Philadelphia Chromosome Positivity Research Articles

Therapy-related acute lymphoblastic leukaemia in women with antecedent breast cancer.

Therapy-related acute lymphoblastic leukaemia (tr-ALL) is a disease entity attributed to previous exposure to chemotherapy and/or radiation for antecedent malignancy. There is observed female predominance for tr-ALL, likely due to high prevalence and excellent curable rate for non-metastatic breast cancer as well as the frequent use of carcinogenic agents as part of adjuvant therapy. Here, we reviewed 37 women with diagnosis of ALL following breast cancer treatment with focus on cytogenetic categorization. Philadelphia chromosome positivity (Ph+), KMT2A alterations and other cytogenetic change groups were observed in 32%, 22% and 46% of patients respectively. Median overall survival (OS) and relapse-free survival (RFS) were 19.4 and 12.9 months, overall while both OS and RFS were superior in tr-ALL with Ph+ disease compared to KMT2Ar and other cytogenetics respectively. Seventeen (45.9%) patients underwent consolidative allogeneic haematopoietic cell transplantation (alloHCT) in CR1 out of which 4 (24%) relapsed following transplant. Both OS and RFS were superior in the KMT2Ar cytogenetics group following alloHCT. Ph chromosome represents the largest genetic entity of tr-ALL following breast cancer therapy, and it may be associated with superior survival outcomes while KMT2Ar may be associated with poorer outcomes that can perhaps be mitigated by alloHSCT.

High Response Rates Following Point-of-Care Anti-CD19 CAR T-Cell Therapy in Adults with Relapsed/Refractory Acute B Lymphoblastic Leukemia

Background Tisagenlecleucel and brexucabtagene autoleucel have demonstrated remarkable efficacy and safety results in adult patients with relapsed/ refractory acute B lymphoblastic leukemia (R/R B-ALL). Long term follow-up of the ZUMA-3 trial recently reported a median duration of response (DOR) of 14.6 months and an overall response rate of 71% (Hadjivassileva, EBMT 2023). Methods and patients We report results of a phase 1b/2 single center clinical trial (NCT02772198) involving point-of-care (POC) anti-CD19/CD28 costimulatory domain chimeric antigen receptor (CAR) T-cell therapy in adults with R/R B-ALL. Inclusion criteria were age ≥18 years, failure of at least 2 prior therapies, and a preserved organ function. Patients underwent a single leukapheresis procedure. Fresh CAR T products were delivered for immediate infusion. Lymphodepletion included fludarabine and cyclophosphamide. Cell dose was 1x10 6 CAR T cells/kg. Primary endpoints were 1-month disease response and safety. Secondary endpoints were the minimal residual disease (MRD) negativity rate, overall survival, progression-free survival (PFS), and production feasibility. Last follow-up was July 2023. Results Between 03/2017-05/2023, 28 patients enrolled. CAR T-cells were successfully produced in 27 patients (96%) who were included in the analysis. The median age was 33 years (range 19-77), and 7 (25%) patients had Karnofsky Performance Status <90%. Six patients (22%) had positive Philadelphia chromosome, and 14 patients (52%) had an extramedullary disease at leukapheresis. Nineteen patients (70%) had ≥3 prior lines of therapy, 18 patients (67%) underwent prior allogeneic hematopoietic stem-cell transplantation (allo-HCT), and 20 patients (74%) had prior exposure to inotuzumab-ozogamicin or blinatumomab. At leukapheresis, 16 patients (60%) had an active disease, while 11 patients (40%) were in complete morphological response (CR; MRD positive, n=7 [26%], MRD negative or not evaluated, n=4 [15%]). The median time between leukapheresis and cell infusion was 11 days (IQR 10-11). Only 3 patients (11%) received bridging chemotherapy. Grade 3-4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndromes were observed in 30% of the patients, each. Six (22%) and 16 (59%) patients were treated with tocilizumab or corticosteroids, respectively. Severe neutropenia (<0.5k/μl) and thrombocytopenia (≤50 K/μl) occurred in 81% and 70% of the patients, respectively, and anemia requiring blood transfusion occurred in 71%. Three patients (11%) had grade 3 cardiovascular events, and 1 patient (4%) had grade 3 pleural effusion. Bloodstream bacterial infection occurred in 3 (11%) patients. Cellular therapy-related mortality was observed in 2 (7%) patients (both due to septic shock). The 1-month overall response rate was 88% (81% CR; MRD negative CR, 63%). MRD was evaluated by RT-PCR in most of the patients. The median follow-up was 19.7 months (IQR 4.7-43.2). Two-year overall survival and PFS were 62% (95% CI: 42-91), and 56% (95% CI: 38-84), respectively. The median DOR was not reached (95% CI: 6.1 months-not reached). PFS was not affected by prior exposure to inotuzumab-ozogamicin or blinatumomab (hazard ratio (HR) 0.7, 95% CI: 0.17-2.68, p=0.6). All eligible patients who achieved a response were offered consolidation with allo-HCT. Eight patients (30%) underwent allo-HCT (2 nd allo-HCT in 3 of them). The DOR was not affected by consolidation of CR with allo-HCT (HR 0.9, 95% CI: 0.2-4.1, p>0.9). Nevertheless, 2 patients (7%) died due to allo-HCT related complications while in CR. Conclusion Treatment with POC CAR T-cells, produced in an academic center, achieved high response and survival rates in adults with R/R B-ALL. These results are also comparable to the FDA approved CAR T-cells. The use of POC CAR T abrogates the need for cryopreservation and shipment of the cells, thus allowing a short vein-to-vein time without the need of bridging therapy in most patients.

