Patients In Blastic Phase Research Articles

Updates on accelerated and blast phase myeloproliferative neoplasms: Are we making progress?

Management approaches for accelerated and blast phase myeloproliferative neoplasms remain challenging for clinicians and patients alike. Despite many therapeutic advances, outcomes for those patients who are not allogeneic haematopoietic cell transplant eligible remain, in general, very poor. Estimated survival rates for such blast phase patients is frequently reported as less than 6 months. No specific immunological, genomic or clinicopathological signature currently exists that accurately predicts the risk and timing of transformation, which frequently induces a high degree of anxiety among patients and clinicians alike. Within this review article, we provide an up-to-date summary of current understanding of the underlying pathogenesis of accelerated and blast phase disease and discuss current therapeutic approaches and realistic outcomes. Finally, we discuss how the horizon may look with the introduction of more novel agents into the clinical arena.

Clinical Response to Upfront Targeted Tyrosine Kinase Inhibitors among Patients with Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Gene Fusion.

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusion (MLN-TK) is an entity encompassed of a heterogeneous group of rare hematopoietic neoplasms that are driven by gene fusion involving PDGDRA/B, FGFR1, JAK2, FLT3 or ETV6::ABL1. Though patients presenting with chronic phase MLN-TK with PDGFRA fusion display a favorable outcome in response to upfront TK inhibitor (TKI) therapy, the outcomes of MLNs driven by other TK fusions are not well described. In this study, we aimed to critically analyze the treatment outcomes of patients with MLN-TK, focusing on the role of upfront TKIs in both chronic- and blast-phase diseases. The retrospective study included patients with confirmed MLN-TK from 3 centers and assessed demographic and clinical variables, treatment, and outcomes. Forty-two patients with confirmed MLN-TK [PDGFRA (n=22), PDGFRB (n=4), FGFR1(n=10), JAK2 (n=2); and FLT3 (n=3)] were included. Fifteen of 25 (60%) chronic-phased patients received upfront TKI therapy had a long-term remission. Nine of 16 (60%) blast-phase patients with upfront TKIs also achieved complete remission and remained alive at a median follow-up of 20 months. All 3 patients with blast phase disease who received upfront chemotherapy without positive response did not respond to subsequent TKI therapy, emphasizing the importance of initiating TKI therapy early. Upfront TKI therapy was associated with longer overall survival in univariate analyses (HR, 0.054 [95% CI, 0.007-0.42]) and multivariate analyses (HR, 0.03 [95% CI, 0.002-0.47]). The outcomes of upfront TKI therapy are excellent for MLN-TK in both chronic and blast phases, regardless of gene abnormalities.

Pathogenesis and management of accelerated and blast phases of chronic myeloid leukemia.

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has been a model for cancer therapy development. Though most patients with CML have a normal quality and duration of life with TKI therapy, some patients progress to accelerated phase (AP) and blast phase (BP), both of which have a relatively poor prognosis. The rates of progression have reduced significantly from over >20% in the pre-TKI era to <5% now, largely due to refinements in CML therapy and response monitoring. Significant insights have been gained into the mechanisms of disease transformation including the role of additional cytogenetic abnormalities, somatic mutations, and other genomic alterations present at diagnosis or evolving on therapy. This knowledge is helping to optimize TKI therapy, improve prognostication and inform the development of novel combination regimens in these patients. While patients with de novo CML-AP have outcomes almost similar to CML in chronic phase (CP), those transformed from previously treated CML-CP should receive second- or third- generation TKIs and be strongly considered for allogeneic stem cell transplantation (allo-SCT). Similarly, patients with transformed CML-BP have particularly dismal outcomes with a median survival usually less than one year. Combination regimens with a potent TKI such as ponatinib followed by allo-SCT can achieve long-term survival in some transformed BP patients. Regimens including venetoclax in myeloid BP or inotuzumab ozogamicin or blinatumomab in lymphoid BP might lead to deeper and longer responses, facilitating potentially curative allo-SCT for patients with CML-BP once CP is achieved. Newer agents and novel combination therapies are further expanding the therapeutic arsenal in advanced phase CML.

Advanced Phases at Diagnosis of Childhood Chronic Myeloid Leukemia : The Experience of the International Registry for Chronic Myeloid Leukemia (CML) in Children and Adolescents (I-CML-Ped Study)

