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Due to the remarkable success of tyrosine kinase inhibitors (TKI) in chronic myeloid leukemia (CML), allogeneic stem cell transplantation (alloSCT) is not first-line treatment for delivering durable, long-term survival. Consequently, alloSCT is reserved for patients with TKI-resistant or TKI-intolerant chronic phase CML (CP-CML) and advanced phase CML (AP-CML). Advances in transplant technology, such as high-resolution HLA typing, introduction of reduced intensity conditioning and increased alternative donor availability, coupled with improved supportive care, have significantly reduced transplant-related mortality and expanded the pool of transplant-eligible patients. Refinement of conditioning regimens, innovative use of post-transplant cellular and pharmacological therapies, and judicious post-transplant monitoring are important strategies for reducing risk of relapse. Given its potential to cure, alloSCT will invariably remain a key part of the treatment algorithm. This article reviews the data underpinning the role and outcomes of alloSCT and provides an update on current recommendations. [ABSTRACT FROM AUTHOR]

Summary: Multiple studies have reported a significant treatment‐free remission (TFR) rate of 50%–60% in patients with chronic myeloid leukaemia (CML) who discontinue tyrosine kinase inhibitor (TKI) therapy. However, the remaining half of these patients still require re‐initiation of TKI therapy for leukaemia control. It remains unclear if TKI drugs should be switched for re‐therapy in patients who failed the first TFR (TFR1) attempt. Our study attempted to determine whether dasatinib therapy after TFR1 failure post‐imatinib discontinuation could improve the likelihood of TFR2. Of 59 patients who lost molecular response after imatinib discontinuation for TFR1, 55 patients (93.2%) were treated with dasatinib, of whom 49 (89.1%) regained MR4.5 or deeper response, with a median time of 1.85 months to achieve MR4.5. Dasatinib was discontinued in 35 patients for TFR2 attempt, of whom 26 patients (74.28%) lost MMR and 6 (17.14%) MR4. Risk factor analysis for the TFR2 after dasatinib discontinuation suggested three significant factors: (1) doubling time of BCR::ABL1 transcript following TFR1 attempt, (2) rapid regaining of molecular response following dasatinib therapy and (3) undetectable BCR::ABL1 transcript prior to TFR2 attempt. The present study showed that dasatinib does not increase the TFR2 rate in general, but a selected group of patients could benefit from this approach. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs) have revolutionized the management of patients with chronic myelogenous leukemia (CML); however, they may cause cardiovascular (CV) toxicities. In this cross-sectional study, we explored whether high-sensitivity C-reactive protein (hsCRP) and novel markers of vascular dysfunction were associated with exposure to specific TKIs, in 262 CML patients. Hs-CRP level was not associated with CML disease activity or treatment with a specific TKI. Body mass index (OR: 1.15, 95% CI: 1.108–1.246; p < 0.001) and CML duration (OR: 1.004, 95% CI: 1.001–1.008; p = 0.024) were independently associated with higher hs-CRP. In exploratory analyses, novel endothelial-centric markers (e.g. ET-1 and VCAM-1) were differential across the various TKIs, particularly amongst nilotinib- and ponatinib-treated patients. While Levels of hs-CRP do not appear to be correlated with specific TKIs, circulating markers of vascular dysfunction were altered in patients treated with specific TKIs and should be explored as potential markers of TKI-associated CV risk. [ABSTRACT FROM AUTHOR]

Summary: Patients with chronic myeloid leukaemia in chronic phase (CML‐CP) who have a sustained deep molecular response (DMR) are eligible to discontinue treatment and attempt treatment‐free remission (TFR). In the DASFREE study (ClinicalTrials.gov; NCT01850004), the 2‐year TFR rate after dasatinib discontinuation was 46%; here we present the 5‐year update. Patients with a stable DMR after ≥2 years of dasatinib therapy discontinued treatment and were followed for 5 years. At a minimum follow‐up of 60 months, in 84 patients discontinuing dasatinib, the 5‐year TFR rate was 44% (n = 37). No relapses occurred after month 39 and all evaluable patients who relapsed and restarted dasatinib (n = 46) regained a major molecular response in a median of 1.9 months. The most common adverse event during the off‐treatment period was arthralgia (18%, 15/84); a total of 15 withdrawal events were reported in nine patients (11%). At the 5‐year final follow‐up, almost half of the patients who discontinued dasatinib after a sustained DMR maintained TFR. All evaluable patients who experienced a relapse quickly regained a DMR after restarting dasatinib, demonstrating that dasatinib discontinuation is a viable and potentially long‐term option in patients with CML‐CP. The safety profile is consistent with the previous report. [ABSTRACT FROM AUTHOR]