A Retrospective Analysis of Autologous Stem Cell Transplantation Outcomes in Adult Philadelphia Chromosome Positive-Acute Lymphoblastic Leukemia

Abstract Introduction Philadelphia chromosome positivity (Ph + ) is a poor prognostic feature in adult acute lymphoblastic leukemia (ALL). Allogenic hematopoietic stem cell transplantation in first complete remission (CR1) is recommended. There is limited literature on the role of consolidation autologous stem cell transplantation (ASCT). This study was undertaken to assess the potential of consolidation ASCT in CR1 in adults with Ph + ALL. Objectives The aim of this study was to analyze the safety and efficacy of ASCT in CR1 in adults with Ph + ALL. Materials and Methods Adult patients diagnosed with Ph + ALL who underwent ASCT in CR1 after modified ALL-BFM95 protocol from 2015 to 2017 were included. Patients who achieved major molecular response or better were considered for ASCT with cyclophosphamide-total body irradiation regimen and peripheral blood stem cells infused on day 0. Toxicities as per Common Terminology Criteria for Adverse Event v4.0, disease-free survival (DFS), and overall survival (OS) were assessed. Inclusion criteria: Following patients were included—patients aged 18 years and above diagnosed with Ph + ALL; patients receiving BFM-95 induction chemotherapy protocol; patients who achieved CR after induction therapy; nonavailability of human leukocyte antigen match from a matched sibling donor or matched unrelated donor. Exclusion criteria: Patients not willing or unfit for ASCT and patients planned for allogenic hematopoietic stem cell transplantation were excluded. Results Six adult patients with Ph + ALL underwent ASCT in CR1 (median age: 23 [range: 19–36] years, five patients were males [83%]). Imatinib was started at a median of 11 days from the start of induction IA (range: 10–21). Five patients achieved morphological CR after induction 1A and, one patient at the end of induction 1B. The median time to ASCT (from diagnosis) was 8 months (range: 6.4–13). All the six patients had disease relapse and died due to progressive ALL. The median DFS and OS were 19.2 months and 23.3 months, respectively. Conclusion Consolidation ASCT yielded poor outcomes in this study. There was a significant delay from diagnosis to ASCT, which might have impacted the results.

Effect of hypoxia on HIF-1α and NOS3 expressions in CD34+ cells of JAK2V617F-positive myeloproliferative neoplasms

PurposeMyeloproliferative neoplasms (MPN) are a heterogeneous group of hematopoietic stem-cell diseases with excessive proliferation of one or more blood cell lines. In this study, we evaluated the effect of different oxygen concentrations on HIF-1α and NOS3 gene expression to determine the effect of the bone marrow microenvironment on JAK2V617F positive Philadelphia chromosome negative (Ph−) MPNs. Patients and methodsPeripheral blood mononuclear cells (MNC) of 12 patients with Ph− MPN were collected. The presence of JAK2V617F allele status was determined with allele-specific nested PCR analysis. MPN CD34+ and CD34depleted populations were isolated from MNC by magnetic beads. Separate cell cultures of CD34+/depleted populations were managed at different oxygen concentrations including anoxia (∼0%), hypoxia (∼3%), and normoxia (∼20%) conditions for 24 ​h. HIF-1α and NOS3 gene expression changes were examined in each population related to JAK2V617F status with real time RT-PCR. ResultIt was revealed that relative HIF-1α and NOS3 expressions were significantly increased in response to decreased oxygen concentration in all samples. Relative HIF-1α and NOS3 expressions were found to be higher especially in CD34+ and CD34depleted populations carrying JAK2V617F mutations compared to MPN patients carrying wild-type JAK2. ConclusionJAK2V617F might have specific role in HIF-1α and NOS3 regulations with respect to low oxygen concentrations in Ph− MPN. Further evaluations might reveal the effect of JAK2V617F on Ph− MPN pathogenesis in bone marrow microenvironment.

Study of Expression of Autophagy Related Gene 5 (ATG5) in Egyptian Patients Newly Diagnosed with Acute Lymphoblastic Leukemia (ALL)

Abstract: BACKGROUND Autophagy is the cellular mechanism for homeostasis maintenance and survival under stressful conditions like hypoxia and nutrient deprivation. It has been extensively studied in various types of malignancies. However, the relationship between cancer and autophagy is still controversial. Researchers have been focusing on the exploitation of autophagy in the invention of new cancer therapeutics. Acute lymphoblastic leukemia is one type of malignancies with the highest resistant rates and worst prognosis. Knowing whether autophagy has a role in its initiation or progression would be of a great benefit. It would open the door to adding autophagy modulator drugs to conventional treatments in clinical trials to improve disease outcome. AIM To assess the basal level of autophagy in newly diagnosed ALL cases using ATG5 expression level, a key autophagy gene, and detect the relationship between the level of autophagy and prognosis. PATIENTS AND METHODS 35 newly diagnosed ALL patients and 15 healthy controls were included in the study. ATG5 RNA transcript level was measured by real time RT-PCR in all subjects using peripheral blood samples. Patients were followed up monthly for a year by Bone marrow aspiration and minimal residual disease using multiparameter color flowcytometry to detect resistance and early relapse. RESULTS ATG5 expression level was significantly higher in the ALL patients compared to the control group. Cases had approximately twice the mean expression value of the control (2.15±2.2 vs 1.09 ± 0.47). (P value = 0.01). The median value of the ATG 5 expression of the cases was used as a cut point to divide them into two groups of low and high expression. More B-ALL patients were in the high ATG5 group (83% vs 53%, P value=0.05). In addition, the high ATG5 group displayed a significantly lower haemoglobin level, platelet count, LDH level and CD 8 expression than the low ATG5 group (Mean Hb level of 7.7 g/dl vs 9.6 g/dl respectively, P value=0.04, Mean Platelet count of almost 55 x 109/L vs 105 x 109/L respectively, P value = 0.01, Mean LDH level of 455 vs 1260 U/L respectively, P value=0.02, CD8 + patients 0% vs 23% respectively, P value=0.05). Although ATG5 level was also more associated with a higher white blood cell count, the presence of extramedullary disease, a positive Philadelphia chromosome and post induction refractoriness, no statistical significance was found. ATG5 expression neither showed a significant relation with patients overall survival nor their disease free survival. CONCLUSION Basal autophagy level is high in ALL disease and associated with more aggressive disease characteristics. More researches are needed to detect its clear relationship with disease prognosis.

