for NHW (HR= 1.259, 95% CI: 1.074-1.476) and NWB (HR=1.879, 95% CI: 1.232-2.864) [Table 2]. Conclusion: Our study shows similar demographic characteristics between AYA and adults ≥40 years old. However, AYAs are less likely to die from CML compared to adults ≥40 years. Hispanic males appear to have a worse outcome than females, an observation seen in both age groups, and is independent of other analyzed prognostic factors. More research is needed to examine and identify other prognostic factors of CML in AYA with the aim of improving their survival outcomes.

Chronic myeloid leukemia, tyrosine kinase inhibitors and cardiovascular system.

Cardiovascular system health becomes important with the extended survival of chronic myeloid leukemia (CML) patients. Cardiotoxicities are related to the second- and third-generation tyrosine kinase inhibitors (TKIs). The most frequent and important cardiovascular events are myocardial infarction, stroke and peripheral arterial disease, QT prolongation, pleural effusions, and both systemic and pulmonary hypertension. The aim of this paper is to review the interactions between administrated TKIs and the cardiovascular system during the clinical course of CML. Elucidation of TKI effects on the cardiovascular system is vital since the current goal of CML therapy is a cure that leads to normal age and gender-similar survival with a normal quality of life. Up to August 2022, literature searches were performed via the internet search engines MEDLINE, EMBASE, GOOGLE SCHOLAR: (i) chronic myeloid leukemia; (ii) tyrosine kinase inhibitor; (iii) cardiovascular system. Only articles in English and research including humans were included in the search. Tailored TKI treatment with individual patient characteristics must account for CML disease risk, patient age, patient comorbidities, patient compliance, TKI drug off-target risk profile, accelerated or blastic phase CML disease, pregnancy and allografting in CML. The treatment-free survival, improving quality of life, limiting adverse events of TKIs, and the optimal dose and administration duration of TKIs are still a matter of controversy. Special attention should be paid to the comorbidities of CML patients and clinical TKI effects on CVS since the aim of CML treatment is a cure that leads to normal age and gender-similar survival with a "normal" quality of life. CVS is an important morbidity and mortality cause for adult patients. The discontinuation of TKI treatment in CML and the treatment-free remission of CML patients are very important in order to reduce the risk for cardiovascular adverse effects of TKIs. The frail CML patients and especially the patients who have cardiac comorbidities, should be carefully evaluated for TKI treatment, and hematopoietic stem cell transplantation (HSCT) should be the last choice in these risky CML patients. The current CML treatment target is a cure that leads to normal age and gender-adjusted survival with a "normal" quality of life. Cardiovascular disorders are one of the major obstacles to reaching this target in CML patients. The treatment choices for CML patients must include a cardiovascular perspective.

The Impact of Improved Treatments on Survival of Adult U.S. Leukemia Patients: 1990-2018.

Molecularly targeted therapies such as tyrosine kinase inhibitors (TKI) are effective treatments for B-cell receptor (BCR)-ABL-bearing leukemias. We evaluated the impact of TKIs on historical chronic myeloid leukemia (CML) mortality trends compared with acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). Because mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 U.S. (SEER) registries (1992-2017) among U.S. adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992-2017) and mortality (1992-2018) trends by subtype and diagnosis year. For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for patients with CML. Five-year CML survival increased dramatically over time, especially between 1996 to 2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992 to 2017. ALL mortality decreased 0.6% annually during 1992 to 2012 and then stopped declining. CLL incidence fluctuated during 1992 to 2017 while mortality decreased 1.1% annually during 1992 to 2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992 to 2016. Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials. Our study highlights the impact of molecularly targeted therapies at the population level.

Second-Line Therapy Tyrosine Kinase Inhibitor for Chronic Phase Chronic Myeloid Leukemia Resistant to Imatinib

Since the era of tyrosine kinase inhibitor (TKI) therapy, there has been an increase in the median survival of chronic myeloid leukemia. Nevertheless, nowadays there were several cases of chronic myeloid leukemia that are resistant to the first-line TKIs, so that several second-line TKIs were introduced. Assessment of the therapeutic response was performed using a complete peripheral blood examination, bone marrow aspiration cytogenetic examination, and quantitative BCR-ABL examination. The treatment failure criteria were applied based on the ELN criteria. In selecting the second line TKI should be based on the results of mutation analysis and consider the safety profile of the second line therapy. This paper will discuss the recommendations for second-line therapy TKI, adjusted to the resources in Indonesia.