Introduction. Chronic myeloid leukemia (CML) is a very rare disease in children and adolescents. The international registry of CML in children and adolescents (I-CML-Ped Study) established in the year 2011 has proven very beneficial to better describe this disease in pediatric cohorts.Aims: To describe the characteristics and the outcome of the pediatric population with advanced phases of CML at initial diagnosis.Patients and Methods: Patients enrolled in the international registry for CML in children and adolescents (I-CML-Ped Study) were the subjects of the study .Disease phases were defined according to the ELN criteria. Characteristics and outcome were determined in children in accelerated (AP) and blastic phase (BP). No recommendations were given regarding the treatment of the patients. Overall survival (OS) was estimated from diagnosis by the Kaplan and Meier method.Results. 479 children and adolescents less than 18 years old with CML were enrolled in the I-CML-Ped study between January 2011 and April 2017. Among them, 37 patients (7.7%) presented at initial diagnosis with CML in advanced phase according to the ELN criteria: 20 children (13 boys and 7 girls, median age 12.6 years - range 3 to 18 years) and 17 children (11 boys and 6 girls, median age 11 years - range 5 to 17 years) were diagnosed in AP and in BP, respectively. Among the 17 patients diagnosed in BP, 12 (70%) had lymphoid and 2 myeloid phenotype (not specified: 2 patients with extramedullary disease as unique criteria of BP). According to the Sokal score for patients less than 45 years, 73% and 82% of the patients in AP and BP at diagnosis were high risk patients, respectively. For the 17 children in BP, treatment consisted of tyrosine kinase inhibitors (TKI) (n=3) or a combination of chemotherapy and TKI successively and/or simultaneously (n=14); 11 of them were transplanted (sibling donor: n=2; unrelated donor n=8; unknown: n=1) with a median time after diagnosis of 7 months (range, 4.5 to 10 months). For the 20 children in AP, treatment consisted of TKI (n=17) or a combination of chemotherapy and TKI successively and/or simultaneously (n=3); 6 of them were transplanted (sibling donor: n=5; unrelated donor n=1) with a median time after diagnosis of 8 months (range, 4 to 21.5 months). With a median time from diagnosis of 3.5 years (range 8 months to 13.5 years), 13 out of 17 patients in BP at initial diagnosis are alive in at least major molecular response (MMR) (11 patients) or without MMR (2 patients) including 5 patients who were not transplanted; death occurred in 3 transplanted patients (relapses: 2 patients; chronic graft versus host disease: 1 patient) and in one patient with progression of the disease. Nineteen out of 20 patients in AP at initial diagnosis are alive (one patient died after progression) in at least MMR (15 patients) or without MMR (2 patients) or unknown status (2 patients). The 5 years OS rates were 94% (95% confidence interval (CI): 66%-99%) and 74% (95% CI: 44%-89%) for patients diagnosed in AP or BP, respectively.Conclusion: The data indicates that the frequency of advanced phases at diagnosis of CML is similar in children and in adults but with a predominance of lymphoid phenotype in children in blastic phase compared to adult population. Hematopoietic stem cell transplantation remains a curative treatment of children in blastic phase at diagnosis.Acknowledgment: The I-CML Ped study is supported by an unrestricted grant from Novartis Pharmaceutical Company DisclosuresNo relevant conflicts of interest to declare.

Treatment of Myeloproliferative Neoplasms in Blastic Phase with Azacytidine. Clinical Results and Identification of Prognostic Factors

Treatment options for patients in blastic phase following evolution of a myeloproliferative neoplasm (MPN-BP) are limited and the overall prognosis is very poor with a survival likelihood of only a few months. There are some reports on a possible role of azacytidine (AZA), but the results are conflicting and no prognostic factors are at present available. In the present study, we focused on the identification of prognostic factors for response and overall survival (OS) in a cohort of 32 patients - M/F 21/11, median age at evolution 70.4 years, interquartile range (IQR) 64.2-77.1 - with MPN-BP treated with AZA and collected in the retrospective database of the Latial cooperative study group. The primary MPN diagnosis was essential thrombocythemia in 10 cases (31.3%), policythemia vera in 8 (25%), primary myelofibrosis in 10 (31.3%) and myelodysplastic syndrome (MDS)/MPN in 4 (12.4%). The JAK-2 V617F mutation was present in 20/29 patients tested (68.9%). All but 2 patients had received previous chemotherapy during the chronic phase. Median time from diagnosis to BP evolution was 61.4 months (IQR 25.5-168.1). All patients were treated with AZA at the standard dose of 75 mg/m2: 29 patients received a 7-day schedule and 3 a 5-day schedule every 28 days. Two patients are too early for response evaluation. Among the remaining 30 patients, 2 died early (6.6%) after AZA initiation due to pulmonary fungal infection and respiratory failure, respectively, 11 patients (36.7%) had a disease progression (DP) or stable disease (SD), 5 patients (16.7%) had a hematological improvement (HI), 4 patient (13.3%) achieved a partial remission (PR) and 8 patients (26.7%) a complete remission (CR): overall, 17/30 patients (56.7%) responded to treatment (HI + PR + CR) with AZA. The median overall survival (OS) from BP evolution of the whole cohort was 11.7 months (95% CI 3.5-19.8). There was no difference in the median OS among patients with HI, PR or CR (p >0.908): thus, we considered together these latter three groups for the analysis of prognostic factors as “responsive patients”, with a median OS of 18.7 months (95% CI 0-65.9) compared to 7.5 months (95% CI 3.6-11.3) in non-responding patients (p=0.001) (Fig. 1). The following features were analyzed as prognostic factors for response achievement and OS: gender, age at evolution, peripheral blood values at evolution, type of previous MPN, JAK-2V617F positivity. Only female sex was significant for both achievement of response (0.009) and OS duration (p=0.001). In conclusion, AZA is useful for the treatment of MPN-BP, with an overall response rate of 56.7% (17/30 patients) and an advantage in OS for responsive patients. In our cohort, only gender showed a prognostic impact, but a more refined prognostic stratification needs to be performed on a larger number of patients. [Display omitted] DisclosuresBreccia:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; Novartis: Consultancy. Foà:Roche, Janssen, Gilead, Amgen, Celgene, BMS, Sandoz, Novartis, AbbVie: Consultancy, Speakers Bureau.

