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We retrospectively examined the results of a new chemo-free approach combining blinatumomab with ponatinib (blina/pona) in 26 relapsed/refractory Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) patients. All but one achieved complete morphologic remission, and 23 achieved a complete molecular response. With a median follow-up of 34.4 months, the median overall (OS) and event-free (EFS) survivals were 20 and 15.3 months, respectively. After blina/pona, 8 patients underwent an allotransplant (allo), while among the 18 non-transplanted cases, 15 received ponatinib in maintenance. Fifteen relapse/progressions occurred with a significant difference between allo and non allo cases (12.5% vs 82.3%

Acute lymphoblastic leukemia (ALL) is an aggressive hematological disease. The incorporation of tyrosine kinase inhibitors (TKIs) into the standard treatment regimen for Philadelphia (Ph)-positive ALL significantly improved clinical outcomes. TKI-based induction chemotherapy, followed by allogeneic hematopoietic cell transplantation (HCT) during the first complete remission (CR), is the standard of care for ALL patients. However, treatment with TKIs alone or TKIs plus low-intensity chemotherapy can achieve CR in some patients. Although this strategy is not enough to induce a deeper molecular response, it can reduce the incidence of treatment-related mortality. Despite promising results from pediatric trials, allogeneic HCT remains an important component of the treatment strategy for Ph-positive adult ALL. However, improving the highly sensitive BCR-ABL1 assays and introducing immunotherapy may decrease the demand for allogeneic HCT. Nevertheless, the treatment of Ph-positive ALL is still challenging, especially in cases with relapsed and refractory disease. Potent TKIs and monoclonal antibodies, such as blinatumomab and inotuzumab, have improved patient outcomes in relapse and refractory cases of ALL. The introduction of effective agents, such as potent TKIs and monoclonal antibodies, may improve the possibility of remission in Ph-positive ALL patients and hopefully cure this disease.

Rare patients with chronic myeloid leukemia (CML) can present initially in lymphoblastic crisis (LBC) mimicking Ph + B-lymphoblastic leukemia (B-ALL). We retrospectively reviewed 275 adults who diagnosed initially as Ph + B-ALL and identified 28 patients with at least one of three features supporting the diagnosis of CML-LBC: 1) a large discrepancy between the blast count and Ph + clone; 2) Ph + clone persistent when B-ALL in remission; 3)

© 2021 Taylor & Francis Group, LLC.Targeting the key enzymes of sphingolipid metabolism including serine palmitoyltransferase (SPT), sphingosine kinase (SK) and glucosylceramide synthase (GCS) has a therapeutic importance. However, sphingolipid metabolism-mediated anti-leukemic actions of resveratrol in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) remain unknown. Therefore, we explored potential mechanisms behind resveratrol-mediated cytotoxicity in SD1 and SUP-B15 Ph + ALL cells in the context of sphingolipid metabolism and apoptosis induction. The anti-proliferative and apoptotic effects of resveratrol alone and in combination with SPT inhibitor (myriocin), SK inhibitor (SKI II), GCS inhibitor (PDMP) were determined by MTT cell proliferation assay and flow cytometry, respectively. The effects of resveratrol on PARP cleavage, SPT, SK and GCS protein levels were investigated by Western blot. Resveratrol inhibited proliferation and triggered apoptosis via PARP activation and externalization of phosphatidylserine (PS). Resveratrol increased the expression of SPT whereas it downregulated SK and GCS. Resveratrol’s combinations with SKI II and PDMP intensified its anti-leukemic activity by increasing the relocalization of PS while its combination with myriocin suppressed apoptosis. Therefore, resveratrol inhibited cell proliferation and induced apoptosis through modulating SK, GCS and SPT expression, which may be considered as novel biomarkers of resveratrol-induced cytotoxicity in Ph + ALL.