With the improving knowledge of CML and its management, the goals of therapy need to be revisited to ensure an optimal use of the BCR::ABL1 TKIs in the frontline and later-line therapy of CML. In the frontline therapy of CML in the chronic phase (CML-CP), imatinib and the three second-generation TKIs (bosutinib, dasatinib and nilotinib) are associated with comparable survival results. The second-generation TKIs may produce earlier deep molecular responses, hence reducing the time to reaching a treatment-free remission (TFR). The choice of the second-generation TKI versus imatinib in frontline therapy is based on the treatment aims (survival, TFR), the CML risk, the drug cost, and the toxicity profile with respect to the patient's comorbidities. The TKI dosing is more flexible than has been described in the registration trials, and dose adjustments can be considered both in the frontline and later-line settings (e.g., dasatinib 50 mg frontline therapy; dose adjusted schedules of bosutinib and ponatinib), as well as during an ongoing TKI therapy to manage toxicities, before considering changing the TKI. In patients who are not candidates for TFR, BCR::ABL1 (International Scale) transcripts levels <1% are acceptable, result in virtually similar survival as with deeper molecular remissions, and need not warrant a change of TKI. For patients with true resistance to second-generation TKIs or with the T315I gatekeeper mutation, the third-generation TKIs are preferred. Ponatinib should be considered first because of the cumulative experience and results in the CML subsets, including in T315I-mutated CML. A response-based dosing of ponatinib is safe and leads to high TKI compliance. Asciminib is a third-generation TKI with possibly a better toxicity profile, but lesser activity in T315I-mutated CML. Olverembatinib is another potent third-generation TKI with early promising results. [ABSTRACT FROM AUTHOR]

HLA-typing is more precise, graft-versus-host-disease prophylaxis and therapy are better and supportive care is better to the point where patients with less robust performance may still be candidates. With the transition to standard tyrosine kinase therapy, transplant almost disappeared as a treatment and now even if appropriate for TKI intolerant or resistant patients, is often forgotten until the disease has progressed and results are not as good. The third is that previous therapy may very well impact the current therapy, both in terms of efficacy and side effects and needs to be taken into consideration when choosing the best drug. In some cases patients can be cured, i.e. come off therapy, or achieve in the words of the late John Goldman, a functional cure, meaning they can live on therapy until they die from something else. [Extracted from the article]

Implications of creatine kinase (CK) elevation, a frequent complication of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukemia (CML), on its key treatment outcomes (overall survival (OS) and event-free survival (EFS)), remain unknown. In this single center, retrospective study on 283 chronic phase CML patients on first-line TKI (median follow-up of 8.8 years), 71.7% patients had hyperCKemia with no difference in incidence between imatinib and second generation TKIs (SG-TKIs). In multivariable Cox regression analysis, hyperCKemia was associated with better OS and intermediate- and high-Sokal risk score with worse OS. In multivariable Cox regression for EFS, hyperCKemia and treatment with SG-TKI were associated with improved EFS while intermediate or high Sokal index and higher comorbidities showed worse EFS. Our study provides an evidence on the prognostic value of hyperCKemia in CML and informs clinicians not to change TKI based solely on laboratory elevations of CK. [ABSTRACT FROM AUTHOR]

Treatment-free remission is achievable in approximately half of patients with chronic myeloid leukemia who attain a sustained, deep molecular response with tyrosine-kinase inhibitor (TKI) therapy. We aimed to identify potential predictors of future achievement of stable MR4.5, defined as a sustained 4.5-log reduction in BCR-ABL1 transcripts for a minimum of 2 years, in 593 patients treated with imatinib as first-line TKI therapy. In multivariable analyses of patient and disease variables including baseline blood counts, disease phase, additional cytogenetic abnormalities, prior therapy, depth and rapidity of molecular response, the only predictor for future achievement of stable MR4.5 was molecular response at 6 months. In this study, patients failing to attain a molecular response of BCR-ABL1≤ 0.16%IS after 6 months of imatinib therapy were unlikely to subsequently achieve stable MR4.5 with imatinib. Our data suggest that achievement of BCR-ABL1≤ 0.16%IS at 6 months is predictive of future stable MR4.5. [ABSTRACT FROM AUTHOR]