Comparison of Outcomes after Myeloablative Versus Reduced Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia

▪Background: Allogeneic hematopoietic cell transplantation (alloHCT) is an effective and curative treatment modality for Chronic Myeloid Leukemia (CML), based on the strong graft-versus-leukemia (GVL) effect. The question about the optimal intensity of conditioning regimen of alloHCT for CML for survival outcomes is relevant, even in the era of tyrosine kinase inhibitors (TKIs). However, no comparison has been attempted between outcomes after myeloablative (MAC) and reduced intensity conditioning/non-myeloablative (RIC) regimens prior to alloHCT. Using the database from the Center for International Blood and Marrow Transplant Research (CIBMTR), we tried to answer the question if RIC alloHCT results in similar outcomes as MAC in patients with CML.Methods: We evaluated 1395 CML patients, between the ages of 18 and 60, who received MAC (n=1204) or RIC (n=191) before alloHCT between 2007 and 2014 and were reported to CIBMTR. The disease status at transplant was divided into the following categories: hematologic complete remission (CR), chronic phase 1 (CP1), chronic phase 2 and beyond (CP2+), accelerated phase (AP). Patients in blast phase (BP) at transplant and alternative donor transplants (haploidentical and cord blood) were excluded. The primary outcome was overall survival (OS) after alloHCT. Assuming a 5-year absolute difference of 15% in favor of RIC (relative risk [RR] 1.56), the study had 92% statistical power to detect this difference if it existed.Results: Median follow up of survivors in the MAC and RIC cohorts was 52 and 60 months, respectively. Patient, disease, and transplantation characteristics were similar with a few exceptions (Table 1). The median ages in MAC and RIC groups were 43 and 51 years, respectively. In vivo T cell depletion using anti-thymocyte globulin or alemtuzumab was used less commonly in MAC (22%) than in RIC group (47%). Multivariate analysis (MVA) showed that there was no significant difference in OS between MAC and RIC groups (p=0.87) (Fig. 1). In addition, disease-free survival (DFS) also did not differ significantly between the two groups (p=0.29) (Fig. 2). MVA failed to show any difference in transplant-related mortality (TRM) between MAC and RIC groups (Cox model p=0.95; Fine-Gray model p=0.58) (Fig. 3). In MVA, compared to MAC, RIC was associated with higher risk of relapse within 5 months of alloHCT (HR 1.85, p=0.001), but after that period, RIC patients had a trend toward lower risk of relapse than MAC (HR 0.64, p=0.09) (Fig. 4). Similar results were obtained with Fine-Gray model. The higher risk of relapse early on after RIC could be due to modest cytoreduction allowing relapse before GVL could take effect. The cumulative incidence of chronic GVHD was lower in RIC compared to MAC (HR 0.77, p=0.02). Subgroup analysis evaluating outcomes in patients who were in CP2+ or AP at transplant showed no significant difference in OS, DFS, TRM, or chronic GVHD and essentially mirrored results of the main model. Interestingly, subgroup analysis among those in CP2+ or AP showed that relapse risk was 2.3 times greater in RIC group during the first 5 months (HR 2.33, p=0.002) and afterward, a lower trend was noted (HR 0.39, p=0.10), compared to MAC.Conclusions: Considering no differences in OS and DFS between MAC and RIC alloHCT for CML in the overall cohort and in a pre-defined subgroup analysis restricted to those in CP2+ or AP, we conclude thatRIC alloHCT is an appropriate choice for CML patients less than 60 years of age. The study showed that higher risk of relapse in the first 5 months post-RIC alloHCT did not lead to inferior DFS or OS, indicating effective salvage treatment of the relapse. In addition, a lower incidence of chronic GVHD associated with RIC is an important consideration in deciding the transplant conditioning regimen for CML. [Display omitted] DisclosuresStuart:Cantex: Research Funding; Agios: Research Funding; ONO: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Astellas: Research Funding; Celator/Jazz: Research Funding; Bayer: Research Funding; Seattle Genetics: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel Support, Research Funding; MedImmune: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding.

A Multicenter Prospective Study on Efficacy and Safety of Ponatinib in Patients with Chronic Myeloid Leukemia Resistant or Intolerant to Previous Therapy: A 3-Year Report