Introduction: Prior to the introduction of tyrosine kinase inhibitors (TKIs), the presence of BCR-ABL1 conferred a poor prognosis in patients with acute lymphoblastic leukemia (ALL). We published in 2017 in Br J Haematology our analysis comparing the survival of Ph-Positive (Ph+) and Ph-negative ALL during the period when TKIs were universally available in the United States for Ph+ ALL using a Surveillance, Epidemiology, and End Results (SEER) Database analysis. Despite using TKIs, we have continued to remain reliant on cytotoxic chemotherapy regimens and allogeneic hematopoietic stem cell transplant (allo-HSCT) to achieve the best long-term outcomes. However, with the introduction of more potent TKIs and other novel agents, as well as better methods for monitoring minimal/measurable residual disease (MRD) the best approach is yet to be determined. In this study we present data from our institution with incorporation of TKIs in our modified USC ALL pediatric-based regimen without pegaspargase (PEG) (Table 1). Methods: This retrospective, single institution chart review included adults aged >18 with newly diagnosed Ph+ ALL between 2016 and 2020. Primary objectives were Overall survival (OS) and event-free survival (EFS) at 3 years for Ph+ ALL patients and secondary objectives were rates of complete remission/complete remission with incomplete recovery (CR/CRi), minimal residual disease (MRD) by flow cytometry and presence of BCR-ABL1 fusion transcript by real time polymerase chain reaction. Descriptive statistics of patients were reported and evaluated using Fisher's exact test. OS and EFS were reported through Kaplan Meier curves and Log-rank tests. Two-sided p value ≤0.05 was significant. RESULTS: 26 Ph+ ALL patients were identified. Median age at diagnosis was 42.5 years, with 42.3% males and 57.7% females. Median BMI was 31.1 kg/m 2, 42.3% had hepatic steatosis and 34.6% had CNS disease pre-induction. After induction 1, 91.3% of patients achieved CR/CRi, 8.7% were refractory, and 64.3% were MRD flow negative with 24% of patients with undetectable BCR-ABL1. After induction 2, 94.1% had achieved CR/CRi, 64.3% were MRD flow negative with 44.4% of patients with undetectable BCR-ABL1. After consolidation I, 78.6% were MRD flow negative. 50% of patients had received blinatumomab for MRD flow positivity early in the course and 34.6% underwent allo-HSCT. Of note, 65.4% of patients received Dasatinib only and 30.8% received at least 2 TKIs. Overall, 11.5% had known relapse, 12.5% died. 3-year OS was 83.3% and 3-year EFS was 86.6% (Table 2). When survival was stratified by transplant status, 3-year OS with allo-HSCT was 100% versus 70% without allo-HSCT (p=0.15) and 3-year EFS with allo-HSCT was 100% compared to 77.9% without allo-HSCT (Table 3). CONCLUSIONS: The use of the modified USC ALL regimen without PEG for the treatment of newly diagnosed Ph+ ALL combined with TKI at our institution led to an excellent 3-year OS (83.3%) and 3-year EFS (86.6%). All patients received TKI, half of the patients received blinatumomab and at least one third received allo-HSCT which likely led to higher OS even without PEG. We also observed a trend towards improved OS in recipients of allo-HSCT compared to patients who did not receive allo-HSCT (100% vs. 70%, p=0.15) although statistically not significant, it highlights the role of allo-HSCT in the management of Ph+ ALL patients. Figure 1 Figure 1. Disclosures Chaudhary: TCR2: Current equity holder in publicly-traded company; Celldex: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; Pancella: Consultancy; Oncotartis: Consultancy; Athelas: Consultancy, Current holder of stock options in a privately-held company; Angeles Therapeutics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Founder, Patents & Royalties: Cell therapy ; Allogene: Current equity holder in publicly-traded company. Douer: Adaptive: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Speakers Bureau; Jazz: Consultancy; Servier: Consultancy, Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Yaghmour: Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; Alexion: Speakers Bureau; Astellas: Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Jazz: Speakers Bureau.