Immunophenotypic and Cytogenetic Characteristics of B Cell Acute Lymphoblastic Leukaemia (ALL). the Tawam Hospital (tertiary referral centre UAE) Experience

Acute Lymphoblastic Leukaemia (ALL) is an aggressive malignant lympho-proliferative neoplasm. Although excellent results are seen in paediatric population the same does not hold true in the adult population. In this retrospective study we looked at the patient characteristics of B cell ALL at Tawam hospital which is a tertiary care referral hospital for cancer therapy in the United Arab EmiratesMethods: Tawam hospital tumour registry was used to identify patients diagnosed with ALL aged 15 years and above between January 2010 till June 2017. Medical records were reviewed to collect data about age, sex, presenting hemogram, immuno-phenotyping, karyotype and outcome.Results: Seventy patients were identified with diagnosis of ALL in the defined period. Sixteen (23 %) patients had diagnosis of T cell ALL. Fifty four (77%) patients had B cell ALL. The median age was 26 years (range 15-71 years). Male to female ratio was 2.85:1. T cell ALL patients were excluded from further analysis.Immuno-phenotypically 29 patients (54 %) were CD 20 positive ALL (> 20 % CD 20 expression) while the other 25 (46%) were CD 20 negative ALL. The median white blood count (WBC) at presentation was 7000 (range 1 to 495 thousand) per millilitre for CD 20 positive ALL while the median WBC was 12000 (range 1-240 thousand) per millilitre for CD 20 negative cohort.Cytogenetic and/or molecular diagnostics showed the presence of Philadelphia chromosome or BCR-ABL positivity in nine patients with CD 20 positive ALL (31 %) while only 4 patients (13%) with CD 20 negative ALL were positive for BCR-ABL. (Table 1)Five patients refused therapy and were lost to follow up after diagnosis. Five patients died of therapy related complications in complete remission (CR) while one patient developed secondary malignancy (Acute myeloid leukaemia and expired). Fifteen patients are in CR1 and in continuous follow up while another twelve patients have been lost to follow up while in CR1. Sixteen patients had either primary refractory or relapsed disease. Ten (62 %) of those had CD 20 positivity while the rest six (38%) were CD 20 negative.Conclusion: In our experience more than half (54 %) of B cell ALL had a CD 20 positive immuno phenotype. Patients with CD 20 positive ALL had a lower median WBC at presentation as compared to the CD 20 negative cohort. Of greater interest is the higher rate of Philadelphia chromosome positivity in CD 20 positive observed in CD 20 positive cohort as compared to CD 20 negative cohort (31% versus 13 %). Patients with CD 20 appear to have a higher rate of relapsed refractory disease (62% versus 38%).CD 20 expression in ALL has been reported as ranging from 30 to 60 %. Similarly there has been controversy of CD 20 positive disease being associated with poor patient outcome. The majority of the previous reports either exclude Philadelphia chromosome positive disease or report no significant difference.Even though CD 20 antibodies have been used previously with variable results, the large disparity in the treatment protocols for ALL for adults makes it difficult to choose a standard approach. Similarly the role of humanized CD 20 anti-bodies like Obinutuzumab and ofatumumab remains undefined.Although our cohort has a big disparity in Philadelphia chromosome positivity between the two sub groups the small sample size makes it difficult to make a definite conclusion and these results should be validated in a larger cohort. [Display omitted] DisclosuresAlam:BMS: Honoraria; Biologix: Honoraria.

Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

BackgroundNon-T-cell depleted haploidentical hematopoietic stem cell transplantation (HaploSCT) is being increasingly used in acute lymphoblastic leukemia (ALL) with improving patient outcomes. We have recently reported that outcomes of adult patients (pts) with ALL in complete remission (CR) receiving HaploSCT are comparable to unrelated donor transplants. We now compared HaploSCT and matched sibling donor (MSD) transplants in pts with ALL.AimTo assess transplantation outcomes of HaploSCT and MSD transplants in pts with ALL in CR.MethodsWe retrospectively analyzed adult patients (≥ 18 years) with ALL who underwent their first allogeneic stem cell transplantation (alloSCT) in first or second CR between 2012 and 2018, either from a T cell replete Haplo or MSD donor, and whose data were reported to the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Multivariate analysis (MVA) adjusting for differences between the groups was performed using the Cox proportional hazards regression model. Propensity score matching was also performed to reduce confounding effects.ResultsThe analysis comprised 2304 patients: HaploSCT-413; MSD-1891. Median follow-up was 25 months. Median age was 37 (range 18–75) and 38 (18–76) years in HaploSCT and MSD, respectively. HaploSCT patients were transplanted more recently than those transplanted from MSD (2016 vs 2015, p < 0.0001). A higher rate of HaploSCT was in CR2 (33.4% vs 16.7%, p < 0.0001), respectively, and fewer received myeloablative conditioning (68% vs 83.2%, p < 0.0001). Cytomegalovirus (CMV) seropositivity was lower in HaploSCT patients (22% vs 28%, p = 0.01) and donors (27.1% vs 33%, p < 0.02), and a higher proportion of the HaploSCTs were performed using a bone marrow (BM) graft (46.2% vs 18.6%, p < 0.0001). The 2 groups did not differ with regard to gender, Karnofsky performance status score, ALL phenotype, Philadelphia chromosome (Ph) positivity and pre-alloSCT measurable residual disease (MRD). Graft versus host disease (GVHD) prophylaxis was mainly post-transplant cyclophosphamide (PTCy) based (92.7%) in the HaploSCT setting, while it was mostly pharmacologic in the setting of MSD (18.7% received ATG). Cumulative incidence of engraftment at day 60 was higher in MSD transplants compared to HaploSCT (98.7% vs 96.3%, p = 0.001), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was higher in HaploSCT vs. MSD: 36.3% vs 28.9% (p = 0.002 and 15.2% vs 10.5% (p = 0.005), respectively. Conversely, the 2-year chronic (c) GVHD and extensive cGVHD were 32% vs 38.8% (p = 0.009) and 11.9% vs 19.5% (p = 0.001) in HaploSCT vs MSD, respectively. Main causes of death were leukemia (31.8% vs 45%), infection (33.1% vs 19.7%) and GVHD (16.6% vs 19.7%) for HaploSCT and MSD, respectively. Two-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 26% vs 31.6%, 22.9% vs 13%, 51% vs 55.4%, 58.8% vs 67.4% and 40.6% vs 39% for HaploSCT and MSD, respectively. In the MVA, RI was significantly lower in HaploSCT in comparison with MSD, hazard ratio (HR) = 0.66 (95% CI 0.52–0.83, p = 0.004), while NRM was significantly higher, HR = 1.9 (95% CI 1.43–2.53, p < 0.0001). aGVHD grade II-IV and grade III-IV were higher in HaploSCT than in MSD HR = 1.53 (95% CI 1.23–1.9, p = 0.0002) and HR = 1.54 (95% CI 1.1–2.15, p = 0.011), respectively. Extensive cGVHD was lower in HaploSCT compared with MSD, HR = 0.61 (95% CI 0.43–0.88, p = 0.007), while total cGVHD did not differ significantly, HR = 0.94 (95% CI 0.74–1.18, p = 0.58). LFS, OS and GRFS did not differ significantly between the 2 transplant groups, HR = 0.96 (95% CI 0.81–1.14, p = 0.66); HR = 1.18 (95% CI 0.96–1.43, p = 0.11) and HR = 0.93 (95% CI 0.79–1.09, p = 0.37), respectively. These results were confirmed in a matched-pair analysis.ConclusionsOutcomes of adult patients with ALL in CR receiving alloSCT from haploidentical donors are not significantly different from those receiving transplants from MSD in terms of LFS, OS and GRFS.