Introduction Tyrosine kinase inhibitors (TKIs) have transformed outcomes in chronic myeloid leukemia (CML). Patients who respond to imatinib, have a life expectancy comparable with that of the global population, however, up to 40% of patients discontinue imatinib due to resistance or intolerance. Ponatinib is a third-generation highly-potent-pan-inhibitor of tyrosine kinases, active in all single resistance ABL kinase mutations, including the T315l mutation. This report presents the results of a prospective analysis of 3-year ponatinib therapy available in Poland by Angelini's donation program for patients in all phases of CML resistant or intolerant to previous TKI therapy. Methods 43 CML patients (20 women, 24 men, aged 19 to 76 years, mean age 49 ± 15 years) were treated in 20 Polish Hematology Centers with ponatinib initiated between March 2016 and December 2019. 23 pts (53%) were in the chronic phase (CP), 3 pts (7%) in accelerated phase (AP), and 17 pts (40%) in blastic phase (BP) (9 myeloblastic and 8 lymphoblastic). The majority of patients received three lines of TKI therapy. The T315I mutation was detected in 30% of patients (the initial characteristics of the 43 analyzed patients are shown in Table 1). The indication for ponatinib and its dose schedule was made according to the discretion of the attending physician. The initial dose of ponatinib was 45 mg/d in 60% of all patients (without statistically significant differences in the initial dose between patients starting treatment in CP, AP, and BP). Molecular biology tests were performed according to ELN guidelines and BCR-ABL/ABL ratios were expressed as % [IS] in all patients. Treatment responses were calculated at each specific time points recommended by ELN. Statistica 12 software (StatSoft, Tulsa, OK, USA) was used for calculations. Results The follow-up ranged from one week to 35.4 months (median 11.4 months) (one male patient died on infection one week after ponatinib introduction and was excluded from further analysis, he did not achieve CHR and he transformed to blast phase-BP). The responses to ponatinib are shown in Table 2. Among 23 CP patients, 18 achieved CHR (78%), 6 (26%) MCyR, 5 (22%) CCyR, and 1 (4%) MMR at 1 month of treatment. There were only 2 patients in this group (9%) who did not achieve CHR. Eleven CP patients (48%) achieved stable MMR. In all 3 AP patients, the best responses (CHR, CCyR, and MMR) were maintained until the end of observation (Table 2). Among 17 BP patients, 8 (47%) achieved CHR. The overall survival was significantly better in those patients who achieved CHR at 1 month of therapy (Figure 1). 19 patients (44%) experienced toxicity of ponatinib including: increase in blood pressure overall 9 patients (21%), hematological toxicity grade 3-4- 12 patients (28%).A total of 19 patients (44%) remained on ponatinib at the end of the observation. Ponatinib dose was reduced during the study in 18 patients (42%): in 11 (61% of those requiring dose reduction) because of toxicity, in 6 (33%) because of good response to treatment, and in 1 patient (6%) because of both reasons. The need for dose reduction was not significantly associated with comorbidities (p=0.4). Eight patients (19%) underwent allo-SCT during the observation. Ponatinib was discontinued in eight patients (19%), in six CP and two BP-patients. In five patients (12%), ponatinib was discontinued because of toxicity (hematological in one, non-hematological in two, and both in one patient); all were CP patients. In two patients (one CP, one BP patient), ponatinib was discontinued as they underwent allo-SCT. Overall, 16 patients (37%) died during the study: 12 of them (28%) due to CML progression. In all 43 patients, median survival was not reached. The estimated 2-year survival was 60% (95% confidence interval 44-76%) (Figure 2A) 84% in CP patients, 100% in AP patients (Figure 2B), and 20% in BP patients. None of the CP patients progressed to AP or BP during the study, i.e. progression-free survival was 100% at the end of observation (35.4 months). The presence of T315I mutation (p=0.2) or the initial dose of ponatinib (p=0.4) was not significantly associated with the overall survival. Conclusion Our study confirmes that ponatinib could induce durable responses with acceptable toxicity profiles in highly pretreated patients with CML resistant or intolerant to previous TKIs treated in standard clinical practice. Disclosures Sacha: Adamed:Consultancy, Honoraria;Bristol-Myers Squibb Company:Consultancy, Honoraria, Speakers Bureau;Pfizer:Consultancy, Honoraria, Speakers Bureau;Novartis:Consultancy, Honoraria, Speakers Bureau;Incyte:Consultancy, Honoraria, Speakers Bureau.Niesiobedzka-Krezel:Angelini Pharma:Other: lecture fee and meeting partcipation.Ciepluch:Copernicus Wojewodzkie centrum Onkologii:Current Employment.

Transcriptome profiling reveals the high incidence of hnRNPA1 exon 8 inclusion in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a malignancy that evolves through a multi-step process. Alternative splicing of several genes has been linked to the progression of the disease, but involvement of alternations in splicing profiles has not been reported. RNA-seq of peripheral blood mononuclear cell (PBMC) samples characterized the differentially expressed and spliced transcripts in five CML chronic phase (CP) and five blast phase (BP) patients, and five healthy controls. Global splicing alteration analysis detected 6474 altered splicing events altered between CML and healthy samples, including many of the previously reported splicing variants and showing a more profound altered splicing deregulation in BP samples. Functional clustering of differentially spliced genes in CP revealed a preferred enrichment relating to cell signaling, while the spliceosome pathway was most overrepresented in BP samples. One differentially spliced spliceosome gene hnRNPA1 showed two splice isoforms; the longer isoform contained exon 8 was preferentially expressed in the BP patients, and the short one excluding exon 8 was specific to healthy controls. Our findings suggested that alternative splicing deregulation played a central role during the progression of CML from CP to BP, and the longer isoform of hnRNPA1 might represent a diagnostic marker and therapeutic target for CML.