PURPOSE Chronic myeloid leukemia (CML) ranks second in terms of disease-related health care expenditures at the Lebanese Ministry of Public Health (MoPH) after breast cancer. With the introduction of tyrosine kinase inhibitors (TKIs), survival of patients with CML has dramatically improved and approached that of the normal population. In recent years, several studies demonstrated that patients who achieve a deep molecular response while receiving TKI therapy could safely attempt treatment-free remission (TFR), the new treatment goal in patients with CML. The objective is to estimate the budget impact of TFR at the MoPH. METHODS Analyses were done on 162 patients with CML receiving imatinib, nilotinib, or dasatinib, as first-line or second-line therapy, over a 4-year time horizon using MoPH drug pricing. The model assumed that patients could attempt TFR after 36 months of TKI therapy, where the last 24 months were at stable molecular response as per MoPH and National Comprehensive Cancer Network guidelines. Duration of TFR was based on European Stop Kinase Inhibitor treatment-free survival curve. RESULTS Out of the 162 patients, 83 were eligible to attempt TFR, 36 patients were not eligible, 32 patients were lost to follow-up, two patients died as a result of CML progression, and five died as a result of other causes. The total cost of CML treatment with TFR from the time of analysis and over 4 years can be reduced by more than 7 million US dollars (57%). CONCLUSION The model can be used to inform health care decision makers on the importance of TFR and the potential savings.

In Ph+ acute lymphoblastic leukaemia (Ph+ ALL), minimal residual disease (MRD) is the most relevant prognostic factor. Currently, its evaluation is based on quantitative real-time polymerase chain reaction (Q-RT-PCR). Digital droplet PCR (ddPCR) was successfully applied to several haematological malignancies. We analyzed 98 samples from 40 Ph+ ALL cases, the majority enrolled in the GIMEMA LAL2116 trial: 10 diagnostic samples and 88 follow-up samples, mostly focusing on positive non-quantifiable (PNQ) or negative samples by Q-RT-PCR to investigate the value of ddPCR for MRD monitoring. DdPCR BCR/ABL1 assay showed good sensitivity and accuracy to detect low levels of transcripts, with a high rate of reproducibility. The analysis of PNQ or negative cases by Q-RT-PCR revealed that ddPCR increased the proportion of quantifiable samples (p

The recent spread of the Covid‐19 infection has raised important questions within the haematology community on how best to manage and treat patients with haematological malignancies, particularly acute leukaemias. Italy has witnessed a dramatic raise in infections and death rates, that has hit in particular certain areas of the most populated Northern regions of the country (Lombardia, Veneto, Piemonte, Emilia Romagna). Within the nationwide Campus ALL programme in the last week of March we sent a questionnaire addressing different issues related to the management of adult ALL patients during the Covid‐19 pandemic to 40 haematology centres located on the entire territory.

Dasatinib, a second-line tyrosine kinase inhibitor (TKI), has been widely used in chronic myeloid leukemia (CML) and Philadelphia-positive B-cell acute lymphoblastic leukemia (Ph + B-ALL). Although dasatinib has been well tolerated, side effects including hemorrhage are not rare. Cases of bleeding disorders ultimately result in thrombocytopenia, but platelet aggregation dysfunction induced by dasatinib has also been demonstrated in Ph + B-ALL and CML patients. We report three Chinese children with Ph + B-ALL who received a combination treatment of chemotherapy and dasatinib and developed gastrointestinal bleeding several months later. The platelet count and clotting tests were normal, and these patients presented with dasatinib-induced platelet dysfunction. These findings reveal that physicians should be aware of and carefully monitor for side effects, including bleeding disorders.

Philadelphia chromosome is well-known chromosomal abnormality in chronic myeloid leukemia (CML). However, B-acute lymphoblastic leukemia (B-ALL) with Philadelphia-positive (Ph′) is a neoplasm of lymphoblast committed to the B-cell lineage. The clinical presentation of B-ALL Ph′+ is similar to B-ALL but is more common in adults than in children. Our 50-year-old male patient presented to psychiatry OPD for deaddiction of alcohol. The patient also complained of generalized weakness and pain in legs which may have been due to chronic alcoholism. He was further investigated and diagnosed as B-precursor ALL with positive BCR-ABL fusion gene. Here, we like to emphasize that overlapping symptoms may lead to delay in diagnosis, so clinician should always investigate the patient thoroughly so that the patient is diagnosed on time and treatment can be started as early as possible and fatal outcomes can be avoided.