Outcomes of Allogeneic Stem Cell Transplant in Chronic Myeloid Leukemia - Blast Phase: A Single-center Experience from South India

AbstractThe blast phase (BP) is challenging to treat and leads to inferior survival in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplant (AlloSCT) is the only curative option for CML-BP. We are sharing our experience of AlloSCT in seven patients with CML-BP who underwent transplants during the period from January 2017 to December 2019. Three patients each had myeloid-BP, lymphoid-BP, and one patient had mixed phenotypic BP. Donors were matched siblings in four, mismatched siblings in one, and haploidentical in two. All patients received peripheral blood stem cell grafts. The median CD34+ dose was 7.6 (range: 6.6–8.9) × 106 cells/kg. Neutrophil engraftment was observed at a median of 15 (10–20) days and platelet engraftment at 19 days (10–22). At a median follow-up of 24 months, the 2-year leukemia-free survival (LFS) and overall survival (OS) were 43% and 57%, respectively. Transplant-related, non-relapse mortality was observed in three patients. AlloSCT results in promising survival for carefully selected patients of CML-BP, especially with a matched sibling donor.

Targeting HIF-2α for the Treatment of CML By Affecting LSCs Metabolism and the Vascular Microenvironment

Although the advent of tyrosine kinase inhibitors (TKI) drugs significantly increased the long-term survival of chronic myeloid leukemia (CML), residual LSCs can still lead to drug resistance and disease recurrence. As LSCs in CML rely on hypoxia-inducible factors (HIF) to maintain their own energy metabolism in the hypoxic environment of bone marrow, HIF-2α has not been systematically explored in CML. Here, we explored how HIF-2α participated in drug resistance and provided a potential new clinical strategy for CML. We first investigated the expression of HIF in the database and found the overexpression of HIF-2α in the bone marrow of CML patients compared with normal subjects, while there was no difference in HIF-1α and HIF-3α (Fig. 1A-B). We then collected bone marrow samples from normal subjects and CML patients. We found that compared with normal hematopoietic stem cells (Lin-CD90+CD34+CD38-), CML LSCs (Lin-CD90+CD34+CD38-) had higher levels of HIF-related proteins than common leukemia cells (Fig. 1C). To further explore the role of HIF-2α in the pathogenesis of CML, we constructed HIF-2α conditional knockout mice through transfecting the plasmid of Cre-BCR-ABL-GFP with transposase and Ctrl-BCR-ABL-GFP without transposition to HSPCs (Fig. 2A). After the first round of leukemia transplantation, the onset of CML was delayed in the HIF-2α knockout mice and the median survival time was prolonged from 31d in the Ctrl group to 60d (Fig. 2B). Next, we harvested fully onset CML mice for the secondary transplantation and found the median survival time extended from 46d to 117d in the HIF-2α knockout group (Fig. 2C). Then we investigate the biological function of HIF-2α in CML LSCs. We performed the clone formation assay on bone marrow cells of the first round of onset CML mice and found that HIF-2α knockout reduced the colony-forming ability of CML cells (Fig. 3A). To explore the tumorigenic ability of HIF-2α knockout, limiting dilution assay (LDA) was performed and found that the LSCs ratio of CML decreased by 30 times after HIF-2α knockout, from 1/76960 to 1/2237970 (Figure. 3B). Meanwhile, we explored the effect of HIF-2α knockout on the chemosensitivity in CML. TKI treatment combined with HIF-2α knockout can significantly improve the efficacy of TKI and extend the mouse survival time (Figure. 3C). To explore the specific mechanism by which HIF2A affects LSCs, we firstly investigate the effect of HIF-2α on LSCs metabolism. We detected metabolism-related indexes of LSCs in the CML model and found that the glycolysis ability of LSCs was weakened after HIF-2α knockout (Fig. 4A). At the same time, its oxidative phosphorylation pathway and reactive oxygen species (ROS) were enhanced (Fig. 4B-C) which may be an important cause of LSCs apoptosis. As HIF-2α can directly promote the transcription of pro-angiogenic factors, we detected the content of vascular endothelial growth factor (VEGF) α in the supernatant of mice bone marrow and found that it was significantly increased after the onset of CML but decreased after HIF-2α knockout (Fig. 5A). Fluorescent staining of bone marrow sections revealed that the density of blood vessels in bone marrow increased, whether in the intima (Fig. 5B) after the onset of CML. Next, we treated CML mice with VEGF Monoclonal antibody and found that it alone could prolong the survival time. However, the VEGF Monoclonal antibody did not affect HIF-2α knockout CML mice (Fig. 5C). These results suggest that HIF-2α is involved in bone marrow vascular remodelling after the onset of CML. To investigate the functional effect of HIF-2α in human CML, the CDX CML mouse model was made with CML cell lines (K562 and MEG-01) to observe the tumorigenesis of CML in nude mice, and they were treated with TKI. We found that HIF-2α knockout could delay the onset of CML and improve the therapeutic effect of TKI (Fig. 6A). To better apply the effect of HIF-2α on CML chemosensitivity to the clinic, we explored the effect of inhibitors of HIF, PT2399, on CML chemosensitivity. PT2399 can significantly increase the chemosensitivity of CML cell lines to TKIs and prolong the survival curve of CML mice treated with TKIs (Fig. 6B). In conclusion, HIF-2α knockout could inhibit the function of LSCs by affecting their metabolic pattern and vascular microenvironment in CML. Therefore, targeting HIF-2α may become a new strategy, and its specific inhibitor PT2399 may be a candidate drug for clinical application in CML treatment. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