FLAG-IDA and Ponatinib in Patients with Blast Phase Chronic Myeloid Leukaemia: Results from the Phase I/II UK Trials Acceleration Programme Matchpoint Trial

FLAG-IDA and Ponatinib in Patients with Blast Phase Chronic Myeloid Leukaemia: Results from the Phase I/II UK Trials Acceleration Programme Matchpoint Trial

Outcomes and Side Effect Profile of Ponatinib in Treatment of Chronic Myeloid Leukemia (CML): A Retrospective Single-Center Experience

BACKGROUND: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) used to treat resistant chronic myeloid leukemia (CML). It has been associated with cardiovascular adverse events (CAEs); most specifically hypertension and arterial thrombotic events. Most CAEs are dose-dependent. The frequency of CAEs in the real-world setting has not been previously described. In this study, we describe the survival outcomes and associated toxicities in ponatinib-treated patients at Moffitt Cancer Center (MCC).METHODS: A retrospective review of CML patients treated with ponatinib at MCC between years 2011 and 2017 was performed to identify patients treated with ponatinib. Demographics, disease-specific variables and clinical outcomes were collected in accordance with the Institutional Board Review approved protocol. Frequency of adverse events on ponatinib were categorized. Pearson's chi-square test for independence was used to determine significance for categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS).RESULTS: A total of 78 patients (38 females/40 males) treated with ponatinib with median age of 42.5 (range 14-70) years were included in the analysis. At the time of ponatinib initiation, 51 patients were in chronic phase (CP), 9 in accelerated phase (AP), and 18 in blast phase (BP). Ponatinib was 3rd or 4th line therapy in 65% of CP patients, with a mean starting dose of 39.65 mg per day. Dose reduction occurred in 64.7% of patients with CP and the mean duration of ponatinib was 14.6 months. The most common non-cardiovascular adverse events (NCAEs) were thrombocytopenia (39.7%), abdominal pain (33.3%), anemia (28.2%), elevated lipase (28.3%), and rash (26.9%) in a dose-dependent fashion. Most common new onset CAEs included arrhythmia (9%) and hypertension (7.7%). Three patients (3.8%) experienced a myocardial infarction, and two of these had significant cardiovascular risk factors at baseline. No other arterial thrombotic events were reported. A total of 18 patients (23.1%) experienced some form of CAE. Prior to 2014, more patients were placed on 45 mg ponatinib and more CAEs occurred during that time. After 2014, there is an increased awareness of potential cardiotoxicity associated with ponatinib and referral to cardio-oncology (CO) became a routine practice in our institution. Figure 1 summarizes the cardiac safety profile of ponatinib and frequency of CO referral. Ponatinib 45 mg and CAEs are not independent (X2 (1, N = 82) = 7.68, p < 0.05), but this correlation was lost when testing CAEs against patients who were on ponatinib 45 mg and either referred to CO or on cardiac protective medications (X2 (1, N = 82) = 3.55, p > 0.05) suggesting CAEs become independent of ponatinib dosing when cardioprotective measures are put in place. In patients with CP-CML, 69.6% achieved a complete cytogenetic response (CCyR) and 58.7% had a major molecular response (MMR). Patients with AP and BP achieved CCyR in 37.5% and 68.8%, respectively. Among the BP patients who achieved at least CCyR (n = 11), 81.1% of the patients had received TKI with chemotherapy at the time of BP. Five-year median OS of the entire cohort was 63%. With a median follow up of 32.5 months, the median OS from ponatinib initiation was not reached (NR) in CP with allogeneic stem cell transplantation (allo-SCT) (n = 17) or without allo-SCT (n = 34); was 32.9 months in AP with allo-SCT (n = 4), NR in AP without allo-SCT (n = 5); and NR in BP with allo-SCT (n = 6), and 5.45 months in BP without allo-SCT (n = 12) (p < 0.0001).CONCLUSIONS: In our series, the incidence of new arterial thrombotic events and hypertension appears lower than reported in the PACE trial. The incidence of CAEs declined after 2014 when early dose reductions became standard practice and early referrals to cardio-oncology increased. Non-CAEs and outcomes were similar to previous reports. Limitations of this analysis include its retrospective nature and small sample size. Future studies analyzing the impact of specific interventions on mitigating cardiovascular events are needed. [Display omitted] DisclosuresSweet:BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; BMS: Honoraria; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau.

Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia

AbstractAllogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.

Characteristics and outcome of chronic myeloid leukemia patients with E255K/V BCR-ABL kinase domain mutations.

Kinase domain (KD) mutations of ABL1 represent the most common resistance mechanism to tyrosine kinase inhibitors (TKI) in CML. Besides T315I, mutations in codon 255 are highly resistant mutations in vitro to all TKI. We aimed to study the incidence, prognosis, and response to treatment in patients with E255K/V. We evaluated 976 patients by sequencing of BCR-ABL1 fusion transcript for ABL1 KD mutations. We identified KD mutations in 381 (39%) patients, including E255K/V in 48 (13% of all mutations). At mutation detection, 14 patients (29%) were in chronic phase (CP), 12 (25%) in accelerated phase (AP), and 22 (46%) in blast phase (BP). 9/14 CP patients responded to treatment (best response complete hematologic response-CHR-4; complete cytogenetic response-CCyR-1; major molecular response-MMR-4); only 4/12 AP patients (CHR 3; MMR 1) and 7/22 BP patients responded (CCyR 2; MMR 2; partial cytogenetic response-PCyR-3). After a median follow-up of 65months from mutation detection, 36 patients (75%) died: 9/14 (64%) in CP, 9/12 (75%) in AP, and 18/22 (82%) in BP (p=0.003); median overall survival was 12months. Patients with E255K/V mutation have a poor prognosis, regardless of the stage of the disease at detection.