Summary: The doubling time (DT) of the BCR–ABL1 quantitative polymerase chain reaction (qPCR) transcript level reflects the re‐growing fraction of leukaemic cells after discontinuation of tyrosine kinase inhibitor (TKI). The present study analyzed monthly DT within six months after imatinib discontinuation in 131 patients. Monthly DT was calculated as x = ln(2)/K, where x is the DT and K is the fold BCR–ABL1 change from the previous value divided by the number of days between each measurement. The optimal DT value was determined as 12·75 days at two months using a recursive partitioning method. The patients were stratified into three groups: the high‐risk group (DT<12·75 days but >0, with rapidly proliferating chronic myeloid leukaemia (CML) cells; n = 26) showed the lowest molecular relapse‐free survival (mRFS) of 7·7% at 12 months, compared to 53·6% in the intermediate‐risk group (DT≥12·75 days, with slowly proliferating CML cells; n = 16) or 90·0% in the low‐risk group (DT≤0, i.e., without proliferating CML cells; n = 71; P < 0·001). Monthly assessment of DT helps identify high‐risk patients for treatment‐free remission failure with an imminent risk of molecular recurrence, and to define low‐risk patients who can be spared the frequent monitoring of monthly molecular tests. [ABSTRACT FROM AUTHOR]

CML patients with deep molecular responses to TKI have restored immune effectors and decreased PD-1 and immune suppressors. Of the 31 patients treated with dasatinib and nivolumab, all discontinued treatment, mostly due to treatment failure ( I n i = 13; 42%) or treatment completion ( I n i = 9; 29%; Supplementary Figure S1). Although treatment with tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes for the majority of patients with chronic myeloid leukemia (CML), approximately 20-30% will require a change in treatment due to resistance, intolerance, or a suboptimal response [[1]]. [Extracted from the article]

Patients completing 12 cycles (dose escalation/dose expansion) had the option to enter the extension phase to continue treatment until disease progression or onset of unacceptable toxicities. The hedgehog (Hh) pathway is activated in BCR-ABL1 + leukemic stem cells (LSCs) and differentiated hematopoietic cells, through a mechanism involving membrane protein smoothened (SMO) upregulation [[1]]. Overall, 11 patients with CML-CP were enrolled and treated (first patient screened: 5 January 2012; last patient last visit: 5 February 2014). [Extracted from the article]

Treatment-free remission (TFR) in patients with chronic myeloid leukemia in chronic phase (CML-CP) is considered a feasible option, especially with the ability of second-generation tyrosine kinase inhibitors to induce higher rates of sustained deep molecular response (DMR). DASFREE is an open-label, single-arm, multicenter phase II trial assessing TFR after dasatinib discontinuation in patients with CML-CP (N = 84). At 2 years, TFR was 46% in all patients. Multivariate analyses revealed statistically significant associations between 2-year TFR and duration of prior dasatinib (≥median; p =.0051), line of therapy (first line; p =.0138), and age (>65 years; p =.0012). No disease transformation occurred, and the most common adverse events experienced off treatment were musculoskeletal (observed in 30 patients); however, dasatinib withdrawal events were reported in nine patients (11%) by the investigator. Overall, these findings support the feasibility of discontinuing dasatinib for patients with CML-CP in sustained DMR in the first line and beyond. [ABSTRACT FROM AUTHOR]