Superior Outcomes in Relapsed/Refractory Childhood B-ALL Than Adult Patients with CD19 CAR-T Cell Therapy: A Single-Center Pilot Prospective Study of 23 Patients

Objective: CD19 CAR-T cell therapy has emerged as a powerful immunotherapy for relapsed/refractory (R/R) B-ALL. The purpose of this study is to compare the efficacy and safety profile of CD19 CAR-T cell therapy for pediatric and adult patients with R/R B-ALL. Methods: We analyzed 23 pediatric and adult R/R B-ALL patients recruited from April 2016 to November 2018 to the clinical trial with CD19 CAR-T cell therapy (ClinicalTrials.gov, NCT03391739). Patients' high-risk features included ≥3 prior lines of treatment (n=11 ), extramedullary infiltration (n=6) , prior allogeneic hematopoietic stem cell transplantation (allo-HSCT, n = 4), Philadelphia chromosome positivity (n = 8) and other poor prognostic factors (n=8). At the time of CAR-T cell therapy, 20 patients had morphologic disease (≥5% blasts in bone marrow [BM] or measurable extramedullary disease), and 3 patients had minimal residual disease (MRD) (&amp;lt;5% blasts in BM) even after the salvage chemotherapy. All patients received fludarabine (25 mg/m2×3d) and cyclophosphamide (900mg/m2/day×2d) as a preconditioning regimen followed by a single infusion of 0.9-4 × 108/kg autologous CD19 CAR-T cells. The primary efficacy end point was the MRD rate post infusion. Secondary end points included persistence of transferred T cells and anti-CD19 activity response. Treatment-related toxicities, particularly cytokine release syndrome (CRS) and neurological toxicities, were observed during the study. Results: Among the 23 patients with R/R B-ALL, 13 were male and 10 female, with the median age of 18 years (1-61 years). 9 cases were pediatric (age≤14 years) and 14 adult (age&amp;gt;14 years). The median duration of therapy prior to CAR-T cell therapy was 19 (2-76) months and 17 (1-36) months, respectively. The CAR-T cell products were similar in phenotype and function between the pediatric and adult groups. The overall remission rate(ORR)was 15/23 (65.22%). Pediatric patients have a better ORR than adults (88% vs 50%, p&amp;lt;0.05). In the pediatric group, 6 (66.67%) patients achieved MRD-negative remission, 2 (22.22%) hematological remission and 1 (11.11%) unevaluable, while in the adult group, only 7 (50%) patients reached MRD-negative remission. 5 (20.83%) patients, including 2 pediatrics and 3 adults, with high leukemic burden (blast in BM &amp;gt;60% ) developed reversible severe CRS (grade 2-4) and/or reversible severe neurotoxicity with the IL-6 receptor blockade w/o lymphotoxic corticosteroids , and there were no deaths or instances of cerebral edema attributable to product toxicity. Persistence of transferred T cells (CD62L+ CD45RO+) were still detectable in 1 pediatric patient at the 3-months follow up post CAR-T infusion, who were the most severe case of CRS/neurotoxicity with the highest blast (98% in bone marrow) and reached MRD-negative remission rapidly. Conclusion: These data demonstrate the superior outcomes in pediatric group compared to that of adult patients, with highly potent antileukemic activity and a tolerable adverse effect profile. Therapeutic failure in most adult patients remains a challenge so far. Severity of CRS may correlate with high disease burden and the treatment response. Disclosures No relevant conflicts of interest to declare.