Cytogenetics-based risk prediction of blastic transformation of chronic myeloid leukemia in the era of TKI therapy.

The high fatality of patients with blast phase (BP) chronic myeloid leukemia (CML) necessitates identification of high-risk (HR) patients to prevent onset of BP. Here, we investigated the risk of BP based on additional chromosomal abnormality (ACA) profiles in a cohort of 2326 CML patients treated with tyrosine kinase inhibitors (TKIs). We examined the time intervals from initial diagnosis to ACA emergence (interval 1), from ACA emergence to onset of BP (interval 2), and survival after onset of BP (interval 3). Based on BP risk associated with each ACA, patients were stratified into intermediate-1, intermediate-2, and HR groups, with a median duration of interval 2 of unreached, 19.2 months, and 1.9 months, respectively. There was no difference in durations of intervals 1 or 3 among 3 groups. Including patients without ACAs who formed the standard-risk group, the overall 5-year cumulative probability of BP was 9.8%, 28.0%, 41.7%, and 67.4% for these 4 groups, respectively. The pre-BP disease course in those who developed BP was similar regardless of cytogenetic alterations, and 84.4% of BP patients developed BP within the first 5 years of diagnosis. In summary, interval 2 is the predominant determinant of BP risk and patient outcome. By prolonging the duration of interval 2, TKI therapy mitigates BP risk associated with low-risk ACAs or no ACAs but does not alter the natural course of CML with HR ACAs. Thus, we have identified a group of patients who have HR of BP and may benefit from timely alternative treatment to prevent onset of BP.

Aberrantly expressed transcription factors C/EBP and SOX4 have positive effects in the development of chronic myeloid leukemia.

The aim of the present study was to examine the expression and significance of CCAAT/enhancer binding protein α (C/EBPα) and SRY‑related high mobility group box containing transcription factor 4 (SOX4) in chronic myeloid leukemia (CML). Bone marrow samples were collected from patients with CML, and peripheral blood mononuclear cells were collected from healthy controls. Protein and mRNA were extracted from the collected samples, and analyzed using western blotting and reverse transcription‑quantitative polymerase chain reaction analyses, respectively. Spearman's method was used to evaluate the correlation between the expression levels of these two genes, with P<0.05 considered to indicate a statistically significant difference. A total of 79patients, including 57patients with newly diagnosed CML and 22patients treated with imatinib therapy, and 30 controls were enrolled. The expression of SOX4 was upregulated in the patients with CML, whereas the expression of C/EBPα was downregulated (P<0.05). However, no differences were observed among the chronic, accelerated and blastic CML phases, respectively (P>0.05). In addition, no associations were found between the changes in expression and age, gender, white blood cells or the expression of breakpoint cluster region/abelson in patients (P>0.05). However, the expression of SOX4 was negatively correlated with the expression of C/EBPα (P<0.01). Following imatinib treatment, the expression of SOX4 was downregulated in the progression‑free patients, but upregulated in the blastic phase patients, whereas the expression of C/EBPα showed the opposite trend. Therefore, C/EBPα and SOX4 were important and negatively associated with the process of CML, and the C/EBPα‑SOX4 axis may be a novel potential therapeutic target for the treatment of CML.

Expression of transcription factors SOX4 and C/EBPα in chronic myeloid leukemia and their significances

Objective To investigate the expression of SOX4 and C/EBPα mRNA in chronic myeloid leukemia (CML) and their clinical significances. Methods Bone marrow samples from 68 cases of CML including 57 newly diagnosed patients and 11 patients treated with imatinib were collected, and peripheral blood mononuclear cells from 30 healthy people were collected as healthy control. The expression of SOX4 and C/EBPα mRNA and protein levels were detected by RT-PCR and Western blot, respectively. The relations between the expression of SOX4 and C/EBPα and the influences of imatinib on SOX4 and C/EBPα were analyzed. Results The expression level of SOX4 mRNA was increased in newly diagnosed CML patients compared with that of normal control group (6.545 5±1.495 2 vs. 0.059 6±0.018 8, t=3.139, P=0.002 3), but the expression level of C/EBPα mRNA was significantly decreased (0.238 8±0.033 8 vs. 0.810 5±0.056 2, t=9.240, P 0.05). The expression level of SOX4 mRNA in 5 patients treated with imatinib was decreased (0.120 6±0.044 9 vs. 0.557 9±0.144 8, t=2.885, P=0.020 4), and the expression level of C/EBPα mRNA was increased (0.330 3±0.042 4 vs. 0.150 5±0.046 5, t=2.855, P=0.021 3). The expression level of SOX4 mRNA in 6 patients who developed blast phase during the treatment of imatinib was increased (0.469 9 ± 0.123 0 vs. 0.050 2 ± 0.036 6, t=2.370, P=0.039 3), and the expression level of C/EBPα mRNA was decreased (0.197 9±0.064 7 vs. 0.378 7±0.042 9, t=2.327, P=0.042 3). The expression of SOX4 mRNA was negatively correlated with C/EBPα mRNA (t=-0.554 6, P=0.002 8). Conclusions In newly diagnosed CML, the expression level of SOX4 is increased, C/EBPα is decreased compared with that of healthy control, and both have negative correlation. In the patients in blast phase after imatinib treatment, SOX4 gene is up-regulated, and C/EBPα is down-regulated. C/EBPα-SOX4 axis may play a role in the occurrence and development of CML. SOX4 may be a new molecular target for the treatment of CML. Key words: Leukemia, myeloid, chronic; SOX4; C/EBPα; Prognosis; Targeted therapy