INFLAMMATORY CYTOKINES PERTURB NK CELL FUNCTION AND GENE SIGNATURE IN CHRONIC MYELOID LEUKEMIA

Natural killer (NK) cells have the capacity to eliminate malignant cells by releasing cytotoxic granules, which makes them a potent anti-cancer immunotherapeutic. NK cells'mature phenotype and counts positively correlate with prolonged treatment-free survival in chronic myeloid leukemia (CML), while dysfunctional NK cells are predictive of relapse in CML patients. The molecular drivers of this impairment during leukemic progression remain unclear. Given the established role of inflammatory cytokines (namely IL1β, IL-6, GM-CSF, TNFα) in driving myeloid malignancies, we aimed to define their effect on NK cell phenotype and function using a unique pre-clinical chimeric mouse model of CML. We hypothesize that leukemic cytokines impede NK cell maturation and cytotoxicity and shift NK cells toward a pro-tumor cytokine-producing phenotype. We establish a chimeric mouse model of CML by transplanting bone marrow BCR-ABL+ CD45.2 cells into sub-lethally irradiated CD45.1 C57BL/6 wild-type mice. For controls, mice are transplanted with non-mutant cells. Such chimeras represent a robust model to study the exposure of non-transformed host cells to leukemia. At the endpoint, splenic, blood, and bone marrow NK cells are harvested and profiled by flow cytometry, RT-qPCR, scRNA-seq, or used for degranulation assay. Blood samples are collected to obtain serum. Consistent with clinical observations, NK cells are severely reduced in numbers and frequencies and display an immature phenotype and diminished expression of activating receptors (Nkp46, Ly49D) while upregulating inhibitory molecules (Lag-3, TIGIT, NKG2A) during leukemia. Moreover, CML-exposed NK cells have a higher proliferation rate and a greater cell death indicating perturbed homeostasis. We revealed a preferential loss of terminally mature CD27−CD11b+ NK subset in CML mice, suggesting a functional shift from cytotoxic phenotype toward the immature cytokine-producing. In agreement, CML-exposed NK cells show impaired cytotoxicity as measured by target-specific degranulation ex vivo . Next, we mapped the transcriptional landscape of CML-exposed NK cells using single-cell RNA-sequencing. We confirmed decreased gene expression of NK maturation and cytotoxicity markers ( Itgam, Cx3cr1, Prf1, Gzma ) and upregulation of inhibitory molecules ( Tigit, Lag-3, Pdcd1lg1/2) and proteins involved in the cell cycle and senescence ( Mki67, Ccna, Ccnb ). Importantly, CML-exposed NK cells had significantly increased mRNA levels of inflammatory cytokines including IL1β, TNF, GM-CSF; cytokine receptors Il6st, Il-2Ra; and negative regulators of STAT signaling SOCS1/2/3 and CIS. Furthermore, IL-6-STAT3 and IL1β/TNF-signaling gene signatures were enriched in CML-exposed NK cells – an effect that is likely to be triggered by inflammatory cytokines. Thus, we next found that peripheral blood serum from CML mice dampens healthy NK cell degranulation ex vivo , compared to serum from control mice. Further ELISA analysis revealed elevated levels of IL-6, IL-1, TNF, and GM-CSF in CML serum samples. Some of these cytokines might be secreted by functionally skewed NK cells, as suggested by gene expression analysis. Altogether, our data suggest that leukemic cytokines contribute to NK cell dysfunction and polarize them toward a pro-inflammatory phenotype, representing optimal targets for NK-boosting CML immunotherapies.