Background: Ponatinib has shown potent activity against chronic myeloid leukaemia that is resistant to available treatment, although it is associated with arterial occlusion. We investigated whether this activity and safety profile would result in superior outcomes compared with imatinib in previously untreated patients with chronic myeloid leukaemia.Methods: The Evaluation of Ponatinib versus Imatinib in Chronic Myeloid Leukemia (EPIC) study was a randomised, open-label, phase 3 trial designed to assess the efficacy and safety of ponatinib, compared with imatinib, in newly diagnosed patients with chronic-phase chronic myeloid leukaemia. Patients from 106 centres in 21 countries were randomly assigned (1:1, with stratification by Sokal score at diagnosis) using an interactive voice and web response system to receive oral ponatinib (45 mg) or imatinib (400 mg) once daily until progression, unacceptable toxicity, or other criteria for withdrawal were met. Eligible patients were at least 18 years of age, within 6 months of diagnosis, and Philadelphia chromosome-positive by cytogenetic assessment, with Eastern Cooperative Oncology Group performance status of 0-2, and had not previously been treated with tyrosine kinase inhibitors. The primary endpoint was major molecular response at 12 months. Patients who remained on study and had molecular assessments at specified timepoints were studied at those timepoints. Safety analyses included all treated patients, as per study protocol. This trial is registered with ClinicalTrials.gov, number NCT01650805.Findings: Between Aug 14, 2012, and Oct 9, 2013, 307 patients were randomly assigned to receive ponatinib (n=155) or imatinib (n=152). The trial was terminated early, on Oct 17, 2013, following concerns about vascular adverse events observed in patients given ponatinib in other trials. Trial termination limited assessment of the primary endpoint of major molecular response at 12 months, as only 13 patients in the imatinib group and ten patients in the ponatinib group could be assessed at this timepoint; the proportion of patients achieving a major molecular response at 12 months did not differ significantly between the two groups (eight [80%] of ten patients given ponatinib and five [38%] of 13 patients given imatinib; p=0·074). 11 (7%) of 154 patients given ponatinib and three (2%) of 152 patients given imatinib had arterial occlusive events (p=0·052); arterial occlusive events were designated serious in ten (6%) of 154 patients given ponatinib and in one (1%) of 152 patients given imatinib (p=0·010). The data monitoring committee criterion for risk assessment (significant difference in serious grade 3 or 4 ischaemic events between groups) was not met (five [3%] of 154 vs one [1%] of 152; p=0·21). Grade 3 or 4 adverse events observed in more than 5% of patients in the ponatinib group were increased lipase (22 [14%] of 154 vs three [2%] of 152 with imatinib), thrombocytopenia (19 [12%] of 154 vs ten [7%] of 152 with imatinib), rash (ten [6%] of 154 vs two [1%] of 152 with imatinib). In the imatinib group, grade 3 or 4 adverse events observed in more than 5% of patients were neutropenia (12 [8%] of 152 vs five [3%] of 154 with ponatinib) and thrombocytopenia (ten [7%] of 152 vs 19 [12%] of 154 with ponatinib). Serious adverse events that occurred in three or more patients given ponatinib were pancreatitis (n=5), atrial fibrillation (n=3), and thrombocytopenia (n=3). No serious adverse event occurred in three or more patients given imatinib.Interpretation: The efficacy of ponatinib treatment of newly diagnosed chronic-phase chronic myeloid leukaemia compared with imatinib could not be assessed due to trial termination, but preliminary data suggest there might be benefit, although with more arterial occlusive events than with imatinib at the doses studied. Because the EPIC trial was terminated early, efficacy of ponatinib in this setting remains to be established.Funding: ARIAD Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Background: The mechanism of action of imatinib is known to involve the Fas-mediated apoptosis pathway. Consequently inter-individual variations in this apoptosis pathway might be associated with imatinib response or resistance.Methods: This study attempted to focus on eight genotypes in the apoptosis pathway including FAS (rs1800682, rs2229521, rs2234767 and rs2234978), FASLG (rs763110), CASP10 (rs13006529), and APAF1 (rs1439123, rs2288713) and analyzed their association with treatment outcomes including molecular response with 4.5 log reduction (MR4.5), following imatinib therapy in 187 Korean CML patients.Results: The GG/GA genotype in FAS (rs2234767) showed a higher rate of MR4.5 than the AA genotype (at 5 years 59.7 vs 37.4 %, p = 0.013). Using a bootstrap procedure for internal validation we confirmed that FAS (rs2234767) correlates with MR4.5 (p = 0.050). Multivariate analysis confirmed that the FAS genotype (rs2234767) is an independent surrogate for MR4.5 (p = 0.019, HR 0.43, 95 % CI [0.22-0.87]).Conclusions: The Fas/FasL signaling pathway may represent the major pathway that mediates apoptosis in CML treated with imatinib. SNP markers in the apoptosis pathway including FAS genotype (rs2234767) can be potential surrogates for predicting deeper molecular response after imatinib therapy. [ABSTRACT FROM AUTHOR]