Turkish Acute Lymphoblastic Leukemia Registry, Retrospective Phase Data

Background and Aim: Significant developments have occurred in clinical management of acute lymphoblastic leukemia (ALL) in adults over recent decades. However, treatment results are still not satisfactory especially in routine practice. The aim of the study was to evaluate the general clinical features, treatment details and outcomes of a large group of patients followed up in multiple centers in Turkey with a diagnosis of ALL. Materials and Methods: A retrospective analysis of the data of patients with ALL was made, which are diagnosed and treated between January 2003 and June 2017 by different protocols in hematology clinics of ten different centers. A total of 288 patients, aged between 17 and 76 years old were included in the study. In this retrospective, multicenter analysis of patients with ALL, classification of patients was done by treatment period, Philadelphia chromosome positivity, treatment regimen and receiving allogeneic hematopoietic stem cell transplantation (alloHSCT). Results: The majority of cases were B-cell in origin, 224 patients were B-ALL and 64 of the patients were T-ALL (Table 1). Median follow-up duration for all patients was 18.2 months (range, 0.03-161.0 months). After induction chemotherapy, 219 patients (76.0%) achieved complete remission, 32 patients were evaluated as treatment refractory (11.2%), and 37 patients (12.8%) deceased. Median OS was 47.7 months (95% CI: 36.1-59.2) and median DFS was 23.4 months (95% CI: 6.7-40.0) for all patients. The 3-year OS and DFS rates were 56% and 45%, respectively. The 5-year OS and DFS rates were 43% and 35%, respectively. Median OS was 33.9 months (95% CI: 17.4-50.3) in Ph+ ALL patients and 73.7 months (95% CI: 33.9-113.5) in Ph chromosome-negative (Ph-) ALL patients (p=0.48). Median DFS was 7.1 months (95% CI: 5.0-9.3) in Ph+ ALL patients and 34.6 months (95% CI: 16.0-53.2) in Ph-ALL patients. DFS was statistically significant longer in Ph- patients than Ph+ patients, (p=0.008). The 5-year OS was 50% in Ph- patients and 16% in Ph+ patients, respectively. The 5-year DFS was 35% in Ph- patients and 11% in Ph+ patients, respectively (Figure 1). Median OS was 53.4 months (95% CI: 37.9-63.5) in patients receiving the pediatric regimen and 42.9 months (95% CI: 19.9-66.6) in patients receiving other intensive regimens (p=0.05). Median DFS was 16.9 months (95% CI: 3.9-23.6) in patients receiving the pediatric regimen and 13.3 months (95% CI: 6.5-20) in patients receiving other intensive regimens (p=0.78). The 5-year OS was 45% in patients who received the pediatric regimen and 43% in patients who received other intensive regimens. The 5-year DFS was 23% in patients who received the pediatric regimen and 25% in patients who received other intensive regimens (Figure 2). The 2-year periods between 2003 and 2017 for treatment regimens are shown in (Figure 3). From 2003 to 2017, the usage of pediatric regimens increased in ALL patients. The count of patients diagnosed with ALL and the treatment protocols used were observed to vary over time. While adult intensive regimens were used more common in the past, there is a tendency to use pediatric regimens in present time. Conclusion: In conclusion, multicenter studies are of great importance for defining the specific clinical features of a particular disease. The results of this study will make a significant contribution to the literature as they reflect real life data providing valuable information about the Turkish ALL patient profile. Disclosures No relevant conflicts of interest to declare.

PCN24 TYROSINE KINASE INHIBITORS: REAL WORLD EVIDENCE ABOUT HEALTH OUTCOMES IN A MIDDLE INCOME COUNTRY

The high cost of antineoplastic therapies generates unprecedented pressure on the health systems in middle income countries; aditionally, the Knowledge Discovery in Databases allows to extract considerable value to evaluated health outcomes. This study assessed the association between adherence and a specific payment model called PGP (Global Prospective Payment, between insurer and provider). Observational retrospective study. Patients with Chronic Myeloid Leukemia (CML) were identified with ICD-10-C921 diagnoses obtained from 2018 High Cost Account database of the institutional cancer cohort. Positive Philadelphia chromosome patients who took Dasatinib or Nilotinib during 2018 were included (n=66). Imatinib was excluded because this drug is included in the health benefit plan in Colombia. Patients who took 100% of the prescribed medication were considered adherent (Morinsky Scale 4/4). Results were analyzed using SPSS version 24, chi-square independence test was used to determine P-value and bivariate analysis was made using binary logistic regression. Dasatinib arm (n=29, median age 65y; 52% female; 62% private regimen), 50% adherent to therapy. Nilotinib arm (n=37, median age 50y; 43% female; 63% private regimen), 59% adherent to therapy. Regardless payment model and TKI, 55% were adherent and 49% had an optimal molecular response. Patients under the PGP model were 100% adherent and, based on the latest available PCR BCR/ABL (real time) report, 89% had an optimal molecular response according to European Leukemia Net recommendations (both TKIs). Significant association were established between Adherence and PGP model (p<0.004; OR=0,49 IC 95% 0,37-0,64) and between optimal molecular response to both TKIs and GPP model (p<0.001; OR=0,43 IC 95% 0,24-0,95). This study provides contemporary real-world evidence about association between adherence to TKIs, optimal molecular response and a prospective payment model in an institution that provides oncological health services. Ensuring adherence to high-cost therapies in middle-income countries through a payment model, could improve health outcomes.

Acute lymphoblastic leukemia in routine practice: A Turkish multicenter study

Objective:Significant developments occurred in the clinical management of acute lymphoblastic leukemia (ALL) in adults in recent decades. However, treatment results are still not satisfactory, especially in routine practice. The objective of this study was to evaluate the general clinical features, treatment details, and outcomes of a large group of patients followed in multiple centers in Turkey with a diagnosis of ALL.Materials and Methods:A retrospective analysis of the data of patients with ALL was made, the patients having been diagnosed and treated between January 2003 and June 2017 by different protocols in the hematology clinics of ten different centers. A total of 288 patients, aged between 17 and 76 years old, were included in the study. In this retrospective multicenter analysis of patients with ALL, classification of patients was performed based on treatment period, Philadelphia chromosome positivity, treatment regimen, and administration of allogeneic hematopoietic stem cell transplantation (allo-HSCT).Results:The majority of cases were B-cell in origin, while 224 patients had B-ALL and 64 of the patients had T-ALL. Median follow-up duration for all patients was 18.2 months (range: 0.03-161 months). Philadelphia chromosome positivity was determined in 49 patients (21.9%), and 54 patients (18.8%) were receiving allo-HSCT. After induction chemotherapy, 219 patients (76.0%) achieved complete remission, 32 patients (11.2%) were evaluated as treatment refractory, and 37 patients (12.8%) were deceased. Median overall survival was 47.7 months (95% confidence interval: 36.1-59.2) and median disease-free survival was 23.4 months (95% confidence interval: 6.7-40.0) for all patients.Conclusion:Multicenter studies are extremely important for defining the specific clinical features of a particular disease. The results of this study will make a significant contribution to the literature as they reflect real-life data providing valuable information about the Turkish ALL patient profile.