IFNγ directly counteracts imatinib-induced apoptosis of primary human CD34+ CML stem/progenitor cells potentially through the upregulation of multiple key survival factors

ABSTRACT Tyrosine kinase inhibitors (TKIs) have dramatically improved the survival in chronic myeloid leukemia (CML), but residual disease typically persists even after prolonged treatment. Several lines of evidence suggest that TKIs administered to CML patients upregulate interferon γ (IFNγ) production, which may counteract the anti-tumorigenic effects of the therapy. We now show that activated T cell-conditioned medium (TCM) enhanced proliferation and counteracted imatinib-induced apoptosis of CML cells, and addition of a neutralizing anti-IFNγ antibody at least partially inhibited the anti-apoptotic effect. Likewise, recombinant IFNγ also reduced imatinib-induced apoptosis of CML cells. This anti-apoptotic effect of IFNγ was independent of alternative IFNγ signaling pathways, but could be notably diminished by STAT1-knockdown. Furthermore, IFNγ upregulated the expression of several anti-apoptotic proteins, including MCL1, PARP9, and PARP14, both in untreated and imatinib-treated primary human CD34+ CML stem/progenitor cells. Our results suggest that activated T cells in imatinib-treated CML patients can directly rescue CML cells from imatinib-induced apoptosis at least partially through the secretion of IFNγ, which exerts a rapid, STAT1-dependent anti-apoptotic effect potentially through the simultaneous upregulation of several key hematopoietic survival factors. These mechanisms may have a major clinical impact, when targeting residual leukemic stem/progenitor cells in CML.

Chronic Myeloid Leukemia (CML) at National Referral Hospital in Indonesia

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome and BCR-ABL fusion oncogene. CML is one of the illnesses that may be treated using Tyrosine Kinase Inhibitors (TKIs), a type of targeted therapy. Since TKIs are the standard of therapy, long-term survival of CML has improved compared to chemotherapy and interferon-alpha. For the first-line treatment for CML, there are four commercially available TKIs that serve as an integral part of the disease management. However, there are many challenges in diagnosing, treating, and monitoring patients with chronic phase CML in Indonesia. This study highlights the epidemiology data of chronic phase CML patients, particularly at Dr. Cipto Mangunkusumo General Hospital, an Indonesian national referral hospital, and how to diagnose, select first-line TKIs, and monitor the response of treatment after TKIs administration.

Clear Improvement in Real-World Chronic Myeloid Leukemia Survival: A Comparison With Randomized Controlled Trials.