Introduction Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) presents with an aggressive clinical course and carries a high risk for relapse. The addition of tyrosine kinase inhibitors (TKI) has revolutionized the induction and maintenance treatment for this disease and has increased the patients achieving and maintaining complete remission. Allogeneic hematopoietic stem cell transplantation (HSCT) is the standard of care at this time for patients who achieve first complete remission (CR1); however, its impact on outcomes is debated. This systematic review and meta-analysis aimed to compare the outcomes of TKI maintenance therapy with or without HSCT in Ph+ ALL patients in CR1. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, a comprehensive literature search was conducted on PubMed, Cochrane, and Clinical trials.gov using MeSH terms and keywords for " Philadelphia chromosome ", "hematopoietic stem cell transplantation" and " protein kinase inhibitors " from date of inception to May 01, 2021. A total of 1691 records were discovered using database searching. All search results were imported into the Endnote X9.0 reference manager, and duplicates were removed. The primary and secondary screening was performed, and after excluding irrelevant and review articles, a total of 6 (3 retrospectives, 3 phase II randomized controlled trials) original articles were included reporting separate outcomes of TKI maintenance therapy (TKI cohort) and HSCT followed by TKI maintenance therapy (HSCT-TKI cohort) for Ph+ ALL in CR1. Quality evaluation was done using the NIH quality assessment tool. The inter-study variance was calculated using the Der Simonian-Laird Estimator. Proportions along with a 95% Confidence Interval (CI) were extracted to compute pooled analysis using the 'meta' package by Schwarzer et al. in the RevMan (version 5.4-1). RESULTS: A total of 413 patients from 6 studies were included for this systematic review and meta-analysis. Out of these, 222 (53.8%) had TKI maintenance after consolidation therapy and 191 (46.2%) patients had HSCT followed by TKI maintenance in CR1. The median age of the whole cohort was 49.3 (17-84) years, while the median age for HSCT-TKI patients was 47 (14-84) years. The proportion of males was 26.2% (n=90) in TKI group versus 37.5% (n=137) in the HSCT-TKI group, as reported by 5 studies. The median follow-up was 28 (0.6-149) months. Imatinib mesylate (first-generation TKI) was used in 55.6% (n=125) patients and Dasatinib (second-generation TKI) was given to 44.4% (n=100) patients. (Table 1) Overall survival (OS) was reported from 100% and 93.3% at 1 year to 49% and 33% at 5 years for TKI and HSCT-TKI cohorts, respectively. At median follow-up time of 4 (3-5) years, a trend towards poor OS was seen with TKI group as compared to HSCT-TKI group (OR 0.46, 95% CI 0.17-1.23, I 2=70%); however, the association was not statistically significant. Disease-free survival (DFS) was reported from 49.3% and 71.3% at 4 years to 38.1% and 50.5% at 5 years for TKI and HSCT-TKI cohorts, respectively. At a median follow-up time of 4 (3-5) years, the pooled analysis showed poor DFS for TKI as compared to HSCT-TKI cohort (OR 0.30, 95% CI 0.17-0.53, I 2=0%). Four studies (n=292) reported separate outcomes for relapse, it was 59.1% (87/147) for TKI versus 14.5% (n=21/145) for HSCT-TKI patients, and odds of developing relapse were higher among patients receiving TKI as compared to HSCT-TKI (OR=8.08, 95% CI=3.81-17.14, I 2=0%). Conclusion: Hematopoietic stem cell transplant in Philadelphia positive acute lymphoblastic leukemia in first complete remission followed by tyrosine kinase inhibitor maintenance therapy confers disease-free and overall survival benefit compared to tyrosine kinase inhibitors maintenance alone. Our findings confirm HSCT as a standard of care in Ph+ ALL in CR1 followed by TKI maintenance and the need for a prospective randomized clinical trial to validate these findings. Figure 1 Figure 1. Disclosures Lin: AbbVie, Aptevo Therapeutics, Astellas Pharma, Bio-Path Holdings, Celgene, Celyad, Genentech-Roche, Gilead Sciences, Incyte, Jazz Pharmaceuticals, Novartis, Ono Pharmaceutical, Pfizer, Prescient Therapeutics, Seattle Genetics, Tolero, Trovagene: Research Funding. Abhyankar: Incyte/Therakos: Consultancy, Research Funding, Speakers Bureau. McGuirk: Astelllas Pharma: Research Funding; Fresenius Biotech: Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding.