Diagnostic challenges of de novo acute leukemia with positive BCR-ABL1 fusion: Case report and review of literature

A 32-year-old female was admitted because of an acute course of gum bleeding and fatigability. On complete blood cell counts, bicytopenia was evident. Morphologic evaluation of the peripheral blood smear and bone marrow materials revealed remarkable involvement by two separate blastic populations (myeloid/B-cell lymphoid). Karyotyping, fluorescence in situ hybridization, and molecular analysis showed positive Philadelphia chromosome and BCR-ABL1 (p210) fusion. chronic myeloid leukemia in blast phase (CML-BP) versus mixed phenotype acute leukemia was critically debated as to which the final diagnosis should be assigned.

Impact of an Additional Chromosome on the Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome–Positive Acute Myeloid Leukemia in Adults

The incidence of Philadelphia chromosome positivity (Ph+) in adults with acute myeloid leukemia (AML) is very low. Ph+ AML is considered to be high risk for failure to attain remission or for early relapse after standard chemotherapy. Because of the low incidence of the disease, it has been difficult to determine the best treatment, including the effects of tyrosine kinase inhibitors. We retrospectively analyzed 29 patients with Ph+ AML (median age, 45 years; range, 18 to 80) managed at our center between 2002 and 2016. Two patients were not treated at all, 3 received repeated low-dose cytarabine, and 24 were treated with 3 + 7 standard induction chemotherapy. All 27 treated patients also received interim imatinib 400 mg orally until the day of the next chemotherapy cycle began or as conditioning for allogeneic hematopoietic cell transplantation (HCT), which was performed in 17 patients. Of the 29 patients with Ph+ AML, 7 (24.1%) had additional inv(16), 3 of whom had therapy-related AML. In the 7 with inv(16), the median age was younger (31 versus 44 years, P = .083) and the complete remission (CR) rate was relatively higher (85.7% versus 54.5%, P = .214) than in those without inv(16). Among the 27 treated patients, 20 (74.1%) achieved CR after standard chemotherapy with interim imatinib and 2 (7.4%) achieved CR after low-dose cytarabine with interim imatinib. After a median follow-up of 65.5 months (range, 13.4 to 156.6), the 5-year overall survival (OS) among all 27 treated patients was 43.1%. For the 17 patients who underwent HCT the 5-year OS of 17 patients (10 in subgroup without inv(16) and 7 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%. All 7 with inv(16) were still alive at the end of the study. In contrast, all patients not treated with HCT died within a median of 6.25 months (range, .2 to 18.2). Interim imatinib combined with chemotherapy yielded an acceptable remission rate in adult patients with Ph+ AML. Allogeneic HCT as a postremission therapy provided long-term disease control in two-thirds of those who underwent the transplant. We also demonstrated that inv(16) was related to a favorable outcome in Ph+ AML, including therapy-related AML.

Acute Myeloid Leukemia with Both Meakaryoblastic &amp; Basophilic Differentation

Acute myeloid leukemia with Megakaryoblastic and Basophilic differentiation and CML with concurrent Megakaryoblastic and Basophilic Blast crisis are very rare diseases with only few reported cases in the literature Diagnosis of this leukemia with two types of blasts of the same lineage can be very challenging and morphology alone is not sufficient especially when the morphology is not classical Flowcytometry and cytogenetic studies are important to establish the diagnosis Here we report a case of AML with Megakaryoblastic basophilic differentiation Positive Philadelphia chromosome by FISH

Age but not Philadelphia positivity impairs outcome in older/elderly patients with acute lymphoblastic leukemia in Sweden.

Older/elderly patients with acute lymphoblastic leukemia (ALL) are poorly represented in clinical trials. Using Swedish national leukemia registries, we investigated disease/patient characteristics, treatment choices, outcome, and the impact of an age-adapted protocol (introduced in 2009) in this population-based study of patients aged 55-85years, diagnosed with ALL 2005-2012. Of 174 patients, 82% had B-phenotype, 11% Burkitt leukemia (excluded), and 7% T-phenotype. Philadelphia chromosome positivity (Ph+) occurred in 35%. Of the 155 B- and T-ALL patients, 80% were treated with intensive protocols, and 20% with a palliative approach. Higher age and WHO performance status ≥2 influenced the choice of palliation. Intensive, palliative, and both approaches resulted in complete remission rate 83/16/70% and 3-year overall survival (OS) 32/3/26%. The age-adapted protocol did not improve outcome. With intensive treatment, platelet count ≤35×109 /L and age ≥75years were adverse prognostic factors for OS, Ph+ was not. Male sex was an adverse prognostic factor in the 55-64 year age-group. We report a high frequency of Ph+ in older/elderly patients, with no evidence of poorer outcome compared to Ph-negative disease. Overall prognosis for elderly patients with ALL remains dismal, despite the use of age-adapted treatment.

Chronic myelogenous leukemia initially presenting with multiple subcutaneous tumors due to extramedullary hematopoiesis

A 53-year-old woman was admitted with right upper-extremity pain and multiple subcutaneous masses. Bone marrow aspirate showed hypercellular marrow with increased myeloid components at all stages of maturation. Cytogenetic analysis of the bone marrow revealed 100% Philadelphia chromosome positivity along with BCR/ABL gene rearrangement, as demonstrated by polymerase chain reaction (PCR). A diagnosis of chronic phase of chronic myeloid leukemia (CML) was therefore made. Biopsy of one of the subcutaneous masses showed proliferation of granulocytes in various stages of differentiation. There were also erythroid cells and megakaryocytes, without p53 and CD34-positive blasts. These results suggested that the subcutaneous masses had developed from extramedullary hematopoiesis, not blastomas. The patient was administered dasatinib (DA) 140 mg, combined with radiation therapy for pain and peripheral neuropathy from the right axial extramedullary tumor. The patient showed complete hematological remission and the subcutaneous masses had disappeared 1 month after starting administration of DA. Because the patient did not achieve a cytogenetic response, the tyrosine kinase inhibitor nilotinib was administered. She will undergo allogeneic stem cell transplantation in the near future. Extramedullary hematopoiesis in the early stages of CML is uncommon. Our case emphasizes the need to elucidate the pathogenesis of extramedullary hematopoiesis in the early stages of CML.