BP1001, a Novel Therapeutic for Chronic Myelogenous Leukemia

Background: The Growth factor receptor bound protein-2 (Grb2) is essential to cancer cell signaling. Grb2 binds to numerous tyrosine kinases, including the Bcr-Abl chimeric oncogene found in Philadelphia chromosome positive chronic myelogenous leukemia (CML) cells. Upon binding to tyrosine kinases, Grb2 transduces the kinases signals to the activation of Ras and its downstream protein, Extracellular signals regulated protein kinases-1,2 (Erk1,2). The direct binding of Grb2 to Bcr-Abl is required for Bcr-Abl to transform fibroblasts and induce CML-like diseases in mice. We hypothesize that Grb2 is a potential therapeutic target against CML. BP1001, a liposome-incorporated antisense oligodeoxynucleotide targeted against the Grb2 mRNA, was developed to inhibit Grb2 expression. Previously we demonstrated that BP1001 suppressed the growth of CML cell lines and CML xenografts.Aim: Since the clinical activity of BP1001 will be investigated in gleevec-resistant CML patients, preclinical studies were conducted to determine whether BP1001 could suppress the proliferation of gleevec-resistant CML cells. Additionally, whether BP1001 could enhance the inhibitory effects of dasatinib in CML cells was determined. The clinical activity of BP1001 was studied in CML blast patients, who were part of a larger Phase I clinical study.Methods: The alamarBlue dye incorporation method and the CellTiter Glow method were used to determine cell viability. Flow cytometry was utilized to analyze cell cycling and Grb2 expression. The clinical study was a standard 3+3 dose-finding study in which BP1001 was given twice weekly, IV over 2-3 hours for 28 days. The clinical activity of BP1001 was evaluated in its ability to reduce target Grb2 protein in CD33-expressing cells and to reduce leukemia blast counts.Results: BP1001 decreased the proliferation of gleevec-resistant CML cells in a dose-dependent manner. Furthermore, BP1001 pretreatment enhanced the inhibitory effects of dasatinib in CML cells, by about 2-6 fold. The major inhibition mechanism of the BP1001 + dasatinib combination was cell death. A total of39 patients with refractory/relapsed hematologic malignancies was enrolled in the clinical trial. Five were CML blast phase patients; they were enrolled in the first cohort (5 mg/m2BP1001). Two CML patients, who had T315I mutation, showed significant reductions in circulating blasts during treatment. One patient’s blasts were reduced from 89% to 9%, while another patient’s blasts were reduced from 17% to 8%. BP1001 decreased >25% Grb2 levels in 10 of 12 samples (average decrease: 49%) and >25% phosphorylated Erk1,2 levels in 7 of 12 samples (average decrease: 52%).Conclusions: BP1001 was active against gleevec-resistant CML cells and enhanced dasatinib efficacy in preclinical studies. BP1001 may have therapeutic activity against CML. We are planning a Phase I/II trial to study the safety and efficacy of BP1001 in combination with dasatinib in accelerated or blast phase CML patients. DisclosuresTari Ashizawa:Bio-Path Holdings, Inc.: Employment, Equity Ownership.

Health-related quality of life during bosutinib (SKI-606) therapy in patients with advanced chronic myeloid leukemia after imatinib failure

Objectives: The tyrosine kinase inhibitor (TKI) bosutinib has demonstrated activity in patients with advanced phase chronic myeloid leukemia (CML), but effects on health-related quality of life (HRQoL) remain unexplored. This study evaluated HRQoL in advanced CML patients receiving bosutinib in an ongoing phase 2 study following resistance or intolerance to prior imatinib therapy.Methods: This analysis included data from 76 accelerated-phase (AP) and 64 blast-phase (BP) patients resistant/intolerant to prior imatinib with or without prior exposure to other TKIs. Patient-reported HRQoL assessments completed at baseline; weeks 4, 8, and 12; every 12 weeks thereafter; and at treatment completion included the Functional Assessment of Cancer Therapy–Leukemia (FACT-Leu); general health status was assessed using the 5-item EuroQol (EQ-5D) instrument and a visual analog scale (VAS).Results: HRQoL at baseline was somewhat worse in BP versus AP CML patients. There was a significant improvement in the mean FACT-Leu Total scale at weeks 24, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, 48, and 96 in BP CML patients compared with baseline. EQ-5D Utility scores were stable throughout treatment in AP CML patients but significantly improved versus baseline in BP CML patients at weeks 4, 8, 12, and 36. Mean VAS scores were significantly improved at weeks 8, 36, and 48 in AP CML patients and at weeks 4, 8, 12, 24, 36, and 96 in BP CML patients. The lack of a comparison group limits attribution of improvements in HRQoL specifically to bosutinib treatment; potential bias due to non-ignorable dropout may limit the ability to generalize these findings to situations where durations of therapy exceed the 96-week follow-up duration of the present study.Conclusion: These findings suggest that bosutinib therapy is associated with improved HRQoL in advanced phase CML patients.Clinical trial registration: NCT00261846.