We present a unique case of pediatric B lymphoblastic leukemia with Philadelphia chromosome, CD56 expression, and predominantly L2 morphology. A review of the current literature demonstrates that this distinct combination of features is rare and may portend a worse prognosis, although there are too few cases to determine whether these features are prognostically independent of one another. Keywords: B lymphoblastic leukemia, Pediatric, Philadelphia chromosome, CD56, L2 morphology

Philadelphia positive acute lymphoblastic leukemia is well documented nowadays but very little is known about Philadelphia positive lymphoblastic lymphoma (LBL). Only two cases are available in literature and both of them died during treatment whereas the patient treated in our center is still alive 3 years after the initial diagnosis. A chemo-free regimen was used in induction with dasatinib plus steroids with local radiotherapy on the mass, and then the patient underwent bone marrow transplant. Philadelphia positive lymphoblastic lymphoma is a difficult diagnosis to make and the management of this extremely rare disease is very challenging.

Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) in children had a worse outcome before the use of tyrosine kinase inhibitors. We have evaluated the demographics and outcome of Ph+ ALL patients treated with imatinib without blood marrow transplantation. Of the 206 children with ALL registered for treatment, the demographic data of 15 Ph+ ALL patients were compared with the remaining Ph- patients. Imatinib (340 mg/m) was started on day 5 (D5) of induction in Ph+ patients, and their overall survival was compared with Ph- high-risk patients treated on similar protocols. Statistical analysis was carried out by the Fisher exact test and the t test. The Kaplan-Meier test was used for survival analysis. Philadelphia positivity noted in 15/206 (7.28%) ALL patients was higher than reported earlier. Median initial total leukocyte count and central nervous system positivity were significantly higher in Ph+ patients. Myeloid markers, CD13 and CD33, were also positive in 33.3% Ph+ patients. D15 and D35 marrow showed remissions in a larger proportion of Ph+ ALL, as compared with Ph- patients, but chemotherapy interruptions and neutropenic deaths were significantly higher after starting imatinib, as compared with Philadelphia high-risk patients. Overall survival was similar in Ph+ and Ph- high-risk ALL patients. Ph+ ALL, noted in 7.28%, presented with high initial white blood cell counts, high central nervous system positivity, poor steroid response, and higher induction deaths, as compared with high-risk Ph- ALL, and raised the question about the appropriate dose and time of introduction of imatinib to prevent toxicity.

Molecular detection of the BCR-ABL1 fusion transcripts is necessary for the genetic confirmation of a chronic myeloid leukemia diagnosis and for the risk classification of acute lymphoblastic leukemia. BCR-ABL1 mRNAs are usually identified using a conventional RT-PCR technique according to the BIOMED-1 method. In this study, we evaluated 122 BCR-ABL1-positive samples with the Q-LAMP assay to establish if this technology may represent a valid alternative to the qualitative BIOMED-1 PCR technique usually employed for the detection and the discrimination of the common BCR-ABL1 transcripts (p190 and p210 isoforms). We found a 100% concordance rate between the two methods. Specifically, the p190- and p210-positive samples were amplified by Q-LAMP with a median threshold time (Tt) of 26.70 min (range: 24.45&ndash, 31.80 min) and 20.26 min (range: 15.25-34.57 min), respectively. A median time of 19.63 was observed in samples displaying both (e13a2/e14a2) p210 isoforms. Moreover, the Q-LAMP assay allowed recognition of the BCR-ABL1 e13a2 and e14a2 isoforms (median Tts 18.48 for e13a2 vs. 26.08 min for e14a2, p &lt, 0.001). Finally, 20 samples harboring rare BCR-ABL1 isoforms (e1a3, e13a3, e14a3, and e19a2) were correctly identified by the Q-LAMP assay. We conclude that the Q-LAMP assay may represent a faster and valid alternative to the qualitative BIOMED-1 RT-PCR for the diagnosis at BCR-ABL1-positive leukemias, especially when samples are analyzed in centers with restricted resources and/or limited technical expertise.