Safety and Efficacy of Nilotinib (NIL) in Patients (Pts) with Chronic Phase (CP) or Accelerated Phase (AP) Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib Mesylate (IM): Results from the Multicenter, Observational NOVEL Study in Taiwan

▪Background: The selective tyrosine kinase inhibitor (TKI) NIL is approved for the treatment of IM resistant CML-CP or CML-AP pts globally, including Taiwan. A non-interventional, multi-center observational study of N ilotinib in pts with CP or AP Philadelphia chrOmosome positiVe (Ph+) chronic myElogenous Leukemia (NOVEL) was conducted to assess the safety and efficacy of NIL in Taiwanese patients with IM intolerance or resistance.Methods: NOVEL was an open-label, single arm, study conducted across 12 centers in Taiwan for a period of up to 2 years (y). Adult CML-CP or CML-AP pts with confirmed Ph+ chromosome (or BCR-ABL) and resistant or intolerant to ≥1 prior CML therapy were enrolled. Also, IM resistant or intolerant pts with prior second-generation TKI therapy could be included. The primary objective was to collect long-term safety data in pts treated with NIL 400 mg twice daily. Efficacy data were collected as secondary objectives.Results: A total of 85 pts including CML-CP (n = 76) pts and CML-AP (n = 9) were enrolled. Median age was 47 y (range, 21-85); 56.5% were males. At baseline, median duration of CML diagnosis was 20.3 (range: 1.4-287.7) months (mo). In 7 pts, confirmed BCR-ABL mutations (E450G, E543A, F317L, F486S, G250E, M244V, M351T) were found, 26 (30.6%) did not have mutations, and 52 (61.2%) did not perform BCR-ABL mutation analysis. All pts (100%) had been treated with prior IM, while 19 pts (22.4%) pts had also received dasatinib; 61 (71.8%) pts had complete hematologic response (CHR) prior to NIL initiation.Of the 85 pts, 54 (63.5%) completed the study while 31 (36.5%) discontinued due to unsatisfactory therapeutic effect (n = 14), consent withdrawal (n = 5), adverse events (n = 4), deaths (n = 3), pregnancy (n = 1), administrative problems (n = 1), unknown (n = 1), and other reasons (n = 2).A total of 1166 AEs were reported by 80 (94.1%) pts, of which 70 (6%) AEs in 28 (32.9%) pts were serious. Of the total AEs, 336 (28.8%) drug-related AEs were reported in 60 (70.6%) pts with the majority (87.5%) being Grade 1 or 2. Of the total drug-related AEs, 85 (25.3%) were hematological and 251 (74.7%) were non-hematological. Common hematological AEs (≥5 % of pts) were thrombocytopenia (n=18; 21.18%) and anemia (n=12; 14.1%). Frequent non-hematological AEs (≥5 % of pts) were increased alanine amino-transferase ([ALT], n = 18; 21.2%), pruritus (n = 15; 17.7%), increased bilirubin (n=12; 14.1%), rash (n = 10; 11.8%), increased aspartate transaminase ([AST], n = 7; 8.2%, and increased lipase (n = 5; 5.9%). Seven deaths were reported during the study and follow-up period, respectively due to cardiopulmonary failure (suspected to be related to study-drug), acute myelogenous leukemia, accident, exacerbation of chronic obstructive pulmonary disease, subarachnoid hemorrhage, pneumonia, and sepsis. Of the 19 pts, who switched to NIL due to known AEs with IM, AEs resolved in 16 (84.2%) pts (Table).Cumulative CHR, major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), MR4.0 (BCR-ABLIS <0.01%) and MR4.5 (BCR-ABLIS <0.0032%) rates are presented in figure. Almost 50% of pts achieved MMR by 18 mo. In pts with confirmed BCR-ABL mutations, the median time to CHR and MMR were 11.9 mo and 37.0 mo compared to 2.3 mo and 16.9 mo in other pts, respectively. In pts without CHR at baseline, median time to CHR and MMR was 3.1 mo and 15.4 mo, respectively. Statistically significant benefit on overall survival (OS) and progression-free survival (PFS) was seen in pts with CML-CP versus pts with CML-AP at screening. Median OS and PFS were not reached for CML-CP pts. In CML-AP pts, median OS was 42.3 mo (95% Confidence interval [CI], 4.4-42.3), and median PFS was 42.3 mo (95% CI, 3.3-42.3).Conclusions: The NOVEL study demonstrates that treatment with NIL was effective in achieving cytogenetic and molecular responses in pts resistant or intolerant to IM in the real world setting. The response outcomes appeared to be influenced by BCR-ABL mutation status and CHR status at baseline, while OS and PFS were influenced by disease status (CML-CP or CML-AP) at screening. Safety profile of NIL was consistent with earlier reports. A number of AEs had lower incidences, with no incidence of peripheral arterial occlusive disorder (PAOD) reported, reflecting appropriate disease management among clinicians in Taiwan. More than 80% of AEs due to IM were resolved after switching to NIL. [Display omitted] [Display omitted] DisclosuresTang:Novartis: Consultancy, Honoraria. Chang:Novartis: Honoraria. Hseih:Novartis: Employment. Lin:Novartis: Employment. Darko:Novartis: Employment. Cheng-Shyong:Novartis: Honoraria, Speakers Bureau.

Does thyroid dysfunction happen in CML patients receiving Imatinib for treatment

Chronic myelogenous leukemia is a myeloproliferative disorder presenting with anemia, elevated blood granulocytosis and the presence of immature granulocytes, basophilia, frequently thrombocytosis and spleen enlargement. The diagnosis is stabilized by hematopoietic stem cell expressing a fusion gene (BCR/ABL) resulted from translocation of 9 and 22 chromosomes. The products of this gene play a central role in developing chronic myelogenous leukemia including maintenance of chronicity and/or progress to accelerated phase and or blastic crisis. Imatinib is the first generated tyrosine kinase Inhibitor, which prevents ATP binding to a specific situation of tyrosine kinase molecules that are involved in phosphorylation of membranous proteins and activation of the pathways that are necessary for tumor cell survey and proliferation. Therefore, tyrosine kinase inhibitor inhibits signaling proteins, which are responsible for tumor growth, invasion, angiogenesis and even metastasis. Although tyrosine kinase inhibitor are specific targeted-designed compounds, every agent interacts with many kinds of tyrosine kinases and produces many unwanted effects. One of the undesirable adverse effects is thyroid dysfunction. The first reported article about tyrosine kinase inhibitor-induced thyroid dysfunction published in 2005 and since then few studies have demonstrated thyroid disturbances ranging from subclinical thyroid dysfunctions to overt clinically thyroid disorders during tyrosine kinase inhibitor therapy. This review attends to summarize only imatinib-induced thyroid disturbances in CML patients with positive Philadelphia chromosome in recent years.