Tyrosine kinase inhibitors (TKIs) have been improving the prognosis of patients with chronic myeloid leukemia (CML), but there are still large differences in survival among European countries. This raises questions on the added value of results from population-based studies, which use real-world data, compared to results of randomized controlled trials (RCTs) involving patients with CML. There are also questions about the extent of the findings on RCTs effectiveness for patients in the general population. We compare survival data extracted from our previous systematic review and meta-analysis of CML RCTs with the latest updated population-based survival data of EUROCARE-6, the widest collaborative study on cancer survival in Europe. The EUROCARE-6 CML survival estimated in patients (15–64 years) diagnosed in 2000–2006 vs. 2007–2013 revealed that the prognostic improvement highlighted by RCTs was confirmed in real-world settings, too. The study shows, evaluating for the first time all European regions, that the optimal outcome figures obtained in controlled settings for CML are also achievable (and indeed achieved) in real-world settings with prompt introduction of TKIs in daily clinical practice. However, some differences still persist, particularly in Eastern European countries, where overall survival values are lower than elsewhere, probably due to a delayed introduction of TKIs. Our results suggest an insufficient adoption of adequate protocols in daily clinical practice in those countries where CML survival values remain lower in real life than the values obtained in RCTs. New high-resolution population-based studies may help to identify failures in the clinical pathways followed there.

Dihydroorotate dehydrogenase inhibition reveals metabolic vulnerability in chronic myeloid leukemia

The development of different generations of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has led to the high overall survival of chronic myeloid leukemia (CML) patients. However, there are CML patients who show resistance to TKI therapy and are prone to progress to more advanced phases of the disease. So, implementing an alternative approach for targeting TKIs insensitive cells would be of the essence. Dihydroorotate dehydrogenase (DHODH) is an enzyme in the de novo pyrimidine biosynthesis pathway that is located in the inner membrane of mitochondria. Here, we found that CML cells are vulnerable to DHODH inhibition mediated by Meds433, a new and potent DHODH inhibitor recently developed by our group. Meds433 significantly activates the apoptotic pathway and leads to the reduction of amino acids and induction of huge metabolic stress in CML CD34+ cells. Altogether, our study shows that DHODH inhibition is a promising approach for targeting CML stem/progenitor cells and may help more patients discontinue the therapy.

POSC54 Health State Utilities of Patients with Chronic Myeloid Leukemia: A Systematic Literature Review

While emerging treatments would prolong survival of chronic myeloid leukemia (CML) which has a substantial impact on patient well-being, these treatments also result in additional monetary costs. Reliable data on individual preference (utility) would be required to accurately evaluate the value of innovative treatments to support payer decision-making. A systematic literature review was therefore conducted to identify and review utility values estimated for CML.

Perturbation of p38α MAPK as a Novel Strategy to Effectively Sensitize Chronic Myeloid Leukemia Cells to Therapeutic BCR-ABL Inhibitors.

Chronic myeloid leukemia (CML) is a hematopoietic malignancy characterized by the presence of the BCR-ABL oncogene. Therapeutic regimens with tyrosine kinase inhibitors (TKIs) specifically targeting BCR-ABL have greatly improved overall survival of CML. However, drug intolerance and related toxicity remain. Combined therapy is effective in reducing drug magnitude while increasing therapeutic efficacy and, thus, lowers undesired adverse side effects. The p38 MAPK activity is critically linked to the pathogenesis of a number of diseases including hematopoietic diseases; however, the role of each isozyme in CML and TKI-mediated effects is still elusive. In this study, we used specific gene knockdown to clearly demonstrate that the deficiency of p38α greatly enhanced the therapeutic efficacy in growth suppression and cytotoxicity of TKIs, first-generation imatinib, and second generation dasatinib by approximately 2.5–3.0-fold in BCR-ABL-positive CML-derived leukemia K562 and KMB5 cells. Knockdown of p38β, which displays the most sequence similarity to p38α, exerted distinct and opposite effects on the TKI-mediated therapeutic efficacy. These results show the importance of isotype-specific intervention in enhancing the therapeutic efficacy of TKI. A highly specific p38α inhibitor, TAK715, also significantly enhanced the imatinib- and dasatinib-mediated therapeutic efficacy, supporting the feasibility of p38α deficiency in future clinic application. Taken together, our results demonstrated that p38α is a promising target for combined therapy with BCR-ABL-targeting tyrosine kinase inhibitors for future application to increase therapeutic efficacy.

Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells

Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors.

Treatment-free remission in patients with chronic myeloid leukemia: recommendations of the LALNET expert panel

AbstractTyrosine kinase inhibitors (TKIs) have dramatically changed the survival of chronic myeloid leukemia (CML) patients, and treatment-free remission (TFR) has recently emerged as a new goal of CML treatment. The aim of this work was to develop recommendations for TKI discontinuation in Latin America (LA), outside of clinical trials. A working group of CML experts from LA discussed 22 questions regarding TFR and reached a consensus for TFR recommendations in the region. TFR is indicated in patients in first chronic phase, with typical BCR-ABL transcripts, under TKI treatment of a minimum of 5 years, in sustained deep molecular response (DMR; molecular response 4.5 [MR4.5]) for 2 years. Sustained DMR must be demonstrated on at least 4 international reporting scale quantitative polymerase chain reaction (PCR) tests, separated by at least 3 months, in the immediate prior 2 years. After second-line therapy, TFR is indicated in previously intolerant, not resistant, patients. Molecular monitoring is recommended monthly for the first 6 months, every 2 to 3 months from months 7 to 12, and every 3 months during the second year, indefinitely. Treatment should be reintroduced if major molecular response is lost. Monitoring of withdrawal syndrome, glucose levels, and lipid profile is recommended after discontinuation. After TKI reintroduction, molecular monitoring is indicated every 2 to 3 months until MR4.0 achievement; later, every 3 to 6 months. For the TFR attempt, having standardized and reliable BCR-ABL PCR tests is mandatory. These recommendations will be useful for safe discontinuation in daily practice and will benefit patients who wish to stop treatment in emergent regions, in particular, with TKI-related chronic adverse events.

Risk and Outcomes of Second Malignant Neoplasms in Chronic Myeloid Leukemia Survivors

BACKGROUND: The introduction of tyrosine kinase inhibitors (TKIs) has significantly improved the long term survival of patients with chronic myeloid leukemia (CML). Patients in cytogenetic remission have life expectancy that approaches that of the general population. The majority of patients with CML remain on TKIs indefinitely. It is unclear whether prolonged exposure to TKIs increases the risk of second malignant neoplasms (SMN) and if malignancies developing in CML survivors harbor similar prognosis to malignancies in non-CML patients. METHODS: We utilized the Surveillance, Epidemiology and End Results 18 (SEER 18) registries to evaluate SMN in adult patients diagnosed with BCR-ABL1 positive CML as first malignant neoplasm between 2001 (introduction of TKIs) and 2014(most recent year with available data). Follow up is current to the end of 2014 (November 2016 submission). Using the multiple primary standardized incidence ratio (SIR) session of the SEER*stat software (version 8.1.5), we calculated the SIR of SMNs for CML survivors. Cases diagnosed at autopsy and by death certificate only were excluded. SMN was defined as a metachronous non-leukemia malignancy that developed at least 6 months after the diagnosis of CML. Survival rates for the most common malignancies in CML survivors were compared with tumor site, age, gender, race/ethnicity, histology, grade and stage-matched cases developing in individuals without a prior diagnosis of CML. RESULTS: There were 3,407 patients included in the analysis with a median follow up of 41 months. The median age at diagnoses was 53 years (range 20-98) and 56% were men. Of these patients, 170 (4.99%) developed a SMN after a median of 36.5 months from diagnosis of CML (range 6-160) with a SIR of 1.40 (95%C.I. 1.19-1.62) and excess risk of 34.92 per 10,000 persons* year. The most commonly occurring SMNs were lung (n=30), prostate (n=28) and colorectal (n=19). A significantly increased risk was noted for cancers of the respiratory tract (n=32, SIR 1.69, 95%C.I. 1.15-2.4), genitourinary (GU) tract (n=54, SIR 1.39, 95%C.I. 1.04-1.81) and skin excluding basal cell and squamous cell carcinoma (n=13, SIR 1.94, 95%C.I. 1.04-3.32). There was no significant increase in risk of gastrointestinal (GI) tract (n=32, SIR 1.36, 95%C.I. 0.93-1.92), head and neck (n=5, SIR 1.51, 95%C.I. 0.49-3.52) and breast cancer (n=13, SIR 0.85, 95%C.I. 0.45-1.46). Using 3:1 matching (3 de novo malignancies to 1 post-CML SMN case), we compared survival data for cancers of the respiratory, GU and GI tract. Patients with GU malignancies developing after CML had worse overall survival than matched patients without prior CML diagnosis (P=0.018). There was no survival difference between post-CML and non-post-CML patients with respiratory or GI malignancies (Figure). CONCLUSION: CML survivors have an increased risk of developing subsequent malignancies as compared to the general population. The increase in risk is more evident for GU, respiratory and non-basal cell, non-squamous cell carcinoma skin cancer. GU malignancies in CML survivors have worse outcomes than in non-CML patients. Future investigation should focus on the biologic mechanism of increased susceptibility of CML survivors to solid tumors. Download : Download high-res image (60KB) Download : Download full-size image Figure . Disclosures No relevant conflicts of interest to declare.