BACKGROUND: Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]). PATIENTS AND METHODS: During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours. RESULTS: A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11). CONCLUSION: Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.

7022 Background: Philadelphia-like Acute Lymphoblastic Leukemia (Ph-like ALL) is a high-risk subset of adult ALL. Until recently, there has not been a systematic platform to recognize this entity in clinical practice. Furthermore, data regarding the role of allogeneic hematopoietic cell transplantation (allo-HCT) is lacking. We conducted this study to identify patients with Ph-like ALL and describe their outcomes in comparison to Ph+ and Ph- ALL with emphasis on the role of allo-HCT. Methods: To identify cases of Ph-like ALL, available diagnostic cytogenetic pellets for patients in the Mayo Clinic ALL cohort (N=365) were tested using a targeted fluorescence in situ hybridization (FISH) panel developed by the Mayo Clinic Genomics Laboratory and includes probes to detect Ph-like-specific rearrangements (i.e., ABL1, ABL2, PDGFRB, JAK2 and CRLF2). Results: Thirty-three (9%) patients with Ph-like ALL were identified, the remaining patients were classified as Ph+ (N=132, 36%) or Ph- ALL (N=200, 55%). Patients with Ph-like ALL were younger (Median: 39 vs. 50 vs. 49 years, P=.01), had higher WBC (Median: 27.9 vs. 21.5 vs. 4.5 x109/L, P

Chronic myeloid leukaemia (CML) is a myeloproliferative neoplasm characterized by Philadelphia chromosome with excessive tyrosine activity leading to uncontrolled proliferation of mature and maturing granulocytes, predominantly neutrophils. If left untreated CML goes though chronic phase, accelerated phase and ultimately Blast Crises. Accelerated phase is characterized by features of disease progression without meeting criteria for chronic phase or blast crises. We present a case of young male with CML who presented with acute bilateral proptosis and rapidly rising white cell count. On work up he was found to have progressed to accelerated phase of CML on the basis of rapidly rising WCC and clonal evolution with new cytogenetic finding of 3q deletion in Philadelphia positive cells. He was treated with high dose Cytarabine with complete resolution of proptosis and hematologic remission.

Background. EsPhALL2004 study showed a 10% advantage in DFS for short, discontinuous use of imatinib after induction in Ph ALL patients receiving BFM therapy and HSCT. Other contemporary studies showed an advantage from continuous protracted exposure to imatinib challenging the indications to transplant. Methods. Patients aged 1-17 years were enrolled in EsPhALL2010 trial and received imatinib 300/mg/m2 continuously from day 15 of induction, during chemotherapy. MRD was measured by IG/TR. Eligibility to HSCT depended on early morphological response and MRD. Imatinib was recommended throughout the first year after transplant. Findings. 155 evaluable patients were registered between 2010-2014. 151 (97%) achieved CR1 after induction and 4 after consolidation phase IB. 59 patients (38%) underwent HSCT in CR1. The 5-year EFS and OS were 57·0 (SE 4·1) and 71.8 (SE 3·8), respectively. The 5-year cumulative incidence of relapse was 26·9% (SE 3·7, 8 relapses in 59 transplanted patients and 32 relapses in 96 patients who received chemotherapy). In patients MRD negative at end of IB, there were no relapses in those transplanted (N=17) and 9 relapses in those (N=30) treated with chemotherapy. In patients with positive MRD at end of IB, 5 relapses each occurred in 15 transplanted and 12 not transplanted patients. WBC count at diagnosis ≥100x109/L was associated with a poor prognosis (HR 3·47, 95% CI 1·74-6·89, p=0·0004). Interpretation. Imatinib given since day 15 of induction markedly improved CR rates to 97% from 78% in EsPhALL2004. Though HSCT rates were significantly lower (38% versus 81%), outcomes were similar in the two studies: 5-year EFS and survival were 57·0% and 71·8% versus 60·3% and 71·6%, respectively. WBC ≥100x109/L was the most relevant independent prognostic factor. Funding. Projet Hospitalier de Recherche Clinique-Cancer and Novartis (France); Bloodwise and CRUK (UK). Wellcome-DBT Margdarshi fellowship (VS). MH CZ- DRO, 00064203 (Czech Republic). AIRC 5‰, Ref. 21147 (AB). AIRC2013, ID 14634 (MGV). Conflict of interest statements. No conflicts of interest have been declared by the authors. Ethics approval statement: EsPhALL2010 is a prospective, single arm trial derived from an amendment of the EsPhALL2004 protocol (EudraCT No. 2004-001647-30) which was approved by the ethics committee of each participating institution in ten national study groups (AIEOP, BFM-G/CH, COALL, French ALL-group, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG).