Lymphoproliferative disorders presenting simultaneously with or subsequent to the occurrence of chronic myeloid leukemia (CML) have rarely been reported. Herein, we report 8 cases of a variety of lymphoproliferative conditions associated with CML at different times during the course of the disease. All 8 patients were treated with tyrosine kinase inhibitors at some point during the course of their illness. The literature regarding the uncommon association of these apparently unrelated disorders is reviewed as well as the possible underlying mechanisms that could be associated with this phenomenon. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The suppression of the immune system creates a permissive environment for development and progression of cancer. One population of immunosuppressive cells that have become the focus of intense study is myeloid derived suppressor cells (MDSCs), immature myeloid cells able to induce immune-escape, angiogenesis, and tumor progression. Two different subpopulations have been identified and studied: granulocytic and mono-cytic MDSCs, with a different immunophenotype and immunosuppressive properties. Recently, an accumulation of both Gr-MDSCs and Mo-MDSCs cells has been found in the peripheral blood of chronic myeloid leukemia (CML) patients. They are part of the tumor clone showing BCR/ABL expression. Imatinib therapy decreases both MDSCs and arginase 1 levels to normal ones. This review will focus on actual knowledge for human MDSCs and their immunosuppressive activity in CML patients, with a critical attention to comparison of Gr-MDSCs and polymorphonuclear cells (PMNs). We will then suggest the monitoring of MDSCs in patients who have discontinued tyrosine kinase inhibitors (TKIs) therapy to evaluate if their increase could correlate with disease relapse. [ABSTRACT FROM AUTHOR]

The article discusses research which was conducted to investigate molecular relapse after allogenic hematopoietic stem cell transplant for chronic myeloid leukemia. Researchers evaluated 118 transplant patients. They found that in eight years of patient follow up only seven patients underwent treatment for relapse.

The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm ( P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free ( P = 0·048) and relapse-free ( P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. [ABSTRACT FROM AUTHOR]

Significant evidence for a germline predisposition to MPN came from the discovery of a particular JAK2 haplotype in chromosome 9p (the GGCC or 46/1 haplotype), which seems to preferentially acquire the JAK2-V617F mutation. In our case, the overt donor clone developed years after the harvesting and only in the donor's bone marrow. [Extracted from the article]

Simple Summary: Approximately 50–60% of patients with chronic myeloid leukemia (CML) achieve a stable deep molecular response (DMR) after tyrosine kinase inhibitor (TKI) therapy. The achievement of DMR is a prerequisite for treatment-free remission. Repurposing statins is a straightforward strategy for enhancing molecular response in CML treatment. Second-generation TKIs have been reported to exhibit cardiovascular toxicity. Thus, statins have been widely prescribed for patients with CML undergoing second-generation TKI therapy for modifying cardiovascular risk factors, such as hyperlipidemia. Furthermore, the results of this study support the therapeutic benefit of the concomitant use of statins in TKI therapy for patients with CML. Additionally, the potential additive effects of statins and TKIs enhance the DMR rate in patients with CML, rendering these effects clinically relevant in these patients. In particular, this combination is a strong candidate for the achievement of DMR in patients with CML who have not achieved DMR with TKI therapy alone. Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (p = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and ABL1 mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS+ cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34+ cells. The growth-inhibitory effects of the statin/imatinib combination against CD34+/CML primary cells were higher than those against CD34+/Norm cells (p = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34+ cells, but not against normal CD34+ cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy. [ABSTRACT FROM AUTHOR]

The article discusses the insignificance of derivative chromosome 9 (der 9, der-del 9) deletion on the clearance kinetics of BCR/ABL fusion transcript, cytogenetic response and treatment failure to imatinib mesylate therapy for chronic myeloid leukemia (CML). The presence of del-der 9 in patients with CML do not influence the response to imatinib mesylate (IM) therapy in terms of hematologic response. The study shows that detecting del-der 9 does not have an impact on CML patient management.