Clinical, immunophenotype and cytogenetic profile of acute lymphoblastic leukemia in children at tertiary health care centre in India

Objective: Data on acute lymphoblastic leukemia (ALL) in Indian children being limited, we analyzed the clinical, immunophenotype and cytogenetic profile of ALL in our pediatric patients. Materials and Methods: This was a prospective and retrospective observational study in which data of 103 children with ALL, aged three months to 18 years were analyzed. Results: Definite male preponderance (70.87%) was observed, 58.25% patients were aged between two to five years. Common clinical features included fever (92.33%), pallor (87.38%), hepatomegaly (85.44%) and splenomegaly (83.50). central nervous system involvement was seen in 6.80% and tumor lysis syndrome in 32.04% patients. Hemoglobin was 50,000 in 20.39% patients. Platelet count was <50,000 cells/hpf in 48.54%. Blast cells in peripheral smear present in 67.96% patients of 97 in whom immunophenotyping was done, 82.44% were Pre B cell ALL. Pre T and T cell ALL was seen in 15/97 (15.46%) patients. Karyotyping revealed hyperdiploidy in 9/89, hypodiploidy in 2/89, miscellaneous changes in 35 patients. FISH analysis in 63 patients revealed Philadelphia chromosome positivity in seven (11.11%). MLL gene was positive in 12.70%. TELAML was positive in 13.64% (3/22) patients. 97.06% patients went in to remission post induction. Conclusion: Most of our patients come under standard risk by their age, WBC count, immunophenotyping and cytogentic analysis. We suggest larger multi-centric studies even in developing countries to understand the clinical profile and RT-PCR technique in cytogenic analysis for better risk stratification to help in risk adopted therapy.

Incidence of Central Nervous System (CNS) Relapse in De Novo Adult Acute Lymphoblastic Leukemia (ALL)

In the era of improved outcomes with systemic chemotherapy for de novo adult ALL, prevention of CNS relapse becomes even more paramount. Isolated CNS relapse may herald eventual marrow relapse in the absence of definitive CNS-directed and systemic chemotherapy strategies. CNS prophylaxis can be successfully achieved with intrathecal chemotherapy treatments (IT) in conjunction with systemic chemotherapy inclusive of high-dose methotrexate (MTX) and/or high-dose cytarabine (ara-C) without use of radiation therapy (XRT). The hyper-CVAD regimen (cycles of fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone alternating with cycles of high dose MTX (1 g/m2) and cytarabine (3 gm/m2; 1 gm/m2 for age > 60 yrs) incorporates IT MTX alternating with IT ara-C during the intensive phase of induction-consolidation. The number of IT treatments was determined by CNS risk (4 IT for low risk = LDH < 1400 U/L and low proliferative index; 16 IT for high risk = LDH > 1400 U/L or high proliferative index; 8 IT for indeterminate risk = one of parameters unknown). An analysis performed in 2000 (Kantarjian et al, J Clin Oncol 18: 547, 2000) identified CNS relapse rates of 6%, 2%, and 0% for the low, high, and indeterminate CNS risk groups, respectively. The number of IT administered was modified from 4 to 6, from 16 to 8, and maintained at 8 for these CNS risk groups, respectively, until 2010, at which point all pts received 8 IT. An analysis was conducted to examine the incidence of CNS relapse for 565 pts with de novo ALL treated with hyper-CVAD-based regimens (n=453, inclusive of nelarabine, monoclonal antibodies such as rituximab, ofatumumab or inotuzumab, and/or tyrosine kinase inhibitors such as imatinib, dasatinib or ponatinib) from 2001 to 2014 or with the augmented BFM regimen (one IT ara-C, 15 IT MTX, Capizzi methotrexate) (n=112) from 2006 to 2014. T-lymphoblastic lymphoma (designated for 8 IT) and Burkitt leukemia/lymphoma (designated for 16 IT) cases were excluded from the analysis. The incidence of CNS relapse (n=42) was 7% overall; 59% were isolated CNS relapses (n=25, 5%) without concurrent marrow relapse. Median time to isolated CNS relapse was 19 mos versus 10 mos for concurrent relapse. The incidence of CNS relapse for cases with CNS disease at initial presentation (n=70) was 19%. Factors predictive of higher incidence of CNS relapse included younger age (12% for 30 yrs or younger, 3.5% for 60 yrs or older, p=.01), elevated LDH > 1400 U/L (13% vs 4%, p<.001), and Philadelphia chromosome positivity (12% vs 6%, p=.05). The overall CNS relapse rates were 4% for the hyper-CVAD and monoclonal antibody regimens; 11% for the augmented BFM regimen, and 14%-15% for the hyper-CVAD and imatinib/dasatinib regimens. The CNS relapse rate declined from 10% for pts treated prior to 2010 to 8% thereafter (8 IT for all risk groups). Overall, the 3-yr survival rates for CNS relapse was 47% vs 63% without CNS relapse (p=0.006). Modifications to the hyper-CVAD and tyrosine kinase inhibitor regimens for Philadelphia positive ALL have been implemented to increase the number of IT from 8 to 12. Similar modifications will be implemented for the augmented BFM regimen with consideration for incorporation of high dose MTX. Additional analyses will further refine the CNS risk model in order to guide CNS prophylaxis. Alternative agents such as IT rituximab may improve outcomes for CD20 positive cases with CNS disease at presentation; a clinical trial in the setting of active CNS disease is underway. DisclosuresNo relevant conflicts of interest to declare.