Refinement of IKZF1 status in pediatric Philadelphia-positive acute lymphoblastic leukemia

The treatment outcome and development of new mutations in patients with imatinib- and/or nilotinib-failure Philadelphia chromosome positive (Ph+) leukemia with highly nilotinib-resistant mutations (Y253H, E255K/V and F359V/C) were assessed on dasatinib therapy. A total of 111 patients with Ph+ leukemia were grouped into three cohorts by baseline BCR-ABL kinase domain mutation status: no mutation (n = 44), non-nilotinib-resistant mutations (n = 26) or nilotinib-resistant mutations (n = 41). The frequencies of hematological, cytogenetic and molecular responses and clinical resistance to dasatinib were similar among the three cohorts during dasatinib therapy. In dasatinib-resistant patients, new mutations were most frequently observed in the cohort with nilotinib-resistant mutations (p = 0.001). Multivariate analysis revealed that advanced disease and harboring Y253H or F359V mutation before dasatinib were independent predictors of developing new mutations. We conclude that patients with Ph+ leukemia with Y253H or F359V mutation have a high likelihood of developing new mutations in the setting of dasatinib resistance.

BCR-ABL-mediated leukemias, either Chronic Myeloid Leukemia (CML) or Philadelphia positive Acute Lymphoblastic Leukemia (ALL), are the paradigm of targeted molecular therapy of cancer due to the impressive clinical responses obtained with BCR-ABL specific tyrosine kinase inhibitors (TKIs). However, BCR-ABL TKIs do not allow completely eradicating both CML and ALL. Furthermore, ALL therapy is associated with much worse responses to TKIs than those observed in CML. The identification of additional pathways that mediate BCR-ABL leukemogenesis is indeed mandatory to achieve synthetic lethality together with TKI. Here, we review the role of BCR-ABL/protein kinase CK2 interaction in BCR-ABL leukemias, with potentially relevant implications for therapy.

The clinical outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) has significantly improved following targeted treatment with tyrosine-kinase inhibitors (...

Myelodysplastic syndrome (MDS) is cytogenetically heterogeneous and retains variable risk for acute myeloid leukemia transformation. Though not yet fully understood, there is an association between genetic abnormalities and defects in gene expression. The functional role for infrequent cytogenetic alteration remains unclear. An uncommon chromosomic abnormality is the presence of the Philadelphia (Ph) chromosome. Here, we report a patient with Ph+ MDS treated with low dose Dasatinib who achieved hematologic response for 7 months. In addition, we also examined the English literature on all de novo Ph + MDS cases between 1996 and 2015 to gain insight into clinical features and outcome.

SUMMARY Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) represents approximately 15–30% of ALL in adults and is characterized by the expression of the fusion protein BCR–ABL with oncogenic activity. Remission and survival rates were lower whereas relapse risk was increased in Ph+ compared with Philadelphia-negative ALL, until remarkable improvements in the management of Ph+ ALL were achieved through the introduction of tyrosine kinase inhibitors that reduce the activity of the BCR–ABL protein. However, in patients achieving complete remission, allogeneic hematopoietic stem cell transplantation is in most cases a mandatory therapeutic step because rate of relapses are still high. This review will illustrate the current therapeutic options for the management of Ph+ ALL and indicate how better curative options may stem from appropriate implementation of tyrosine kinase inhibitors and novel antitumoral agents.