Concomitant Medications and Comorbidities Affect Early Response in CML Patients Treated with Imatinib: A Retrospective Analysis of 340 Patients from the Polish Adult Leukemia Group (PALG) Registry

Background : It has been consistently shown that early molecular response is associated with positive long-term outcome in terms of overall survival and progression-free survival in chronic myeloid leukemia (CML) patients treated with tyrosine kinase inhibitors (TKIs). Achieving a BCR-ABL(IS) <10% at three months has thereby become an important goal of treatment. According to current European LeukemiaNet recommendations, the optimal treatment response is defined as BCR-ABL(IS) ≤ 10% at three months and BCR-ABL(IS)<1% and/or complete cytogenetic response (CCyR) at six months. Factors influencing the early response are still largely unknown.Our previous study demonstrated that more than half of newly diagnosed CML patients in Poland had comorbid conditions and received concomitant medications. TKIs are metabolized by the CYP3A4 isoenzyme and have been reported to be substrates of ABCB1 (MDR1) and ABCG2 (BCRP) transporters. Importantly, numerous commonly used drugs are transported and metabolized through the same pathways as TKIs. Drug interactions should therefore be considered when administering inhibitors or inducers of CYP3A4, ABCB1 and ABCG2 in combination with TKIs. Furthermore, it has been shown that the presence of comorbidities and the necessity of additional therapies may significantly affect treatment compliance.Objectives: The primary objective of the study was to investigate whether the presence of comorbidities and additional therapies affected early response in CML patients treated with imatinib.Patients and methods : We retrospectively analyzed patients with newly diagnosed CML who were receiving imatinib as the initial therapy for CML at nine Polish hematological tertiary care centers. Inclusion criteria were as follows: 1) age ≥18 years and 2) diagnosis of chronic phase CML between January 1st 2005 and December 31st 2014. Data on presence of comorbid conditions, concomitant drugs, cytogenetic and molecular response were anonymously collected through electronic case reports forms. Patients in whom therapy was changed because of imatinib intolerance were excluded. Influence of potential prognostic factors on probability of response at three and six months was tested by univariate and multivariate logistic regression.Results : We enrolled 340 patients with CML in the chronic phase, with median age 53 years (range, 41-62) where 50 % were males. According to the Sokal score, 190 patients (55.9%) were classified as low risk, 107 (31.5%) as intermediate risk and 43 (12.5%) as high risk. Overall, 142 (41.8%) patients reported no comorbidities, 121 (35.6%) reported one or two comorbidities and 77 (22.7%) had more than two comorbid conditions. The most common comorbidities were: hypertension (30%), hypercholesterolemia (16%), ischemic heart disease (10%) and diabetes (9%). One hundred thirty (38.2%) patients received no additional therapies, 110 (32.4%) patients received one or two therapies and 100 patients (29.4%) more than two. The most frequently used drugs were: beta blockers (22% of patients), ACE inhibitors (19%) and statins (15%). At three months, a molecular analysis was done in 194 patients and 144 (74%) achieved BCR ABL(IS) of less than 10%. At six months, 217 patients underwent molecular analysis and 305 had cytogenetic assessment. One hundred thirty five patients (62%) achieved BCR-ABL(IS) < 1% and 198 (65%) achieved CCyR. Multivariate analysis revealed that at three months patients who had a low Sokal score, more than two comorbidities and received more than two concomitant therapies, significantly more often achieved BCR-ABL <1% (p=0.013, p=0.054 and p=0.005 respectively). At six months, patients who received more than two concomitant medications still tended to have a higher probability of optimal response: BCR-ABL(IS) <1% (p=0.062) and CCyR (p=0.035). Other potential prognostic factors analyzed including patients' age, sex and BMI had no impact on the probability of optimal response.Conclusions: We found that comorbidities and concomitant therapies did not adversely affect early response to imatinib in CML patients. In contrast, patients with more than two additional therapies and comorbidities seem to more often achieve treatment goals. The potential explanations for these findings are drug interactions that increase imatinib exposure and better adherence to therapy of patients accustomed to systematic use of medications. DisclosuresGora Tybor:BMS: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Sacha:Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau. Lewandowski:BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Warzocha:BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Jamroziak:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria.