Allogeneic Stem Cell Transplantation for Patients with T315I BCR-ABL Mutated Chronic Myeloid Leukemia

Allogeneic stem cell transplantation (SCT) is currently the only curative treatment option for chronic myeloid leukemia (CML) patients with BCR-ABL T315I mutations. We report the outcome of SCT in 22 patients with T315I+ CML, most (n = 16) from haploidentical family donors (HID-SCT). At the time the mutation was detected, 8 patients were in the chronic phase (CP), 7 in the accelerated phase (AP), and 7 in the blast phase (BP). At the time of SCT 7 were in the CP, 8 in the AP or returning to the CP post-AP (AP/AP-CPn), and 7 in the BP or returning to CP post-BP (BP/BP-CPn). The cumulative incidence of grades III to IV acute graft-versus-host disease was 9.1%. Chronic graft-versus-host disease was observed in 60.0% of patients, including 25.0% who suffered from severe disease. Four patients died of transplant-related complications at a median interval from SCT of 16.3 months. The estimated 2-year leukemia-free survival rate was 80.0%, 72.9%, and 0% in CP, AP/AP-CPn and BP/BP-CPn groups at the time of SCT, respectively. After a median follow-up of 17.3 months from SCT, 14 patients are alive, including 13 in complete molecular response and 1 with an extramedullary relapse. In conclusion, HID-SCT is a potentially curative treatment for T315I + CML patients. For patients in CP/AP, immediate SCT might result in promising survival. The outcome of patients in BP with T315I+ mutation remains very poor.

Dasatinib treatment based on BCR- ABL mutation detection in imatinib- resistant patients with chronic myeloid leukemia

目的探讨在BCR-ABL突变检测指导下选用达沙替尼治疗伊马替尼耐药慢性髓性白血病（CML）患者的有效性。方法83例伊马替尼耐药和39例伊马替尼与尼洛替尼均耐药的CML患者，持续口服达沙替尼，其中慢性期（CP) 55例，加速期（AP) 21例，急变期（BP) 46例。达沙替尼治疗前，经BCR-ABL突变筛查，除外具有对达沙替尼高度耐药突变类型（T315I/A、F317L/V/C和V299L）的患者。定期监测血液学、细胞遗传学和分子学反应，评估疾病进展和生存情况。当发生达沙替尼治疗失败时检测BCR-ABL突变。结果CP患者中，完全血液学反应（CHR）率为92.7%，完全细胞遗传学反应（CCyR）率为53.7%，主要分子学反应（MMR）率为29.6%，MR4.5率为14.8%，4年疾病无进展生存（PFS）率和总生存（OS）率分别为84.4％和89.5%。AP患者中，血液学反应（HR）率和CCyR率分别为81.0％和35.0%，3年PFS率和OS率分别为56.1％和59.3%。BP患者中，HR率和CCyR率分别为63.0%和21.4%，1年PFS率和OS率分别为43.6％和61.8%。达沙替尼作为二线和三线酪氨酸激酶抑制剂时，治疗反应相似。当发生达沙替尼治疗失败时，75例患者中37例（48.7%）检出新突变，T315I最为多见（59.5%）。达沙替尼治疗前存在突变的患者与无突变患者相比，治疗反应、PFS和OS差异均无统计学意义，但当出现达沙替尼耐药时，发生新突变的可能性显著增高（65.7％对34.1%，P=0.006）。结论达沙替尼可以有效治疗伊马替尼耐药或伊马替尼与尼洛替尼均耐药的CML各期患者，CP和AP患者疗效持久。达沙替尼治疗前BCR-ABL突变筛查及治疗中突变监测非常重要。

Correlation between point mutation in ABL kinase and clinical outcome of chronic myeloid leukemia patients

To analyze the association of different types of ABL tyrosine point mutations and imatinib resistance to probe the relation between ABL tyrosine point mutations and the prognosis of patients with chronic myeloid leukemia (CML). Nested reverse transcriptasepolym erase chain reaction was performed on samples from 70 patients to amplify the ABL kinase domain. Then, the amplified product was purified and sequenced in both direction. The homologous analysis was performed in combination of clinical data. The ABL domain point mutations were detected in 32 patients (45.7%) including 16 patients in chronic phase (CP), 6 patients in accelerated phase(AP)and 10 patients in blast phase (BP), which were detected as T315I, E255K, C475Y, Y253H, G321W, G250E, F317L, E258K, F359V, E459K and F311I, respectively. Sokal score with intermediate and high risk and Ph+ chromosome with complex karyotype were important risk factors for ABL domain point mutations. The 5-year overall survival (OS) was not significantly different between the patients with or without ABL domain point mutations (78.1% vs 84.2%, P=0.985), while the 5-year cumulative event-free survival (EFS) of two groups were 34.4% and 68.4% (P=0.034), respectively. The rate of complete cytogenetic response was higher in patients treated with allogenic hematopetic stem cell transplantation (allo-HSCT) compared with patients merely treated with second-generation tyrosine kinase inhibitors or chemotherapeutics (P=0.001). Patients with ABL domain point mutations had poor efficacy and prognosis compared to those without ABL domain point mutations. Detection of ABL domain point mutations in CML-CP was helpful for the adjustment of therapeutic options and improvement of prognosis. And allo-HSCT was a more effective therapy for patients with advanced phase.