The efficacy and safety of peginterferon-α-2a (40 kD) (PEG-IFNα-2a), 450 µg once weekly, versus IFNα-2a, 9 MIU once daily, for 12 months, was evaluated in a Phase II study in IFN-naïve patients with chronic-phase, Philadelphia-chromosome-positive CML. At the end of the treatment, complete hematological response was observed in 66.2% (47/71) and 45.2% (33/73) of the PEG-IFNα-2a group and IFNα-2a groups, respectively (p = 0.009), and major cytogenetic response occurred in 35.2% and 17.8%, respectively (p = 0.016). PEG-IFNα-2a was at least as effective as IFNα-2a overall, including progression-free survival at the end of treatment, and overall survival after 30 months of follow-up. Adverse events necessitated fewer withdrawals but more dose adjustments in the PEG-IFNα-2a group compared with the IFNα-2a group (11%versus 23%, and 84.5%versus 65.8%, respectively). In conclusion, PEG-IFNα-2a (40 kD), 450 µg once weekly, compared with IFNα-2a, 9 MIU once daily, resulted in higher rates of hematologic and cytogenetic response and greater overall survival. [ABSTRACT FROM AUTHOR]

The potent clinical responses seen in patients with chronic myeloid leukemia (CML) after administration of donor-specific lymphocytes, as well as the correlation between the presence of antigen specific T cells and prolonged remission in these patients, suggests a role for the immunological control of CML. Here we propose Aldara™, a clinically used formulation of imiquimod, as an agent for augmenting immune responses to CML antigens. Our proposition is based upon 3 tenets: 1) Endogenous dendritic cells (DC) of CML patients, which are known to be derived from the malignant clone, express and present various leukemic antigens; 2) CML-antigen reactive T cell clones exist in the patient but in many situations are ineffectively stimulated to cause significant hematological responses; and 3) Antigen presentation by mature, activated DC, which endogenously express CML-antigens may endow the pre-existing ineffective T cell responses with ability to control CML progression. The practical use of Aldara™ as a localized activator of DC in the context of present day leukemic therapeutics, as well as various properties of this unique immune modulator will be discussed. [ABSTRACT FROM AUTHOR]

Key Clinical Message Gastric antral vascular ectasia (GAVE) has been reported very rarely in imatinib-treated gastrointestinal stromal tumor (GIST) and scleroderma/pulmonary hypertension patients. We present the first report of a case of GAVE in a chronic myeloid leukemia (CML) patient after treatment with imatinib. This diagnosis should be considered in CML patients with upper gastrointestinal symptoms and anemia. [ABSTRACT FROM AUTHOR]

Highlights • A 1.3 log reduction in BCR-ABL levels within 3 months post HCT is prognostic in TKI resistance or intolerance. • HCT remains a potential cure for patients with CML resistant or intolerant of TKI therapy. • Advanced phase disease remains a poor prognostic factor post HCT even in the TKI era. Abstract The majority of patients with TKI failure respond to HCT. However, the relapse risk remains high. This study has evaluated transplant outcomes in 223 CML patients with TKI failure due to resistance (n = 132) or intolerance (n = 29), as well as those that were TKI naïve/responding with advanced disease (n = 35) or with chronic phase (CP, n = 27). We studied outcomes according to post-transplant BCR-ABL transcript level within 3 months. With respect to transplant outcomes according to the post-transplant BCR/ ABLtranscript level within 3 months, the group failing to achieve a 1.3 log reduction (n = 14, 12.4%) showed the highest relapse rate of 78.6% at 5 years, compared to 26.2% and 24.1% in the groups achieving 1.3–4.0 log reduction (n = 45, 39.8%), and ≥4.1 log reduction (n = 54, 47.8%) respectively (p < 0.001). Multivariate analysis confirmed that the group failing to achieve a 1.3 log reduction had a 2.3-fold higher risk of death and 6.6 times higher risk of relapse. Poor overall survival after HCT was associated with advanced disease at diagnosis, but not disease status prior to HCT. Of 61 patients who relapsed after HCT, 47 were treated with post-transplant TKI therapy; those receiving TKI after loss of MR2 or MMR showed higher rates of response and survival compared to those receiving TKI after hematologic relapse (p < 0.001). QPCR log reduction level within 3 months post transplantation is prognostic in this population. [ABSTRACT FROM AUTHOR]