Rheb1-Deficient Neutrophils Promote Hematopoietic Stem/Progenitor Cell Proliferation via Mesenchymal Stem Cells.

Myeloid cells have been identified as hematopoietic stem cell (HSC)-regulating cells. However, the mechanisms by which myeloid cells regulate the function of HSCs are not fully defined. Our previous study indicated that the HSCs are over-expanded in Vav1-Cre;Rheb1fl/fl mice. Here, using in vivo and in vitro models, we found that Rheb1-deficient neutrophils remodeled the bone marrow environment and induced expansion of HSCs in vivo. Further studies showed that loss of Rheb1 impaired neutrophils’ ability to secrete IL-6, led mesenchymal stem cells (MSCs) to produce more SCF, and promote HSC proliferation. We further found that IL-6 suppressed SCF mRNA expression in human MSCs. Interesting, the high level of IL-6 was also related with poor survival of chronic myeloid leukemia (CML) patients, and higher expression of IL-6 in CML cells is associated with the lower expression of SCF in MSCs in patients. Our studies suggested that blocking IL-6 signaling pathway might stimulate MSCs to secrete more SCF, and to support hematopoietic stem/progenitor cells proliferation.

Perturbed function of natural killer cells by inflammatory cytokines in chronic myeloid leukemia

Abstract Natural killer (NK) cells’ mature phenotype and counts positively correlate with prolonged treatment-free survival in chronic myeloid leukemia (CML), while dysfunctional NK cells are predictive of relapse in leukemic patients. However, the molecular drivers of NK cell alterations during leukemia remain unclear. Given an established role of inflammatory cytokines in CML progression, we define the leukemic environmental cues impacting NK maturation and function in a BCR-ABL chimeric mouse model of CML where NK cells do not carry the CML oncogene. Reflecting clinical observations, NK cell frequencies and numbers are severely decreased in leukemic mice. Moreover, terminally mature NK subsets are the most affected, implying preferential loss of cells with potent anti-leukemic activity. In addition, this phenotype suggests a shift toward the immature cytokine-producing state of NK development, which could favor the survival of leukemia-initiating cells. We map the transcriptional landscape of NK cells using single-cell RNA-sequencing from multiple tissues. NK cells exposed to CML microenvironment possess a lowered expression of surface activating receptors such as Nkp46 while upregulating inhibitory molecules Tim-3 and TIGIT. BCR-ABL reversion for six weeks partially restored these defects, consistent with findings in patients before and after TKI initiation. Finally, we found that leukemia-associated soluble factors dampen target-specific degranulation of NK cells by applying serum samples from healthy or leukemic mice. These data indicate that the altered cytokine milieu contributes to NK cell dysfunction and represents an optimal target for NK-boosting CML immunotherapies of leukemia.