Objective The development of tyrosine kinase inhibitors (TKIs) has significantly improved the treatment of chronic myeloid leukemia (CML). However, approximately one third of patients are resistant to TKI and/or progress to advanced disease stages. TKI therapy failure has a well-known association with ABL1 kinase domain (KD) mutations, but only around half of TKI non-responders have detectable ABL1 KD mutations. Method We attempt to identify genetic markers associated with TKI therapy failure in 13 patients (5 resistant, 8 progressed) without ABL1 KD mutations using whole-exome sequencing. Results In 6 patients, we detected mutations in 6 genes commonly mutated in other myeloid neoplasms: ABL1 , ASXL1 , DNMT3A , IDH1 , SETBP1 , and TP63 . We then used targeted deep sequencing to validate our finding in an independent cohort consisting of 100 CML patients with varying drug responses (74 responsive, 18 resistant, and 8 progressed patients). Mutations in genes associated with epigenetic regulations such as DNMT3A and ASXL1 seem to play an important role in the pathogenesis of CML progression and TKI-resistance independent of ABL1 KD mutations. Conclusion This study suggests the involvement of other somatic mutations in the development of TKI resistant progression to advanced disease stages in CML, particularly in patients lacking ABL1 KD mutations. [ABSTRACT FROM AUTHOR]

Somatic mutations commonly detected in a variety of myeloid neoplasms have not been systematically investigated in chronic myeloid leukemia (CML). We performed targeted deep sequencing on a total of 300 serial samples from 100 CML patients; 37 patients carried mutations. Sixteen of these had evidence of mutations originating from preleukemic clones. Using unsupervised hierarchical clustering, we identified 5 distinct patterns of mutation dynamics arising following tyrosine kinase inhibitor (TKI) therapy. This study demonstrates that patterns of mutation acquisition, persistence, and clearance vary but have a number of interesting correlations with clinical outcomes. Mutation burden often persisted despite successful TKI response (pattern 1), providing indirect evidence that these mutations also originated from preleukemic mutations, whereas patients exhibiting mutation clearance (pattern 3) showed mixed clinical outcomes. Unsurprisingly, patients acquiring new mutations during treatment failed TKI therapy (pattern 2). These patterns show that CML mutation dynamics following TKI therapy are markedly distinct from other myeloid neoplasms. In summary, clinical implications of mutation profiles and dynamics in CML should be interpreted with caution. [ABSTRACT FROM AUTHOR]

In the current study, we identified 2 genetic markers for susceptibility to chronic myeloid leukemia (CML) using a genome-wide analysis. A total of 2744 subjects (671 cases and 2073 controls) were included, with 202 Korean CML patients and 497 control subjects enrolled as a discovery set. Significant findings in the discovery set were validated in a second Korean set of 237 patients and 1000 control subjects and in an additional Canadian cohort of European descent, including 232 patients and 576 control subjects. Analysis revealed significant associations of 2 candidate loci, 6q25.1 and 17p11.1, with CML susceptibility, with the lowest combined P values of 2.4 × 10-6 and 1.3 × 10-12, respectively. Candidate genes in those regions include RMND1, AKAP12, ZBTB2, and WSB1. The locus 6q25.1 was validated in both Korean and European cohorts, whereas 17p11.1 was validated only in the Korean cohort. These findings suggest that genetic variants of 6q25.1 and 17p11.1 may predispose one to the development of CML. [ABSTRACT FROM AUTHOR]

Predicting reduction of bcr-abl levels early in treatment of Chronic Myeloid Leukemia (CML) is desirable to identify patients that will inadequately respond to first line therapy. Here, we sought to determine if intracellular imatinib levels early in treatment predict molecular response to imatinib for patients with newly diagnosed chronic phase CML. 13 L.N. Eadie, T.P. Hughes, D.L. White, Patients with low OCT-1 activity and high ABCB1 fold rise have poor long-term outcomes in response to tyrosine kinase inhibitor therapy. [Extracted from the article]